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Wang K, Osei-Hwedieh DO, Walhart TA, Hung YP, Wang Y, Cattaneo G, Ma T, Dotti G, Wang X, Ferrone S, Schwab JH. B7-H3 CAR-T cell therapy combined with irradiation is effective in targeting bulk and radiation-resistant chordoma cancer cells. J Immunother Cancer 2025; 13:e009544. [PMID: 39848690 PMCID: PMC11784168 DOI: 10.1136/jitc-2024-009544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 12/30/2024] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND Chordoma is a slow-growing, primary malignant bone tumor that arises from notochordal tissue in the midline of the axial skeleton. Surgical excision with negative margins is the mainstay of treatment, but high local recurrence rates are reported even with negative margins. High-dose radiation therapy (RT), such as with proton or carbon ions, has been used as an alternative to surgery, but late local failure remains a problem. B7-H3 is an immune checkpoint, transmembrane protein that is dysregulated in many cancers, including chordoma. This study explores the efficacy of B7-H3 chimeric antigen receptor T (CAR-T) therapy in vitro and in vivo. METHODS Chordoma cancer stem cells (CCSCs) were identified using flow cytometry, sphere formation, and western blot analysis. The expression of B7-H3 in paraffin-embedded chordoma tissue was determined by immunohistochemical staining, and the expression of B7-H3 in chordoma cells was measured by flow cytometry. Retroviral particles containing either B7-H3 or CD19 CAR-expressing virus were transduced into T cells derived from peripheral blood mononuclear cells isolated from healthy human donor blood to prepare CAR-T cells. Animal bioluminescent imaging was used to evaluate the killing effect of CAR-T cells on chordoma cells in vivo. An irradiator was used for all irradiation (IR) experiments. RESULTS The combination of B7-H3 CAR-T cell therapy and IR has a greater killing effect on killing radiation-resistant CCSCs and bulk chordoma cells compared with CAR-T cell or IR monotherapy. Additionally, increased expression of B7-H3 antigens on CCSCs and bulk tumor cells is associated with enhanced CAR-T cell killing in vitro and in vivo xenograft mouse models. Upregulation of B7-H3 expression by IR increases CCSCs sensitivity to B7-H3 CAR-T cell-mediated killing. CONCLUSIONS Our preliminary data show that IR and B7-H3 CAR-T cell therapy is synergistically more effective than either IR or CAR-T cell monotherapy in killing chordoma cells in vitro and in a xenograft mouse model. These results provide preclinical evidence for further developing this combinatorial RT and B7-H3 CAR-T cell therapy model in chordoma.
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Affiliation(s)
- Kun Wang
- Department of Orthopedic Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
- Department of Spine Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - David O Osei-Hwedieh
- Department of Orthopedic Surgery, Orthopedic Oncology Service, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Tara A Walhart
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Yin P Hung
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Yufeng Wang
- Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Giulia Cattaneo
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Tao Ma
- Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Gianpietro Dotti
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Xinhui Wang
- Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Soldano Ferrone
- Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Joseph H Schwab
- Department of Orthopedic Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Chen J, Zhou Y, Pang Y, Fu K, Luo Q, Sun L, Wu H, Lin Q, Su G, Chen X, Zhao L, Chen H. FAP-targeted radioligand therapy with 68Ga/ 177Lu-DOTA-2P(FAPI) 2 enhance immunogenicity and synergize with PD-L1 inhibitors for improved antitumor efficacy. J Immunother Cancer 2025; 13:e010212. [PMID: 39800373 PMCID: PMC11749305 DOI: 10.1136/jitc-2024-010212] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Accepted: 11/28/2024] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND Fibroblast activation protein (FAP)-targeted radioligand therapy, with immunomodulatory effects, has shown efficacy in both preclinical and clinical studies. We recently reported on a novel dimeric FAP-targeting radiopharmaceutical, 68Ga/177Lu-DOTA-2P(FAPI)2, which demonstrated increased tumor uptake and prolonged retention in various cancers. However, further exploration is required to understand the therapeutic efficacy and underlying mechanisms of combining 68Ga/177Lu-DOTA-2P(FAPI)2 radioligand therapy with PD-1/PD-L1 immunotherapy. METHODS Regarding the change in PD-L1 expression and DNA double-strand breaks induced by radiopharmaceuticals, CT26-FAP tumor cells were incubated with 68Ga and 177Lu labeled DOTA-2P(FAPI)2, respectively. Monotherapy with 68Ga-DOTA-2P(FAPI)2, 177Lu-DOTA-2P(FAPI)2, and PD-L1 immunotherapy as well as combination therapy (68Ga/177Lu-DOTA-2P(FAPI)2 and PD-L1 immunotherapy) were tested and evaluated to evaluate in vivo antitumor efficacy. Furthermore, immunohistochemical staining and single-cell RNA sequencing were used to analyze changes in the tumor microenvironment (TME) and elucidate the underlying mechanisms of action of this combination therapy. RESULTS Our findings indicated that FAP-targeting radiopharmaceuticals can induce DNA double-strand breaks and upregulate PD-L1 expression, with 177Lu-DOTA-2P(FAPI)2 proving to be more effective than 68Ga-DOTA-2P(FAPI)2. Both 68Ga-DOTA-2P(FAPI)2 and 177Lu-DOTA-2P(FAPI)2 radiopharmaceuticals significantly improved therapeutic outcomes when combined with anti-PD-L1 monoclonal antibody (αPD-L1 mAb). Notably, the combination of 177Lu-DOTA-2P(FAPI)2 with αPD-L1 mAb immunotherapy eliminated tumors in mouse models. Mice treated with this regimen not only exhibited exceptional responses to the initial immune checkpoint inhibitor therapy but also showed 100% tumor rejection on subsequent tumor cell re-inoculation. Further mechanistic studies have shown that 177Lu-DOTA-2P(FAPI)2 combined with αPD-L1 mAb can reprogram the TME, enhancing antitumor intercellular communication, which activates antitumor-related intercellular contacts such as FasL-Fas interactions between T cells and NK cells with tumor cells and increasing the proportion of infiltrating CD8+ T-cells while reducing regulatory T cells and inhibiting tumor progression. Our research also demonstrates that mature neutrophils play a role in enhancing the efficacy of the combined therapy, as shown in neutrophil-blocking experiments. CONCLUSIONS Our study robustly advocates for use of FAP-targeting radiopharmaceuticals, particularly 177Lu-DOTA-2P(FAPI)2, alongside immunotherapy in treating FAP-positive tumors. This combination therapy transforms the TME and enables a translatable approach to increasing the sensitivity to PD-1/PD-L1 immunotherapy, leading to improved complete remission rates and extended overall survival.
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Affiliation(s)
- Jianhao Chen
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Department of Colorectal Tumor Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Yangfan Zhou
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Yizhen Pang
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Kaili Fu
- Department of Oncology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Qicong Luo
- Laboratory of Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Long Sun
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Hua Wu
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Qin Lin
- Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Guoqiang Su
- Department of Colorectal Tumor Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Xiaoyuan Chen
- Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore
| | - Liang Zhao
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Haojun Chen
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
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Li Y, Ren M, Li H, Zhang Z, Yuan K, Huang Y, Yuan S, Ju W, He Y, Xu K, Zeng L. Silencing endomucin in bone marrow sinusoids improves hematopoietic stem and progenitor cell homing during transplantation. Stem Cells 2024; 42:889-901. [PMID: 38995653 DOI: 10.1093/stmcls/sxae046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 06/13/2024] [Indexed: 07/13/2024]
Abstract
Efficient homing of infused hematopoietic stem and progenitor cells (HSPCs) into the bone marrow (BM) is the prerequisite for successful hematopoietic stem cell transplantation. However, only a small part of infused HSPCs find their way to the BM niche. A better understanding of the mechanisms that facilitate HSPC homing will help to develop strategies to improve the initial HSPC engraftment and subsequent hematopoietic regeneration. Here, we show that irradiation upregulates the endomucin expression of endothelial cells in vivo and in vitro. Furthermore, depletion of endomucin in irradiated endothelial cells with short-interfering RNA (siRNA) increases the HSPC-endothelial cell adhesion in vitro. To abrogate the endomucin of BM sinusoidal endothelial cells (BM-SECs) in vivo, we develop a siRNA-loaded bovine serum albumin nanoparticle for targeted delivery. Nanoparticle-mediated siRNA delivery successfully silences endomucin expression in BM-SECs and improves HSPC homing during transplantation. These results reveal that endomucin plays a critical role in HSPC homing during transplantation and that gene-based manipulation of BM-SEC endomucin in vivo can be exploited to improve the efficacy of HSPC transplantation.
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Affiliation(s)
- Yue Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- School of Medical Technology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, People's Republic of China
| | - Miao Ren
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
| | - Hu Li
- School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, People's Republic of China
| | - Zuo Zhang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- School of Medical Technology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, People's Republic of China
| | - Ke Yuan
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
| | - Yujin Huang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
| | - Shengnan Yuan
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- School of Medical Technology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, People's Republic of China
| | - Wen Ju
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
| | - Yuan He
- School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, People's Republic of China
| | - Kailin Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
| | - Lingyu Zeng
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou 221006, Jiangsu, People's Republic of China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu, People's Republic of China
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Jagodinsky JC, Vera JM, Jin WJ, Shea AG, Clark PA, Sriramaneni RN, Havighurst TC, Chakravarthy I, Allawi RH, Kim K, Harari PM, Sondel PM, Newton MA, Crittenden MR, Gough MJ, Miller JR, Ong IM, Morris ZS. Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade. Sci Transl Med 2024; 16:eadk0642. [PMID: 39292804 PMCID: PMC11522033 DOI: 10.1126/scitranslmed.adk0642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 04/03/2024] [Accepted: 08/08/2024] [Indexed: 09/20/2024]
Abstract
Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. These findings illuminate the breadth of dose-dependent effects of RT on the TME and the capacity of heterogeneous RT to promote antitumor immunity when combined with immune checkpoint inhibitors.
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Affiliation(s)
- Justin C. Jagodinsky
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA
| | - Jessica M. Vera
- Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
- Sage Bionetworks, 2901 Third Ave. Suite 330, Seattle, WA 98121, USA
| | - Won Jong Jin
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Amanda G. Shea
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Paul A. Clark
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Raghava N. Sriramaneni
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Thomas C. Havighurst
- Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
| | - Ishan Chakravarthy
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Raad H. Allawi
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - KyungMann Kim
- Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
| | - Paul M. Harari
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Paul M. Sondel
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
| | - Michael A. Newton
- Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
| | - Marka R. Crittenden
- Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, NE Glisan St., Portland, OR 97213, USA
- Oregon Clinic, Portland, OR 97232, USA
| | - Michael J. Gough
- Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, NE Glisan St., Portland, OR 97213, USA
| | - Jessica R. Miller
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Irene M. Ong
- Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
- Department of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
| | - Zachary S. Morris
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
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Zhang Y, Huang J, Zhang Y, Jiang F, Li S, He S, Sun J, Chen D, Tong Y, Pang Q, Wu Y. The Mitochondrial-Derived Peptide MOTS-c Alleviates Radiation Pneumonitis via an Nrf2-Dependent Mechanism. Antioxidants (Basel) 2024; 13:613. [PMID: 38790718 PMCID: PMC11117534 DOI: 10.3390/antiox13050613] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 04/30/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
Radiation pneumonitis (RP) is a prevalent and fatal complication of thoracic radiotherapy due to the lack of effective treatment options. RP primarily arises from mitochondrial injury in lung epithelial cells. The mitochondrial-derived peptide MOTS-c has demonstrated protective effects against various diseases by mitigating mitochondrial injury. C57BL/6 mice were exposed to 20 Gy of lung irradiation (IR) and received daily intraperitoneal injections of MOTS-c for 2 weeks. MOTS-c significantly ameliorated lung tissue damage, inflammation, and oxidative stress caused by radiation. Meanwhile, MOTS-c reversed the apoptosis and mitochondrial damage of alveolar epithelial cells in RP mice. Furthermore, MOTS-c significantly inhibited oxidative stress and mitochondrial damage in MLE-12 cells and primary mouse lung epithelial cells. Mechanistically, MOTS-c increased the nuclear factor erythroid 2-related factor (Nrf2) level and promoted its nuclear translocation. Notably, Nrf2 deficiency abolished the protective function of MOTS-c in mice with RP. In conclusion, MOTS-c alleviates RP by protecting mitochondrial function through an Nrf2-dependent mechanism, indicating that MOTS-c may be a novel potential protective agent against RP.
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Affiliation(s)
- Yanli Zhang
- Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, China; (Y.Z.); (Y.Z.); (F.J.); (S.L.); (S.H.); (J.S.); (D.C.); (Y.T.); (Q.P.)
| | - Jianfeng Huang
- Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi 214000, China;
| | - Yaru Zhang
- Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, China; (Y.Z.); (Y.Z.); (F.J.); (S.L.); (S.H.); (J.S.); (D.C.); (Y.T.); (Q.P.)
| | - Fengjuan Jiang
- Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, China; (Y.Z.); (Y.Z.); (F.J.); (S.L.); (S.H.); (J.S.); (D.C.); (Y.T.); (Q.P.)
| | - Shengpeng Li
- Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, China; (Y.Z.); (Y.Z.); (F.J.); (S.L.); (S.H.); (J.S.); (D.C.); (Y.T.); (Q.P.)
| | - Shuai He
- Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, China; (Y.Z.); (Y.Z.); (F.J.); (S.L.); (S.H.); (J.S.); (D.C.); (Y.T.); (Q.P.)
| | - Jiaojiao Sun
- Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, China; (Y.Z.); (Y.Z.); (F.J.); (S.L.); (S.H.); (J.S.); (D.C.); (Y.T.); (Q.P.)
| | - Dan Chen
- Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, China; (Y.Z.); (Y.Z.); (F.J.); (S.L.); (S.H.); (J.S.); (D.C.); (Y.T.); (Q.P.)
| | - Ying Tong
- Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, China; (Y.Z.); (Y.Z.); (F.J.); (S.L.); (S.H.); (J.S.); (D.C.); (Y.T.); (Q.P.)
| | - Qingfeng Pang
- Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, China; (Y.Z.); (Y.Z.); (F.J.); (S.L.); (S.H.); (J.S.); (D.C.); (Y.T.); (Q.P.)
- Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi 214000, China;
| | - Yaxian Wu
- Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, China; (Y.Z.); (Y.Z.); (F.J.); (S.L.); (S.H.); (J.S.); (D.C.); (Y.T.); (Q.P.)
- Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi 214000, China;
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, China
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Hao J, Song Z, Su J, Li L, Zou L, Zou K. The PRX-1/TLR4 axis promotes hypoxia-induced radiotherapy resistance in non-small cell lung cancer by targeting the NF-κB/p65 pathway. Cell Signal 2023; 110:110806. [PMID: 37468052 DOI: 10.1016/j.cellsig.2023.110806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 06/29/2023] [Accepted: 07/12/2023] [Indexed: 07/21/2023]
Abstract
Hypoxic lung cancer cells are highly resistant to radiation. Peroxiredoxin-1 (PRX-1), a transcriptional coactivator that enhances the DNA-binding activity of serum reactive factor, has been identified as a target for radiotherapy sensitization, but the underlying molecular mechanism remains unclear. This study aimed to investigate the influence of PRX-1 on radiotherapy sensitivity in hypoxic tumors. Hypoxic lung cancer cells exhibited radiotherapy-resistant phenotypes after irradiation, including increased proliferation, DNA damage repair, cell migration, invasion and stemness. Radio-resistant hypoxic lung cancer cells showed high expression levels of PRX-1. Furthermore, we observed that PRX-1 bound to the promoter region of TRL4 (-300 to -600) and promoted its transcription and expression and that PRX-1/TRL4 activated the NF-κB/p65 signaling pathway. Increased radiotherapy resistance of hypoxic lung cancer cells increased their ability to proliferate, migrate, and maintain stemness in vivo and in vitro. These findings suggest that PRX-1/TRL4 could be used as a target for the treatment of radiotherapy-resistant lung cancer cells and further provide a theoretical basis for the clinical treatment of hypoxic lung cancer cells.
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Affiliation(s)
- Jiaojiao Hao
- The First Affiliated Hospital, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Zhuo Song
- The First Affiliated Hospital, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Jiayi Su
- The First Affiliated Hospital, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Longjie Li
- The First Affiliated Hospital, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Lijian Zou
- The First Affiliated Hospital, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
| | - Kun Zou
- The First Affiliated Hospital, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
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Pontoriero A, Critelli P, Chillari F, Ferrantelli G, Sciacca M, Brogna A, Parisi S, Pergolizzi S. Modulation of Radiation Doses and Chimeric Antigen Receptor T Cells: A Promising New Weapon in Solid Tumors-A Narrative Review. J Pers Med 2023; 13:1261. [PMID: 37623511 PMCID: PMC10455986 DOI: 10.3390/jpm13081261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/04/2023] [Accepted: 08/09/2023] [Indexed: 08/26/2023] Open
Abstract
Tumor behavior is determined by its interaction with the tumor microenvironment (TME). Chimeric antigen receptor (CART) cell therapy represents a new form of cellular immunotherapy (IT). Immune cells present a different sensitivity to radiation therapy (RT). RT can affect tumor cells both modifying the TME and inducing DNA damage, with different effects depending on the low and high doses delivered, and can favor the expression of CART cells. CART cells are patients' T cells genetically engineered to recognize surface structure and to eradicate cancer cells. High-dose radiation therapy (HDRT, >10-20 Gy/fractions) converts immunologically "cold" tumors into "hot" ones by inducing necrosis and massive inflammation and death. LDRT (low-dose radiation therapy, >5-10 Gy/fractions) increases the expansion of CART cells and leads to non-immunogenetic death. An innovative approach, defined as the LATTICE technique, combines a high dose in higher FDG- uptake areas and a low dose to the tumor periphery. The association of RT and immune checkpoint inhibitors increases tumor immunogenicity and immune response both in irradiated and non-irradiated sites. The aim of this narrative review is to clarify the knowledge, to date, on CART cell therapy and its possible association with radiation therapy in solid tumors.
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Affiliation(s)
- Antonio Pontoriero
- Radiation Oncology Unit, Department of Biomedical, Dental Science and Morphological and Functional Images, University of Messina, 98125 Messina, Italy; (A.P.); (F.C.); (G.F.); (M.S.); (S.P.); (S.P.)
| | - Paola Critelli
- Radiation Oncology Unit, Department of Biomedical, Dental Science and Morphological and Functional Images, University of Messina, 98125 Messina, Italy; (A.P.); (F.C.); (G.F.); (M.S.); (S.P.); (S.P.)
| | - Federico Chillari
- Radiation Oncology Unit, Department of Biomedical, Dental Science and Morphological and Functional Images, University of Messina, 98125 Messina, Italy; (A.P.); (F.C.); (G.F.); (M.S.); (S.P.); (S.P.)
| | - Giacomo Ferrantelli
- Radiation Oncology Unit, Department of Biomedical, Dental Science and Morphological and Functional Images, University of Messina, 98125 Messina, Italy; (A.P.); (F.C.); (G.F.); (M.S.); (S.P.); (S.P.)
| | - Miriam Sciacca
- Radiation Oncology Unit, Department of Biomedical, Dental Science and Morphological and Functional Images, University of Messina, 98125 Messina, Italy; (A.P.); (F.C.); (G.F.); (M.S.); (S.P.); (S.P.)
| | - Anna Brogna
- Radiotherapy Unit, Medical Physics Unit, A.O.U. “G. Martino”, 98125 Messina, Italy;
| | - Silvana Parisi
- Radiation Oncology Unit, Department of Biomedical, Dental Science and Morphological and Functional Images, University of Messina, 98125 Messina, Italy; (A.P.); (F.C.); (G.F.); (M.S.); (S.P.); (S.P.)
| | - Stefano Pergolizzi
- Radiation Oncology Unit, Department of Biomedical, Dental Science and Morphological and Functional Images, University of Messina, 98125 Messina, Italy; (A.P.); (F.C.); (G.F.); (M.S.); (S.P.); (S.P.)
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8
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Zhong L, Li Y, Muluh TA, Wang Y. Combination of CAR‑T cell therapy and radiotherapy: Opportunities and challenges in solid tumors (Review). Oncol Lett 2023; 26:281. [PMID: 37274466 PMCID: PMC10236127 DOI: 10.3892/ol.2023.13867] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 04/28/2023] [Indexed: 06/06/2023] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapy has emerged as a new and breakthrough cancer immunotherapy. Although CAR-T cell therapy has made significant progress clinically in patients with refractory or drug-resistant hematological malignancies, there are numerous challenges in its application to solid tumor therapy, including antigen escape, severe toxic reactions, abnormal vascularization, tumor hypoxia, insufficient infiltration of CAR-T cells and immunosuppression. As a conventional mode of anti-tumor therapy, radiotherapy has shown promising effects in combination with CAR-T cell therapy by enhancing the specific immunity of endogenous target antigens, which promoted the infiltration and expansion of CAR-T cells and improved the hypoxic tumor microenvironment. This review focuses on the obstacles to the application of CAR-T technology in solid tumor therapy, the potential opportunities and challenges of combined radiotherapy and CAR-T cell therapy, and the review of recent literature to evaluate the best combination for the treatment of solid tumors.
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Affiliation(s)
- Liqiang Zhong
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, P.R. China
- Department of Oncology, The Second People's Hospital of Yibin, Yibin, Sichuan 644000, P.R. China
| | - Yi Li
- Department of Oncology, The Second People's Hospital of Yibin, Yibin, Sichuan 644000, P.R. China
| | - Tobias Achu Muluh
- Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518060, P.R. China
| | - Yongsheng Wang
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, P.R. China
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9
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Hovhannisyan L, Riether C, Aebersold DM, Medová M, Zimmer Y. CAR T cell-based immunotherapy and radiation therapy: potential, promises and risks. Mol Cancer 2023; 22:82. [PMID: 37173782 PMCID: PMC10176707 DOI: 10.1186/s12943-023-01775-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/11/2023] [Indexed: 05/15/2023] Open
Abstract
CAR T cell-based therapies have revolutionized the treatment of hematological malignancies such as leukemia and lymphoma within the last years. In contrast to the success in hematological cancers, the treatment of solid tumors with CAR T cells is still a major challenge in the field and attempts to overcome these hurdles have not been successful yet. Radiation therapy is used for management of various malignancies for decades and its therapeutic role ranges from local therapy to a priming agent in cancer immunotherapy. Combinations of radiation with immune checkpoint inhibitors have already proven successful in clinical trials. Therefore, a combination of radiation therapy may have the potential to overcome the current limitations of CAR T cell therapy in solid tumor entities. So far, only limited research was conducted in the area of CAR T cells and radiation. In this review we will discuss the potential and risks of such a combination in the treatment of cancer patients.
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Affiliation(s)
- Lusine Hovhannisyan
- Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, Bern, 3008, Switzerland
- Department for Biomedical Research, Radiation Oncology, University of Bern, Murtenstrasse 35, Bern, 3008, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, 3010, Switzerland
| | - Carsten Riether
- Department of Medical Oncology, Inselspital, University Hospital and University of Bern, Bern, 3010, Switzerland
| | - Daniel M Aebersold
- Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, Bern, 3008, Switzerland
- Department for Biomedical Research, Radiation Oncology, University of Bern, Murtenstrasse 35, Bern, 3008, Switzerland
| | - Michaela Medová
- Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, Bern, 3008, Switzerland
- Department for Biomedical Research, Radiation Oncology, University of Bern, Murtenstrasse 35, Bern, 3008, Switzerland
| | - Yitzhak Zimmer
- Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, Bern, 3008, Switzerland.
- Department for Biomedical Research, Radiation Oncology, University of Bern, Murtenstrasse 35, Bern, 3008, Switzerland.
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10
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Su C, Himes JE, Kirsch DG. Relationship between the tumor microenvironment and the efficacy of the combination of radiotherapy and immunotherapy. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 378:201-232. [PMID: 37438018 DOI: 10.1016/bs.ircmb.2023.03.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/14/2023]
Abstract
Activating and recruiting the immune system is critical for successful cancer treatment. Since the discovery of immune checkpoint inhibitors, immunotherapy has become the standard of care for many types of cancers. However, many patients fail to respond to immunotherapy. Further research is needed to understand the mechanisms of resistance and adjuvant therapies that can help sensitize patients to immunotherapies. Here, we will discuss how radiotherapy can change the tumor microenvironment and work synergistically with immunotherapy. We will examine different pre-clinical models focusing on their limitations and their unique advantages in studying the efficacy of treatments and the tumor microenvironment. We will also describe emerging findings from clinical trials testing the combination of immunotherapy and radiotherapy.
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Affiliation(s)
- Chang Su
- Molecular Cancer Biology Program and Medical Scientist Training Program, Duke University School of Medicine, Durham, NC, United States
| | - Jonathon E Himes
- Molecular Cancer Biology Program and Medical Scientist Training Program, Duke University School of Medicine, Durham, NC, United States
| | - David G Kirsch
- Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, United States; Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, United States.
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11
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The mutual relationship between the host immune system and radiotherapy: stimulating the action of immune cells by irradiation. Int J Clin Oncol 2023; 28:201-208. [PMID: 35556190 DOI: 10.1007/s10147-022-02172-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 04/13/2022] [Indexed: 02/03/2023]
Abstract
The effects of irradiation on tumor tissue and the host immune system are interrelated. The antitumor effect of irradiation is attenuated in the immunocompromised hosts. In addition, radiation alone positively and negatively influences the host immune system. The positive effects of radiation are summarized by the ability to help induce and enhance tumor-antigen-specific immune responses. The cancer-immunity cycle is a multistep framework that illustrates how the tumor-antigen-specific immune responses are induced and how the induced antigen-specific immune cells exert their functions in tumor tissues. Irradiation affects each step of this cancer-immunity cycle, primarily in a positive manner. In contrast, radiation also has negative effects on the immune system. The first is that irradiation has the possibility to kill irradiated effector immune cells. The second is that irradiation upregulates immunosuppressive molecules in the tumor microenvironment, whereas the third is that irradiation to the tumor condenses immunosuppressor cells in the tumor microenvironment. When used in conjunction with radiotherapy, immune checkpoint inhibitors can further leverage the positive effects of radiation on the immune system and compensate for the negative effects of irradiation, which supports the rationale for the combination of radiotherapy and immune checkpoint inhibitors. In this review, we summarize the preclinical evidence for the reciprocal effects of radiation exposure and the immune system, and up-front topics of the combination therapy of immune checkpoint inhibitors and radiotherapy.
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12
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Heng Z, Zhao C, Gao Y. Comparison of urine proteomes from tumor-bearing mice with those from tumor-resected mice. PeerJ 2023; 11:e14737. [PMID: 36718454 PMCID: PMC9884041 DOI: 10.7717/peerj.14737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 12/22/2022] [Indexed: 01/26/2023] Open
Abstract
Objective This study aimed to address on the most important concern of surgeons-whether to completely resect tumor. Urine can indicate early changes associated with physiological or pathophysiological processes. Based on these ideas, we conducted experiments to explore changes in the urine proteome between tumor-bearing mice and tumor-resected mice. Method The tumor-bearing mouse model was established with MC38 mouse colon cancer cells, and the mice were divided into the control group, tumor-resected group, and tumor-bearing group. Urine was collected 7 and 30 days after tumor resection. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used to identify the urine proteome, which was analyzed for differentially expressed proteins and functional annotation. Results (1) Seven days after tumor resection, 20 differentially expressed proteins distinguished the tumor-resected group and the tumor-bearing group. The identified biological processes included circadian rhythm, Notch signaling pathway, leukocyte cell-cell adhesion, and heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules. (2) Thirty days after tumor resection, 33 differentially expressed proteins distinguished the tumor-resected group and the tumor-bearing group. The identified biological processes included cell adhesion; complement activation, the alternative pathway; the immune system process; and angiogenesis. (3) The difference in the urine proteome between the tumor-resected group and the healthy control group was smaller 30 days after tumor resection. Conclusion Changes in the urinary proteome can reflect the complete resection of MC38 tumors.
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Affiliation(s)
- Ziqi Heng
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Beijing Normal University, Gene Engineering Drug and Biotechnology Beijing Key Laboratory, Beijing, China
| | - Chenyang Zhao
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Beijing Normal University, Gene Engineering Drug and Biotechnology Beijing Key Laboratory, Beijing, China
| | - Youhe Gao
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Beijing Normal University, Gene Engineering Drug and Biotechnology Beijing Key Laboratory, Beijing, China
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13
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The Lymphatic Endothelium in the Context of Radioimmuno-Oncology. Cancers (Basel) 2022; 15:cancers15010021. [PMID: 36612017 PMCID: PMC9817924 DOI: 10.3390/cancers15010021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/11/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
The study of lymphatic tumor vasculature has been gaining interest in the context of cancer immunotherapy. These vessels constitute conduits for immune cells' transit toward the lymph nodes, and they endow tumors with routes to metastasize to the lymph nodes and, from them, toward distant sites. In addition, this vasculature participates in the modulation of the immune response directly through the interaction with tumor-infiltrating leukocytes and indirectly through the secretion of cytokines and chemokines that attract leukocytes and tumor cells. Radiotherapy constitutes the therapeutic option for more than 50% of solid tumors. Besides impacting transformed cells, RT affects stromal cells such as endothelial and immune cells. Mature lymphatic endothelial cells are resistant to RT, but we do not know to what extent RT may affect tumor-aberrant lymphatics. RT compromises lymphatic integrity and functionality, and it is a risk factor to the onset of lymphedema, a condition characterized by deficient lymphatic drainage and compromised tissue homeostasis. This review aims to provide evidence of RT's effects on tumor vessels, particularly on lymphatic endothelial cell physiology and immune properties. We will also explore the therapeutic options available so far to modulate signaling through lymphatic endothelial cell receptors and their repercussions on tumor immune cells in the context of cancer. There is a need for careful consideration of the RT dosage to come to terms with the participation of the lymphatic vasculature in anti-tumor response. Here, we provide new approaches to enhance the contribution of the lymphatic endothelium to radioimmuno-oncology.
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14
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Koukourakis IM, Tiniakos D, Kouloulias V, Zygogianni A. The molecular basis of immuno-radiotherapy. Int J Radiat Biol 2022; 99:715-736. [PMID: 36383201 DOI: 10.1080/09553002.2023.2144960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
PURPOSE Radiotherapy (RT) and immunotherapy are powerful anti-tumor treatment modalities. Experimental research has demonstrated an important interplay between the cytotoxic effects of RT and the immune system. This systematic review provides an overview of the basics of anti-tumor immunity and focuses on the mechanisms underlying the interplay between RT and immune anti-tumor response that set the molecular basis of immuno-RT. CONCLUSIONS An 'immunity acquired equilibrium' mimicking tumor dormancy can be achieved post-irradiation treatment, with the balance shifted toward tumor eradication or regrowth when immune cells' cytotoxic effects or cancer proliferation rate prevail, respectively. RT has both immunosuppressive and immune-enhancing properties. The latter effect is also known as radio-vaccination. Its mechanisms involve up- or down-regulation of membrane molecules, such as PD-L1, HLA-class-I, CD80/86, CD47, and Fas/CD95, that play a vital role in immune checkpoint pathways and increased cytokine expression (e.g. INFα,β,γ, IL1,2, and TNFα) by cancer or immune cells. Moreover, the interactions of radiation with the tumor microenvironment (fibroblasts, tumor-infiltrating lymphocytes, monocytes, and dendritic cells are also an important component of radio-vaccination. Thus, RT may have anti-tumor vaccine properties, whose sequels can be exploited by immunotherapy agents to treat different cancer subtypes effectively.
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Affiliation(s)
- Ioannis M. Koukourakis
- Radiation Oncology Unit, First Department of Radiology, Medical School, Aretaieion Hospital, National and Kapodistrian University of Athens (NKUOA), Athens, Greece
| | - Dina Tiniakos
- Department of Pathology, Aretaieion University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Vassilis Kouloulias
- Radiation Oncology Unit, Second Department of Radiology, School of Medicine, Rimini 1, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna Zygogianni
- Radiation Oncology Unit, First Department of Radiology, Medical School, Aretaieion Hospital, National and Kapodistrian University of Athens (NKUOA), Athens, Greece
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15
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Roy A, Bera S, Saso L, Dwarakanath BS. Role of autophagy in tumor response to radiation: Implications for improving radiotherapy. Front Oncol 2022; 12:957373. [PMID: 36172166 PMCID: PMC9510974 DOI: 10.3389/fonc.2022.957373] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Autophagy is an evolutionary conserved, lysosome-involved cellular process that facilitates the recycling of damaged macromolecules, cellular structures, and organelles, thereby generating precursors for macromolecular biosynthesis through the salvage pathway. It plays an important role in mediating biological responses toward various stress, including those caused by ionizing radiation at the cellular, tissue, and systemic levels thereby implying an instrumental role in shaping the tumor responses to radiotherapy. While a successful execution of autophagy appears to facilitate cell survival, abortive or interruptions in the completion of autophagy drive cell death in a context-dependent manner. Pre-clinical studies establishing its ubiquitous role in cells and tissues, and the systemic response to focal irradiation of tumors have prompted the initiation of clinical trials using pharmacologic modifiers of autophagy for enhancing the efficacy of radiotherapy. However, the outcome from the Phase I/II trials in many human malignancies has so far been equivocal. Such observations have not only precluded the advancement of these autophagy modifiers in the Phase III trial but have also raised concerns regarding their introduction as an adjuvant to radiotherapy. This warrants a thorough understanding of the biology of the cancer cells, including its spatio-temporal context, as well as its microenvironment all of which might be the crucial factors that determine the success of an autophagy modifier as an anticancer agent. This review captures the current understanding of the interplay between radiation induced autophagy and the biological responses to radiation damage as well as provides insight into the potentials and limitations of targeting autophagy for improving the radiotherapy of tumors.
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Affiliation(s)
- Amrita Roy
- Department of Biotechnology, Indian Academy Degree College (Autonomous), Bengaluru, Karnataka, India
- *Correspondence: Amrita Roy, ; ; Soumen Bera, ; ; Bilikere S. Dwarakanath, ;
| | - Soumen Bera
- B. S. Abdur Rahman Crescent Institute of Science and Technology, Chennai, India
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, United States
- *Correspondence: Amrita Roy, ; ; Soumen Bera, ; ; Bilikere S. Dwarakanath, ;
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University, Rome, Italy
| | - Bilikere S. Dwarakanath
- Central Research Facility, Sri Ramachandra Institute of Higher Education and Research Institute, Chennai, India
- *Correspondence: Amrita Roy, ; ; Soumen Bera, ; ; Bilikere S. Dwarakanath, ;
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Hartmann L, Osen W, Eichmüller OL, Kordaß T, Furkel J, Dickes E, Reid C, Debus J, Brons S, Abdollahi A, Moustafa M, Rieken S, Eichmüller SB. Carbon ion irradiation plus CTLA4 blockade elicits therapeutic immune responses in a murine tumor model. Cancer Lett 2022; 550:215928. [DOI: 10.1016/j.canlet.2022.215928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/14/2022] [Accepted: 09/21/2022] [Indexed: 11/02/2022]
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17
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Tagliaferri L, Lancellotta V, Fionda B, Mangoni M, Casà C, Di Stefani A, Pagliara MM, D’Aviero A, Schinzari G, Chiesa S, Mazzarella C, Manfrida S, Colloca GF, Marazzi F, Morganti AG, Blasi MA, Peris K, Tortora G, Valentini V. Immunotherapy and radiotherapy in melanoma: a multidisciplinary comprehensive review. Hum Vaccin Immunother 2022; 18:1903827. [PMID: 33847208 PMCID: PMC9122308 DOI: 10.1080/21645515.2021.1903827] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/16/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023] Open
Abstract
Melanoma is an extremely aggressive tumor and is considered to be an extremely immunogenic tumor because compared to other cancers it usually presents a well-expressed lymphoid infiltration. The aim of this paper is to perform a multidisciplinary comprehensive review of the evidence available about the combination of radiotherapy and immunotherapy for melanoma. Radiation, in fact, can increase tumor antigens visibility and promote priming of T cells but can also exert immunosuppressive action on tumor microenvironment. Combining radiotherapy with immunotherapy provides an opportunity to increase immunostimulatory potential of radiation. We therefore provide the latest clinical evidence about radiobiological rationale, radiotherapy techniques, timing, and role both in advanced and systemic disease (with a special focus on ocular melanoma and brain, liver, and bone metastases) with a particular attention also in geriatric patients. The combination of immunotherapy and radiotherapy seems to be a safe therapeutic option, supported by a clear biological rationale, even though the available data confirm that radiotherapy is employed more for metastatic than for non-metastatic disease. Such a combination shows promising results in terms of survival outcomes; however, further studies, hopefully prospective, are needed to confirm such evidence.
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Affiliation(s)
- Luca Tagliaferri
- UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Valentina Lancellotta
- UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Bruno Fionda
- UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Monica Mangoni
- Sezione di Radioterapia Oncologica, Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università di Firenze, Florence, Italy
| | - Calogero Casà
- UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Alessandro Di Stefani
- UOC Dermatologia, Dipartimento di Scienze mediche e chirurgiche, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Monica Maria Pagliara
- UOC Oncologia Oculare, Dipartimento di Scienze dell'Invecchiamento, neurologiche ortopediche e della testa collo, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Andrea D’Aviero
- UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Giovanni Schinzari
- UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
- Università Cattolica del Sacro Cuore, Roma, Italy
| | - Silvia Chiesa
- UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Ciro Mazzarella
- UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Stefania Manfrida
- UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Giuseppe Ferdinando Colloca
- UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Fabio Marazzi
- UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Alessio Giuseppe Morganti
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Settore Scientifico Disciplinare, Università di Bologna, Bologna, Italy
| | - Maria Antonietta Blasi
- UOC Oncologia Oculare, Dipartimento di Scienze dell'Invecchiamento, neurologiche ortopediche e della testa collo, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
- Università Cattolica del Sacro Cuore, Roma, Italy
| | - Ketty Peris
- UOC Dermatologia, Dipartimento di Scienze mediche e chirurgiche, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
- Università Cattolica del Sacro Cuore, Roma, Italy
| | - Giampaolo Tortora
- UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
- Università Cattolica del Sacro Cuore, Roma, Italy
| | - Vincenzo Valentini
- UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
- Università Cattolica del Sacro Cuore, Roma, Italy
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18
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Milošević N, Rütter M, David A. Endothelial Cell Adhesion Molecules- (un)Attainable Targets for Nanomedicines. FRONTIERS IN MEDICAL TECHNOLOGY 2022; 4:846065. [PMID: 35463298 PMCID: PMC9021548 DOI: 10.3389/fmedt.2022.846065] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 02/15/2022] [Indexed: 01/21/2023] Open
Abstract
Endothelial cell adhesion molecules have long been proposed as promising targets in many pathologies. Despite promising preclinical data, several efforts to develop small molecule inhibitors or monoclonal antibodies (mAbs) against cell adhesion molecules (CAMs) ended in clinical-stage failure. In parallel, many well-validated approaches for targeting CAMs with nanomedicine (NM) were reported over the years. A wide range of potential applications has been demonstrated in various preclinical studies, from drug delivery to the tumor vasculature, imaging of the inflamed endothelium, or blocking immune cells infiltration. However, no NM drug candidate emerged further into clinical development. In this review, we will summarize the most advanced examples of CAM-targeted NMs and juxtapose them with known traditional drugs against CAMs, in an attempt to identify important translational hurdles. Most importantly, we will summarize the proposed strategies to enhance endothelial CAM targeting by NMs, in an attempt to offer a catalog of tools for further development.
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Lambin T, Lafon C, Drainville RA, Pioche M, Prat F. Locoregional therapies and their effects on the tumoral microenvironment of pancreatic ductal adenocarcinoma. World J Gastroenterol 2022; 28:1288-1303. [PMID: 35645539 PMCID: PMC9099187 DOI: 10.3748/wjg.v28.i13.1288] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/10/2022] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of death from cancer by 2030. Despite intensive research in the field of therapeutics, the 5-year overall survival is approximately 8%, with only 20% of patients eligible for surgery at the time of diagnosis. The tumoral microenvironment (TME) of the PDAC is one of the main causes for resistance to antitumoral treatments due to the presence of tumor vasculature, stroma, and a modified immune response. The TME of PDAC is characterized by high stiffness due to fibrosis, with hypo microvascular perfusion, along with an immunosuppressive environment that constitutes a barrier to effective antitumoral treatment. While systemic therapies often produce severe side effects that can alter patients' quality of life, locoregional therapies have gained attention since their action is localized to the pancreas and can thus alleviate some of the barriers to effective antitumoral treatment due to their physical effects. Local hyperthermia using radiofrequency ablation and radiation therapy - most commonly using a local high single dose - are the two main modalities holding promise for clinical efficacy. Recently, irreversible electroporation and focused ultrasound-derived cavitation have gained increasing attention. To date, most of the data are limited to preclinical studies, but ongoing clinical trials may help better define the role of these locoregional therapies in the management of PDAC patients.
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Affiliation(s)
- Thomas Lambin
- LabTAU, INSERM, Centre Léon Bérard, Université Lyon 1, Univ Lyon, Lyon 69003, France
- Department of Gastroenterology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon 69008, France
| | - Cyril Lafon
- LabTAU, INSERM, Centre Léon Bérard, Université Lyon 1, Univ Lyon, Lyon 69003, France
| | | | - Mathieu Pioche
- Department of Gastroenterology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon 69008, France
| | - Frédéric Prat
- Service d’Endoscopie Digestive, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy 92110, France
- INSERM U1016, Institut Cochin, Université de Paris, Paris 75014, France
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Yin G, Guo W, Huang Z, Chen X. Efficacy of radiotherapy combined with immune checkpoint inhibitors in patients with melanoma: a systemic review and meta-analysis. Melanoma Res 2022; 32:71-78. [PMID: 35254329 DOI: 10.1097/cmr.0000000000000800] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The purpose of this study is to review the efficacy of radiotherapy combined with immune checkpoint inhibitors (ICIs) in the treatment of melanoma and systematically evaluate the efficacy and safety of this combined treatment compared with ICIs alone. We searched a number of online databases up to 1 July 2021. Comprehensive Meta-Analysis 2.0 and RevMan 5.0 were used for summary analysis. The overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and treatment adverse effects (AEs) were calculated. In total, 624 patients were included from 12 studies, including nine published studies and the results of three clinical trials. Radiotherapy combined with ICIs had a higher ORR compared with ICIs alone (35.00 vs. 20.39%). In terms of survival effect, radiotherapy combined with ICIs had no obvious advantage in OS. There was no statistically significant difference between 6-month and 12-month OS (P = 0.13; P = 0.69). There was no significant difference in PFS at 6 months (P = 0.08), but there was a significant difference in PFS at 12 months (P = 0.005). For patients with melanoma, radiotherapy combined with ICIs can improve the effective rate of treatment. Although there is no obvious OS advantage, it can improve PFS without serious adverse effects. Most of the studies included in this article are retrospective analyses, and there are few randomized controlled studies at present. Therefore, more prospective studies are still needed to explore the efficacy of radiotherapy combined with immunotherapy in melanoma.
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Affiliation(s)
- Gaofei Yin
- Department of Otorhinolaryngology and Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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21
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Charpentier M, Spada S, VanNest S, Demaria S. Radiation therapy-induced remodeling of the tumor immune microenvironment. Semin Cancer Biol 2022; 86:737-747. [DOI: 10.1016/j.semcancer.2022.04.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/01/2022] [Accepted: 04/06/2022] [Indexed: 12/20/2022]
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Wen X, Shi C, Zeng X, Zhao L, Yao L, Liu Z, Feng L, Zhang D, Huang J, Li Y, Lin Q, Chen H, Zhuang R, Chen X, Zhang X, Guo Z. A paradigm of cancer immunotherapy based on 2-[18F]FDG and anti-PD-L1 mAb combination to enhance the anti-tumor effect. Clin Cancer Res 2022; 28:2923-2937. [PMID: 35320358 DOI: 10.1158/1078-0432.ccr-22-0159] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/24/2022] [Accepted: 03/21/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE Efforts have been devoted to select eligible candidates for PD-1/PD-L1 immune checkpoint blocker (ICB) immunotherapy. Here, we have a serendipitous finding of positron emitting tomography (PET) imaging tracer 2-[18F]FDG as a potential immunomodulator. Therefore, we hypothesize that 2-[18F]FDG could induce PD-L1 expression change and create an immune-favorable microenvironment for tumor immunotherapy. EXPERIMENTAL DESIGN We designed a series of assays to verify PD-L1 upregulation, and tested immunotherapy regimens based on 2-[18F]FDG and anti-PD-L1 mAb, as monotherapy and in combination, in fully immunocompetent mice of MC38 and CT26 models. PD-L1 expression and tumor microenvironment (TME) changes were analyzed by western blot, transcriptomics study and flow-cytometric analysis. RESULTS PD-L1 was upregulated in a time- and dose-dependent manner after being induced by 2-[18F]FDG. The activation of NF-κB/IRF3 pathway and STAT1/3-IRF1 pathway play crucial parts in modulating PD-L1 expression after DNA damage and repair. Improved αPD-L1 mAb utilization rate and significant tumor growth delay were observed when the personalized therapeutic alliance of 2-[18F]FDG stimulation and ICB were employed. In addition, combination of 2-[18F]FDG with αPD-L1 mAb could reprogram a TME from "cold" to "hot", to make low immunoactivity tumors sensitive to ICB therapy. CONCLUSIONS In summary, this promising paradigm has the potential to expand the traditional tumor theranostics. [18F]FDG-based ICB immunotherapy is highly significant in enhancing anti-tumor effect.
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Affiliation(s)
| | | | | | - Liang Zhao
- First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Lanlin Yao
- First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Zhida Liu
- Shanxi Academy of Advanced Research and Innovation, Taiyuan, China
| | | | | | | | - Yesen Li
- Xiamen University, Xiamen, China
| | - Qin Lin
- First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Haojun Chen
- First Affiliated Hospital of Xiamen University, Xiamen, China
| | | | - Xiaoyuan Chen
- National University of Singapore, Sinagpore, Singapore
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23
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Pieper AA, Zangl LM, Speigelman DV, Feils AS, Hoefges A, Jagodinsky JC, Felder MA, Tsarovsky NW, Arthur IS, Brown RJ, Birstler J, Le T, Carlson PM, Bates AM, Hank JA, Rakhmilevich AL, Erbe AK, Sondel PM, Patel RB, Morris ZS. Radiation Augments the Local Anti-Tumor Effect of In Situ Vaccine With CpG-Oligodeoxynucleotides and Anti-OX40 in Immunologically Cold Tumor Models. Front Immunol 2021; 12:763888. [PMID: 34868010 PMCID: PMC8634717 DOI: 10.3389/fimmu.2021.763888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/13/2021] [Indexed: 11/25/2022] Open
Abstract
Introduction Combining CpG oligodeoxynucleotides with anti-OX40 agonist antibody (CpG+OX40) is able to generate an effective in situ vaccine in some tumor models, including the A20 lymphoma model. Immunologically "cold" tumors, which are typically less responsive to immunotherapy, are characterized by few tumor infiltrating lymphocytes (TILs), low mutation burden, and limited neoantigen expression. Radiation therapy (RT) can change the tumor microenvironment (TME) of an immunologically "cold" tumor. This study investigated the effect of combining RT with the in situ vaccine CpG+OX40 in immunologically "cold" tumor models. Methods Mice bearing flank tumors (A20 lymphoma, B78 melanoma or 4T1 breast cancer) were treated with combinations of local RT, CpG, and/or OX40, and response to treatment was monitored. Flow cytometry and quantitative polymerase chain reaction (qPCR) experiments were conducted to study differences in the TME, secondary lymphoid organs, and immune activation after treatment. Results An in situ vaccine regimen of CpG+OX40, which was effective in the A20 model, did not significantly improve tumor response or survival in the "cold" B78 and 4T1 models, as tested here. In both models, treatment with RT prior to CpG+OX40 enabled a local response to this in situ vaccine, significantly improving the anti-tumor response and survival compared to RT alone or CpG+OX40 alone. RT increased OX40 expression on tumor infiltrating CD4+ non-regulatory T cells. RT+CpG+OX40 increased the ratio of tumor-infiltrating effector T cells to T regulatory cells and significantly increased CD4+ and CD8+ T cell activation in the tumor draining lymph node (TDLN) and spleen. Conclusion RT significantly improves the local anti-tumor effect of the in situ vaccine CpG+OX40 in immunologically "cold", solid, murine tumor models where RT or CpG+OX40 alone fail to stimulate tumor regression.
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Affiliation(s)
- Alexander A. Pieper
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Luke M. Zangl
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Dan V. Speigelman
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Arika S. Feils
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Anna Hoefges
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Justin C. Jagodinsky
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Mildred A. Felder
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Noah W. Tsarovsky
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Ian S. Arthur
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Ryan J. Brown
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Jen Birstler
- Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Trang Le
- Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Peter M. Carlson
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Amber M. Bates
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Jacquelyn A. Hank
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Alexander L. Rakhmilevich
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Amy K. Erbe
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Paul M. Sondel
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Ravi B. Patel
- Department of Radiation Oncology and Bioengineering, University of Pittsburgh Hillman Cancer Center, Pittsburgh, PA, United States
| | - Zachary S. Morris
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
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Jagodinsky JC, Morris ZS. Priming and Propagating Anti-tumor Immunity: Focal Hypofractionated Radiation for in Situ Vaccination and Systemic Targeted Radionuclide Theranostics for Immunomodulation of Tumor Microenvironments. Semin Radiat Oncol 2021; 30:181-186. [PMID: 32381297 DOI: 10.1016/j.semradonc.2019.12.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Recent preclinical and clinical studies have elucidated mechanisms whereby radiation therapy influences the anti-tumor immune response. Immunogenic cell death and phenotypic changes in tumor cells surviving radiation may underlie this effect and contribute to the capacity of radiation to elicit an in situ tumor vaccine effect. In situ vaccination is a therapeutic strategy that seeks to convert a patient's own tumor into a source of enhanced antigen recognition for the purpose of augmenting a systemic anti-tumor immune response. Capitalizing on the in situ vaccine effect of radiation, several groups have demonstrated anti-tumor efficacy in preclinical models by combining radiation with immune checkpoint blockade. Local delivery of immune adjuvants and/or immune stimulatory cytokines via direct injection into the radiated tumor microenvironment may further increase the in situ vaccine capacity of radiation therapy. However, recent studies suggest that in some contexts this effect is antagonized by the presence of distant untreated sites of disease that may dampen the systemic immune response generated by in situ vaccination through a phenomenon termed concomitant immune tolerance. Concomitant immune tolerance may be overcome by delivering radiation to all sites of metastatic disease, however this is often not possible to safely achieve using external beam radiation therapy without considerable risk of lymphopenia that would negate the immune effects of in situ vaccination. For patients with widespread metastatic disease, alternative strategies may include systemic treatment with targeted radionuclide therapies alone or in combination with an external beam radiation therapy-based in situ vaccine approach.
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Affiliation(s)
- Justin C Jagodinsky
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Zachary S Morris
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
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Oslina D, Rybkina V, Adamova G, Zhuntova G, Bannikova M, Azizova T. Biomarkers of Atherosclerotic Vascular Disease in Workers Chronically Exposed to Ionizing Radiation. HEALTH PHYSICS 2021; 121:92-101. [PMID: 33867435 DOI: 10.1097/hp.0000000000001416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
ABSTRACT It is well established that cohorts of individuals exposed to ionizing radiation demonstrate increased risks of cardio- and cerebrovascular diseases. However, mechanisms of these radiation-induced diseases developing in individuals exposed to ionizing radiation remain unclear. To identify biomarkers of the atherosclerotic vessel damage in workers chronically exposed to ionizing radiation, this study considered 49 workers of the Russian nuclear production facility-the Mayak Production Association (mean age of 68.73 ± 6.92 years)-and 38 unexposed individuals (mean age of 68.84 ± 6.20 y) who had never been exposed to ionizing radiation (control). All workers were chronically exposed to combined radiation (external gamma rays and internal alpha particles). The mean cumulative liver absorbed dose from external gamma-ray exposure was 0.18 ± 0.12 Gy; the mean cumulative liver absorbed dose from internal alpha-particles was 0.14 ± 0.21 Gy. Levels of biomarkers in blood serum of the study participants were measured using the ELISA method. Elevated levels of apolipoprotein B, superoxide dismutase, monocyte chemoattractant protein 1, vascular cell adhesion protein 1, and a decreased level of endothelin-1 were observed in blood serum of Mayak PA workers chronically exposed to combined radiation compared to control individuals. A significant positive correlation was demonstrated between the vascular cell adhesion protein 1 level and cumulative liver absorbed doses from external gamma radiation and internal alpha radiation. Findings of the study suggest that molecular changes in blood of individuals occupationally exposed to ionizing radiation (combined internal exposure to alpha particles and external exposure to gamma rays) may indicate dyslipidemia, oxidative stress, inflammation, and endothelial dysfunction involved in atherosclerosis development.
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Affiliation(s)
- Darya Oslina
- Federal State Unitary Enterprise "Southern Urals Biophysics Institute" at the Federal Medical Biological Agency of the Russian Federation, Ozyorskoe shosse 19, Ozyorsk Chelyabinsk Region, 456780 Russia
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26
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Patel RB, Hernandez R, Carlson P, Grudzinski J, Bates AM, Jagodinsky JC, Erbe A, Marsh IR, Arthur I, Aluicio-Sarduy E, Sriramaneni RN, Jin WJ, Massey C, Rakhmilevich AL, Vail D, Engle JW, Le T, Kim K, Bednarz B, Sondel PM, Weichert J, Morris ZS. Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade. Sci Transl Med 2021; 13:eabb3631. [PMID: 34261797 PMCID: PMC8449934 DOI: 10.1126/scitranslmed.abb3631] [Citation(s) in RCA: 137] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 02/10/2021] [Accepted: 06/24/2021] [Indexed: 12/12/2022]
Abstract
Molecular and cellular effects of radiotherapy on tumor microenvironment (TME) can help prime and propagate antitumor immunity. We hypothesized that delivering radiation to all tumor sites could augment response to immunotherapies. We tested an approach to enhance response to immune checkpoint inhibitors (ICIs) by using targeted radionuclide therapy (TRT) to deliver radiation semiselectively to tumors. NM600, an alkylphosphocholine analog that preferentially accumulates in most tumor types, chelates a radioisotope and semiselectively delivers it to the TME for therapeutic or diagnostic applications. Using serial 86Y-NM600 positron emission tomography (PET) imaging, we estimated the dosimetry of 90Y-NM600 in immunologically cold syngeneic murine models that do not respond to ICIs alone. We observed strong therapeutic efficacy and reported optimal dose (2.5 to 5 gray) and sequence for 90Y-NM600 in combination with ICIs. After combined treatment, 45 to 66% of mice exhibited complete response and tumor-specific T cell memory, compared to 0% with 90Y-NM600 or ICI alone. This required expression of STING in tumor cells. Combined TRT and ICI activated production of proinflammatory cytokines in the TME, promoted tumor infiltration by and clonal expansion of CD8+ T cells, and reduced metastases. In mice bearing multiple tumors, combining TRT with moderate-dose (12 gray) external beam radiotherapy (EBRT) targeting a single tumor augmented response to ICIs compared to combination of ICIs with either TRT or EBRT alone. The safety of TRT was confirmed in a companion canine study. Low-dose TRT represents a translatable approach to promote response to ICIs for many tumor types, regardless of location.
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Affiliation(s)
- Ravi B Patel
- Department of Radiation Oncology, University of Pittsburgh Hillman Cancer Center, Pittsburgh, PA 15213, USA.
| | - Reinier Hernandez
- Department of Radiology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Peter Carlson
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Joseph Grudzinski
- Department of Radiology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Amber M Bates
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Justin C Jagodinsky
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Amy Erbe
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Ian R Marsh
- Department of Medical Physics, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Ian Arthur
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | | | - Raghava N Sriramaneni
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Won Jong Jin
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Christopher Massey
- Department of Radiology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | | | - David Vail
- Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53792, USA
- Barbara A. Suran Comparative Oncology Institute, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Johnathan W Engle
- Department of Radiology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Trang Le
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - KyungMann Kim
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Bryan Bednarz
- Department of Radiology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Paul M Sondel
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA
- Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Jamey Weichert
- Department of Radiology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Zachary S Morris
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA.
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Demaria S, Guha C, Schoenfeld J, Morris Z, Monjazeb A, Sikora A, Crittenden M, Shiao S, Khleif S, Gupta S, Formenti SC, Vikram B, Coleman CN, Ahmed MM. Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose? J Immunother Cancer 2021; 9:jitc-2020-002038. [PMID: 33827904 PMCID: PMC8031689 DOI: 10.1136/jitc-2020-002038] [Citation(s) in RCA: 181] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2021] [Indexed: 12/12/2022] Open
Abstract
Recent evidence indicates that ionizing radiation can enhance immune responses to tumors. Advances in radiation delivery techniques allow hypofractionated delivery of conformal radiotherapy. Hypofractionation or other modifications of standard fractionation may improve radiation’s ability to promote immune responses to tumors. Other novel delivery options may also affect immune responses, including T-cell activation and tumor-antigen presentation changes. However, there is limited understanding of the immunological impact of hypofractionated and unique multifractionated radiotherapy regimens, as these observations are relatively recent. Hence, these differences in radiotherapy fractionation result in distinct immune-modulatory effects. Radiation oncologists and immunologists convened a virtual consensus discussion to identify current deficiencies, challenges, pitfalls and critical gaps when combining radiotherapy with immunotherapy and making recommendations to the field and advise National Cancer Institute on new directions and initiatives that will help further development of these two fields. This commentary aims to raise the awareness of this complexity so that the need to study radiation dose, fractionation, type and volume is understood and valued by the immuno-oncology research community. Divergence of approaches and findings between preclinical studies and clinical trials highlights the need for evaluating the design of future clinical studies with particular emphasis on radiation dose and fractionation, immune biomarkers and selecting appropriate end points for combination radiation/immune modulator trials, recognizing that direct effect on the tumor and potential abscopal effect may well be different. Similarly, preclinical studies should be designed as much as possible to model the intended clinical setting. This article describes a conceptual framework for testing different radiation therapy regimens as separate models of how radiation itself functions as an immunomodulatory ‘drug’ to provide alternatives to the widely adopted ‘one-size-fits-all’ strategy of frequently used 8 Gy×3 regimens immunomodulation.
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Affiliation(s)
- Sandra Demaria
- Department of Radiation Oncology, Weill Cornell Medical College, New York, New York, USA
| | - Chandan Guha
- Radiation Oncology, Pathology and Urology, and Institute of Onco-Physics, Montefiore Hospital and Medical Center, Bronx, New York, USA
| | - Jonathan Schoenfeld
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Zachary Morris
- Human Oncology, University of Wisconsin Madison School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Arta Monjazeb
- Radiation Oncology, UC Davis, Davis, California, USA
| | - Andrew Sikora
- Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Marka Crittenden
- Department of Radiation Oncology, Providence Portland Medical Center, Portland, Oregon, USA
| | - Stephen Shiao
- Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Samir Khleif
- The Loop Immuno-Oncology Laboratory, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Seema Gupta
- The Loop Immuno-Oncology Laboratory, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Silvia Chiara Formenti
- Department of Radiation Oncology, Weill Cornell Medical College, New York, New York, USA
| | - Bhadrasain Vikram
- Radiation Research Program, National Cancer Institute Division of Cancer Treatment and Diagnosis, Bethesda, Maryland, USA
| | - C Norman Coleman
- Radiation Research Program, National Cancer Institute Division of Cancer Treatment and Diagnosis, Bethesda, Maryland, USA
| | - Mansoor M Ahmed
- Radiation Research Program, National Cancer Institute Division of Cancer Treatment and Diagnosis, Bethesda, Maryland, USA
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28
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Jagodinsky JC, Medeiros G, Raj HH, Razuan A, Locsin A, Dempsey TG, Tang B, Chakravarty I, Clark PA, Sriramaneni RN, Jin WJ, Lan KH, Das RK, Miller JR, Suarez-Gonzalez D, Morris ZS. A multipurpose brachytherapy catheter to enable intratumoral injection. Brachytherapy 2021; 20:900-910. [PMID: 33785280 DOI: 10.1016/j.brachy.2020.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 10/16/2020] [Accepted: 10/23/2020] [Indexed: 11/30/2022]
Abstract
PURPOSE To create and test a multipurpose brachytherapy catheter prototype enabling intratumoral injection and brachytherapy after a single catheter insertion. METHODS AND MATERIALS The design of the prototype consists of an outer tube and an inner syringe tube that can be filled with injectable agent. The outer sheath and inner syringe tube were constructed using polytetrafluoroethylene tubing, and the other components were 3D printed using dental resin and polylactic acid material. To demonstrate functionality, we injected in vitro phantoms with dyed saline. For proof of concept, we demonstrated the potential for the prototype to deliver cell therapy, enhance tumor delineation, deliver tattoo ink for pathology marking, avoid toxicity through local delivery of chemotherapy, and facilitate combination brachytherapy and immunotherapy. RESULTS The prototype enables accurate injection in vitro and in vivo without altering dosimetry. To illustrate the potential for delivery of cell therapies, we injected luciferase-expressing splenocytes and confirmed their delivery with bioluminescence imaging. To demonstrate feasibility of radiographically visualizing injected material, we delivered iohexol contrast intratumorally and confirmed tumor retention using Faxitron x-ray imaging. In addition, we show the potential of intratumoral administration to reduce toxicity associated with cyclophosphamide compared with systemic administration. To demonstrate feasibility, we treated tumor-bearing mice with brachytherapy (192Ir source, 2 Gy to 5 mm) in combination with intratumoral injection of 375,000 U of interleukin 2 and observed no increased toxicity. CONCLUSIONS These results demonstrate that a prototype multipurpose brachytherapy catheter enables accurate intratumoral injection and support the feasibility of combining intratumoral injection with brachytherapy.
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Affiliation(s)
- Justin C Jagodinsky
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
| | - Gabriella Medeiros
- Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison, Madison, WI
| | - Hayley H Raj
- Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison, Madison, WI
| | - Amira Razuan
- Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison, Madison, WI
| | - Alexis Locsin
- Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison, Madison, WI
| | - Tirhas G Dempsey
- Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison, Madison, WI
| | - Beixiao Tang
- Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison, Madison, WI
| | - Ishan Chakravarty
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Paul A Clark
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Raghava N Sriramaneni
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Won Jong Jin
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Keng-Hsueh Lan
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Rupak K Das
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Jessica R Miller
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Darilis Suarez-Gonzalez
- Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison, Madison, WI
| | - Zachary S Morris
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
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Modi C, Berim L, Isserow L, Malhotra J, Patel M, Langenfeld J, Aisner J, Almeldin D, Jabbour SK. Combining radiation therapy and immunotherapy for lung cancers: a narrative review. ACTA ACUST UNITED AC 2021; 5. [PMID: 33521559 PMCID: PMC7842553 DOI: 10.21037/shc-20-66] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Lung cancer remains the leading cause of cancer morbidity and mortality worldwide among both men and women. While surgical resection remains the standard of care for early stage NSCLC, chemoradiation has been a mainstay of treatment for locally advanced non-small-cell lung cancer (LA-NSCLC) patients for decades. Consolidation immunotherapy has improved survival in this subset of patients after conventional chemoradiation, and has emerged as the new standard. The synergy between immunotherapy and radiation, as well as ongoing research on the effects of radiation on the immune system, allows for the exploration of new avenues in the treatment of LA-NSCLC. In addition to the use of durvalumab as consolidative systemic therapy after concurrent chemoradiotherapy for Stage III NSCLC, other combination regimens have been shown to be effective in various disease stages in preclinical and clinical studies. These regimens include CTLA-4 and PD/PDL-1 checkpoint inhibitors combined with radiation treatment. While these combined regimens have demonstrated efficacy, they are not without toxicity, and require additional evaluation when combined with radiation. In this review, we have summarized the immunostimulatory and immunosuppressive effects of radiation therapy. We also evaluate the current evidence and ongoing research supporting the combination of radiotherapy and immunotherapy across early to LA-NSCLC.
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Affiliation(s)
- Chirag Modi
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Lyudmyla Berim
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Lauren Isserow
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Jyoti Malhotra
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Malini Patel
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - John Langenfeld
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Joseph Aisner
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Doaa Almeldin
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Salma K Jabbour
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
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Abstract
Radiopharmaceutical therapy or targeted radionuclide therapy (TRT) is a well-established class of cancer therapeutics that includes a growing number of FDA-approved drugs and a promising pipeline of experimental therapeutics. Radiobiology is fundamental to a mechanistic understanding of the therapeutic capacity of these agents and their potential toxicities. However, the field of radiobiology has historically focused on external beam radiation. Critical differences exist between TRT and external beam radiotherapy with respect to dosimetry, dose rate, linear energy transfer, duration of treatment delivery, fractionation, range, and target volume. These distinctions simultaneously make it difficult to extrapolate from the radiobiology of external beam radiation to that of TRT and pose considerable challenges for preclinical and clinical studies investigating TRT. Here, we discuss these challenges and explore the current understanding of the radiobiology of radiopharmaceuticals.
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Affiliation(s)
- Zachary S Morris
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Andrew Z Wang
- Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC
| | - Susan J Knox
- Department of Radiation Oncology, Stanford University, Palo Alto, CA.
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31
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Keam S, Gill S, Ebert MA, Nowak AK, Cook AM. Enhancing the efficacy of immunotherapy using radiotherapy. Clin Transl Immunology 2020; 9:e1169. [PMID: 32994997 PMCID: PMC7507442 DOI: 10.1002/cti2.1169] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 05/04/2020] [Accepted: 08/02/2020] [Indexed: 12/12/2022] Open
Abstract
Recent clinical breakthroughs in cancer immunotherapy, especially with immune checkpoint blockade, offer great hope for cancer sufferers - and have greatly changed the landscape of cancer treatment. However, whilst many patients achieve clinical responses, others experience minimal benefit or do not respond to immune checkpoint blockade at all. Researchers are therefore exploring multimodal approaches by combining immune checkpoint blockade with conventional cancer therapies to enhance the efficacy of treatment. A growing body of evidence from both preclinical studies and clinical observations indicates that radiotherapy could be a powerful driver to augment the efficacy of immune checkpoint blockade, because of its ability to activate the antitumor immune response and potentially overcome resistance. In this review, we describe how radiotherapy induces DNA damage and apoptosis, generates immunogenic cell death and alters the characteristics of key immune cells in the tumor microenvironment. We also discuss recent preclinical work and clinical trials combining radiotherapy and immune checkpoint blockade in thoracic and other cancers. Finally, we discuss the scheduling of immune checkpoint blockade and radiotherapy, biomarkers predicting responses to combination therapy, and how these novel data may be translated into the clinic.
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Affiliation(s)
- Synat Keam
- National Centre for Asbestos Related DiseasesPerthWAAustralia
- School of MedicineThe University of Western AustraliaPerthWAAustralia
| | - Suki Gill
- Department of Radiation OncologySir Charles Gairdner HospitalPerthWAAustralia
| | - Martin A Ebert
- Department of Radiation OncologySir Charles Gairdner HospitalPerthWAAustralia
- School of Physics, Mathematics and ComputingThe University of Western AustraliaPerthWAAustralia
| | - Anna K Nowak
- National Centre for Asbestos Related DiseasesPerthWAAustralia
- School of MedicineThe University of Western AustraliaPerthWAAustralia
- Department of Medical OncologySir Charles Gairdner HospitalNedlands, PerthWAAustralia
| | - Alistair M Cook
- National Centre for Asbestos Related DiseasesPerthWAAustralia
- School of MedicineThe University of Western AustraliaPerthWAAustralia
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Jagodinsky JC, Harari PM, Morris ZS. The Promise of Combining Radiation Therapy With Immunotherapy. Int J Radiat Oncol Biol Phys 2020; 108:6-16. [PMID: 32335187 PMCID: PMC7442714 DOI: 10.1016/j.ijrobp.2020.04.023] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/30/2020] [Accepted: 04/13/2020] [Indexed: 12/17/2022]
Abstract
The development of immunotherapy in oncology builds upon many years of scientific investigation into the cellular mechanics underlying interactions between tumor cells and immune cell populations. The past decade has brought an accelerating pace to the clinical investigation of new immunotherapy agents, particularly in the setting of metastatic disease. The integration of immunotherapy into phase 3 clinical trial design has lagged in settings of advanced locoregional disease, where combination with radiation therapy may be critical. Yet, such may be the settings where immunotherapies have their greatest potential to affect patient survival and achieve curative outcomes. In this review, we discuss the interaction of radiation with the immune system and the potential to augment antitumor immunity through combined-modality approaches that integrate radiation and immunotherapies. The dynamics of cellular and tumor response to radiation offer unique opportunities for beneficial interplay with immunotherapy that may go unrecognized with conventional screening and monotherapy clinical testing of novel pharmaceutical agents. Using immune checkpoint blockade as a primary example, we discuss recent preclinical and clinical studies that illustrate the potential synergy of such therapies in combination with radiation, and we highlight the potential clinical value of such interactions. For various immunotherapy agents, their greatest clinical effect may rest in combination with radiation, and efforts to facilitate systematic investigation of this approach are highly warranted.
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Affiliation(s)
- Justin C Jagodinsky
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Paul M Harari
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Zachary S Morris
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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33
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Mosley M, Baguña Torres J, Allen D, Cornelissen B. Immuno-imaging of ICAM-1 in tumours by SPECT. Nucl Med Biol 2020; 84-85:73-79. [PMID: 32135474 PMCID: PMC7294224 DOI: 10.1016/j.nucmedbio.2020.02.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 02/24/2020] [Accepted: 02/24/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Molecular imaging of cancer cells' reaction to radiation damage can provide a non-invasive measure of tumour response to treatment. The cell surface glycoprotein ICAM-1 (CD54) was identified as a potential radiation response marker. SPECT imaging using an 111In-radiolabelled anti-ICAM-1 antibody was explored. METHODS PSN-1 cells were irradiated (10 Gy), and protein expression changes were investigated using an antibody array on cell lysates 24 h later. Results were confirmed by western blot, flow cytometry and immunofluorescence. We confirmed the affinity of an 111In-labelled anti-ICAM-1 antibody in vitro, and in vivo, in PSN-1-xenograft bearing mice. The xenografts were irradiated (0 or 10 Gy), and [111In]In-anti-ICAM-1 SPECT/CT images were acquired 24, 48 and 72 h after intravenous administration. RESULTS ICAM-1 was identified as a potential marker of radiation treatment using an antibody array in PSN-1 cell lysates following irradiation, showing a significant increase in ICAM-1 signal compared to non-irradiated cells. Western blot and immunohistochemistry confirmed this upregulation, with an up to 20-fold increase in ICAM-1 signal. Radiolabelled anti-ICAM-1 bound to ICAM-1 expressing cells with good affinity (Kd = 24.0 ± 4.0 nM). [111In]In-anti-ICAM-1 uptake in tumours at 72 h post injection was approximately 3-fold higher than non-specific isotype-matched [111In]In-mIgG2a control (19.3 ± 2.5%ID/g versus 6.3 ± 2.2%ID/g, P = 0.0002). However, ICAM1 levels, and [111In]In-anti-ICAM-1 uptake in tumours was no different after irradiation (uptake 9.2%ID/g versus 14.8%ID/g). Western blots of the xenograft lysates showed no significant differences, confirming these results. CONCLUSION Imaging of ICAM-1 is feasible in mouse models of pancreatic cancer. Although ICAM-1 is upregulated post-irradiation in in vitro models of pancreatic cancer, it shows little change in expression in an in vivo mouse xenograft model.
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Affiliation(s)
- Michael Mosley
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom of Great Britain and Northern Ireland
| | - Julia Baguña Torres
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom of Great Britain and Northern Ireland
| | - Danny Allen
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom of Great Britain and Northern Ireland
| | - Bart Cornelissen
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom of Great Britain and Northern Ireland.
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Rodriguez-Ruiz ME, Vitale I, Harrington KJ, Melero I, Galluzzi L. Immunological impact of cell death signaling driven by radiation on the tumor microenvironment. Nat Immunol 2020; 21:120-134. [PMID: 31873291 DOI: 10.1038/s41590-019-0561-4] [Citation(s) in RCA: 251] [Impact Index Per Article: 50.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 11/14/2019] [Indexed: 12/12/2022]
Abstract
Therapeutic irradiation of the tumor microenvironment causes differential activation of pro-survival and pro-death pathways in malignant, stromal, endothelial and immune cells, hence causing a profound cellular and biological reconfiguration via multiple, non-redundant mechanisms. Such mechanisms include the selective elimination of particularly radiosensitive cell types and consequent loss of specific cellular functions, the local release of cytokines and danger signals by dying radiosensitive cells, and altered cytokine secretion by surviving radioresistant cells. Altogether, these processes create chemotactic and immunomodulatory cues for incoming and resident immune cells. Here we discuss how cytoprotective and cytotoxic signaling modules activated by radiation in specific cell populations reshape the immunological tumor microenvironment.
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Affiliation(s)
- Maria Esperanza Rodriguez-Ruiz
- Department of Radiation Oncology, University of Navarra Clinic, Pamplona, Spain
- Centro de Investigación Médica Aplicada (CIMA), Pamplona, Spain
| | - Ilio Vitale
- IIGM-Italian Institute for Genomic Medicine, c/o IRCCS Candiolo, Turin, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Kevin J Harrington
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK
- The Royal Marsden Hospital/Institute of Cancer Research National Institute for Health Biomedical Research Centre, London, UK
| | - Ignacio Melero
- Department of Radiation Oncology, University of Navarra Clinic, Pamplona, Spain
- Centro de Investigación Médica Aplicada (CIMA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
- Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.
- Université de Paris, Paris, France.
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35
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Annede P, Cosset JM, Van Limbergen E, Deutsch E, Haie-Meder C, Chargari C. Radiobiology: Foundation and New Insights in Modeling Brachytherapy Effects. Semin Radiat Oncol 2020; 30:4-15. [DOI: 10.1016/j.semradonc.2019.08.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy. Cancers (Basel) 2019; 12:cancers12010079. [PMID: 31905723 PMCID: PMC7017108 DOI: 10.3390/cancers12010079] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 12/19/2019] [Accepted: 12/24/2019] [Indexed: 12/12/2022] Open
Abstract
Radiation-induced immunogenic cell death has been described to contribute to the efficacy of external beam radiotherapy in local treatment of solid tumors. It is well established that radiation therapy can induce immunogenic cell death in cancer cells under certain conditions. Initial clinical studies combining radiotherapy with immunotherapies suggest a synergistic potential of this approach. Improving our understanding of how radiation reconditions the tumor immune microenvironment should pave the way for designing rational and robust combinations with immunotherapeutic drugs that enhance both local and systemic anti-cancer immune effects. In this review, we summarize irradiation-induced types of immunogenic cell death and their effects on the tumor microenvironment. We discuss preclinical insights on mechanisms and benefits of combining radiotherapy with immunotherapy, focusing on immune checkpoint inhibitors. In addition, we elaborate how these observations were translated into clinical studies and which parameters may be optimized to achieve best results in future clinical trials.
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37
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Grudzinski JJ, Hernandez R, Marsh I, Patel RB, Aluicio-Sarduy E, Engle J, Morris Z, Bednarz B, Weichert J. Preclinical Characterization of 86/90Y-NM600 in a Variety of Murine and Human Cancer Tumor Models. J Nucl Med 2019; 60:1622-1628. [PMID: 30954941 PMCID: PMC12076096 DOI: 10.2967/jnumed.118.224808] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 03/26/2019] [Indexed: 11/16/2022] Open
Abstract
We characterize the in vivo biodistribution and tumor selectivity of 86Y-NM600, a theranostic alkylphosphocholine radiometal chelate with broad tumor selectivity, in a variety of preclinical cancer models. Methods: Mice bearing flank tumors (representative of lung, pancreatic, prostate, liver, skin, and lymphoid cancers) were injected intravenously with 9.25 MBq of 86Y-NM600 and imaged longitudinally over 4-5 d using small-animal PET/CT. Percentage injected activity per gram (%IA/g) for each volume of interest was measured at each time point for the organs of interest. Mice were euthanized after the final time point, and the tumor and organs of interest were counted with an automatic γ-counter. Absorbed doses delivered by 90Y-NM600 per injected activity (Gy/MBq) were estimated. Mice bearing B78 flank tumors were injected with a prescription of 90Y-NM600 that delivered 2.5 Gy of absorbed tumor dose and was compared with an equivalent absorbed dose delivered via external-beam radiotherapy using tumor volume as a measure of response. Histology and complete blood counts were analyzed in naïve C57BL/6 mice that were injected with 9.25 MBq of 90Y-NM600 at 5, 10, and 28 d after injection. Results: PET imaging showed consistent tumor accumulation and retention across all tumor models investigated, with little off-target retention of NM600 except in the liver, as is characteristic of hepatobiliary metabolism. The tumor uptake was highest in the pancreatic and lymphoid cancer models, reaching peak concentrations of 9.34 ± 2.66 %IA/g (n = 3) and 9.10 ± 0.13 %IA/g (n = 3), respectively, at approximately 40-48 h after injection. These corresponded to tumor dose estimates of 2.72 ± 0.33 Gy/MBq and 2.67 ± 0.32 Gy/MBq, respectively. In the toxicity study, there were no visible signs of acute toxicity by histology, and perturbation of hematologic parameters was transient when observed, returning to pretherapy levels after 28 d. Conclusion: NM600 is a theranostic agent with a unique ability to selectively target a variety of cancer types, presenting a unique opportunity for PET image-guided targeted radionuclide therapy and combination with immunotherapies.
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Affiliation(s)
- Joseph J Grudzinski
- Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
| | - Reinier Hernandez
- Department of Radiology, University of Wisconsin, Madison, Wisconsin
| | - Ian Marsh
- Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
| | - Ravi B Patel
- Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin; and
| | | | - Jon Engle
- Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
- Department of Radiology, University of Wisconsin, Madison, Wisconsin
| | - Zachary Morris
- Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin; and
| | - Bryan Bednarz
- Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
- Department of Radiology, University of Wisconsin, Madison, Wisconsin
- Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin; and
| | - Jamey Weichert
- Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
- Department of Radiology, University of Wisconsin, Madison, Wisconsin
- University of Wisconsin Carbone Cancer Center, Madison, Wisconsin
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Huang W, Fan Y, Cheng X, Liang H, Pan H, Xiao T, Chen M, Guan J. A preliminary Study on the Effect of Head and Neck Chemoradiotherapy on Systematic Immunity. Dose Response 2019; 17:1559325819884186. [PMID: 31695581 PMCID: PMC6820191 DOI: 10.1177/1559325819884186] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 09/06/2019] [Accepted: 09/24/2019] [Indexed: 12/24/2022] Open
Abstract
Background This study was designed initially to explore the effect of chemoradiotherapy on patients diagnosed with head and neck cancer (HNC) with respect to the alteration of systematic immunity. Methods We did a retrospective study enrolling patients received concurrent chemoradiotherapy (CCRT), with or without induction chemotherapy (IC). Blood tests were performed before IC, before and after CCRT. Flow cytometric analysis and turbidimetric inhibition immunoassay were used for detection. Results A total number of 58 patients were included from April 1, 2018, to March 31, 2019. Levels of immunoglobulins (Ig), including IgA, IgG, and IgM, declined after 2 to 3 cycles of IC and CCRT, respectively. Serum level of total hemolytic complement (CH50) increased (P < .001) after IC, but kept stably post-CCRT. Natural killer (NK) cells decreased (P < .01) after IC and enhanced (P < .001) post-CCRT. The number of CD3+CD4+ T cells got increased (P < .01) after IC and decreased (P < .001) post-CCRT. Consistently, both IC and CCRT induced the increase in CD3+CD8+ T cells significantly (P < .001 vs P < .01). Conclusion Both radiotherapy (RT) and chemotherapy (CT) induced dual effect of immune response. Concurrent chemoradiotherapy created an active immune response based on the effect induced by IC, suggesting that RT exerted a potential function on mobilizing immune system.
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Affiliation(s)
- Weiqiang Huang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yao Fan
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaoya Cheng
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Huazhen Liang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Hua Pan
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Ting Xiao
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Min Chen
- Department of Radiation Oncology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Jian Guan
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Xu SJ, Zhang F, Wang LJ, Hao MH, Yang XJ, Li NN, Ji HL, Xu P. Flavonoids of Rosa roxburghii Tratt offers protection against radiation induced apoptosis and inflammation in mouse thymus. Apoptosis 2019; 23:470-483. [PMID: 29995207 DOI: 10.1007/s10495-018-1466-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
The present study evaluated the protective effect of the natural compound flavonoids of Rosa roxburghii Tratt (FRT) against γ-radiation-induced apoptosis and inflammation in mouse thymus cells in vivo and in vitro. Thymus cells and mice were exposed to 60Co γ-ray at a dose of 6 Gy. The radiation treatment induced significant cell apoptosis and inflammation. Radiation increased the expressions of cleaved caspase 3/8-10, AIF, and PARP-1, and FRT could mitigate their activation and inhibit subsequent apoptosis in the thymus both in vitro or in vivo. Irradiation increased the mRNA expression of ICAM-1/VCAM-1, IL-1α/IL-6 and TNF-α/NF-κB. Our results also indicated that FRT alleviated gene expression of some inflammatory factors such as ICAM-1/VCAM-1, TNF-α/NF-κB, but not IL-1α/IL-6. Irradiation increased the protein expression levels of ICAM-1/VCAM-1, IL-1α/IL-6 and TNF-α/NF-Κb, and our results also indicated that FRT alleviated protein level expression of certain inflammatory factors such as ICAM-1, IL-1α/IL-6, TNF-α/NF-κB, but not VCAM-1. Our results suggested that FRT enhanced radioprotection at least partially by regulating caspase 3/8-10, AIF, and PARP-1 to reduce apoptosis and by regulating ICAM-1, IL-1α/IL-6, TNF-α/NF-κB to reduce inflammation.
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Affiliation(s)
- Sai-Juan Xu
- Department of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Fan Zhang
- Department of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Li-Juan Wang
- Department of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Ming-Hua Hao
- Department of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Xian-Jun Yang
- International Joint Research Laboratory for Recombiant Pharmaceutical Protein Expression System of Henan, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Na-Na Li
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
| | - Hong-Long Ji
- Department of Cellular and Molecular Biology, University of Texas Health Northeast, Tyler, TX, 75708, USA. .,Institute of Lung and Molecular Therapy, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
| | - Ping Xu
- Department of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
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Novel treatment planning approaches to enhance the therapeutic ratio: targeting the molecular mechanisms of radiation therapy. Clin Transl Oncol 2019; 22:447-456. [PMID: 31254253 DOI: 10.1007/s12094-019-02165-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 06/16/2019] [Indexed: 12/16/2022]
Abstract
Radiation acts not only through cell death but has also angiogenic, immunomodulatory and bystander effects. The realization of its systemic implications has led to extensive research on the combination of radiotherapy with systemic treatments, including immunotherapy and antiangiogenic agents. Parameters such as dose, fractionation and sequencing of treatments are key determinants of the outcome. However, recent high-quality research indicates that these are not the only radiation therapy parameters that influence its systemic effect. To effectively integrate systemic agents with radiation therapy, these new aspects of radiation therapy planning will have to be taken into consideration in future clinical trials. Our aim is to review these new treatment planning parameters that can influence the balance between contradicting effects of radiation therapy so as to enhance the therapeutic ratio.
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Menon H, Ramapriyan R, Cushman TR, Verma V, Kim HH, Schoenhals JE, Atalar C, Selek U, Chun SG, Chang JY, Barsoumian HB, Nguyen QN, Altan M, Cortez MA, Hahn SM, Welsh JW. Role of Radiation Therapy in Modulation of the Tumor Stroma and Microenvironment. Front Immunol 2019; 10:193. [PMID: 30828330 PMCID: PMC6384252 DOI: 10.3389/fimmu.2019.00193] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 01/23/2019] [Indexed: 12/22/2022] Open
Abstract
In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has been the cross-talk between tumor cells and the surrounding environment or stroma. This tumor stroma, comprised of various cells, and extracellular matrix (ECM), has been shown to aid in suppressing host immune responses against tumor cells. Through immunosuppressive cytokine secretion, metabolic alterations, and other mechanisms, the tumor stroma provides a complex network of safeguards for tumor proliferation. With recent advances in more effective, localized treatment, radiation therapy (XRT) has allowed for strategies that can effectively alter and ablate tumor stromal tissue. This includes promoting immunogenic cell death through tumor antigen release to increasing immune cell trafficking, XRT has a unique advantage against the tumoral immune evasion mechanisms that are orchestrated by stromal cells. Current studies are underway to elucidate pathways within the tumor stroma as potential targets for immunotherapy and chemoradiation. This review summarizes the effects of tumor stroma in tumor immune evasion, explains how XRT may help overcome these effects, with potential combinatorial approaches for future treatment modalities.
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Affiliation(s)
- Hari Menon
- Departments of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Rishab Ramapriyan
- Departments of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Taylor R. Cushman
- Departments of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Vivek Verma
- Department of Radiation Oncology, Allegheny General Hospital, Pittsburgh, PA, United States
| | - Hans H. Kim
- Department of Radiation Medicine, School of Medicine, Oregon Health and Sciences University, Portland, OR, United States
| | | | - Cemre Atalar
- Departments of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ugur Selek
- Department of Radiation Oncology, School of Medicine, Koç University, Istanbul, Turkey
| | - Stephen G. Chun
- Departments of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Joe Y. Chang
- Departments of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Hampartsoum B. Barsoumian
- Departments of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Quynh-Nhu Nguyen
- Departments of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mehmet Altan
- Thoracic/Head and Neck Medical Oncology, Houston, TX, United States
| | - Maria A. Cortez
- Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Stephen M. Hahn
- Departments of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - James W. Welsh
- Departments of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
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43
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Goedegebuure RSA, de Klerk LK, Bass AJ, Derks S, Thijssen VLJL. Combining Radiotherapy With Anti-angiogenic Therapy and Immunotherapy; A Therapeutic Triad for Cancer? Front Immunol 2019; 9:3107. [PMID: 30692993 PMCID: PMC6339950 DOI: 10.3389/fimmu.2018.03107] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 12/17/2018] [Indexed: 12/19/2022] Open
Abstract
Radiotherapy has been used for the treatment of cancer for over a century. Throughout this period, the therapeutic benefit of radiotherapy has continuously progressed due to technical developments and increased insight in the biological mechanisms underlying the cellular responses to irradiation. In order to further improve radiotherapy efficacy, there is a mounting interest in combining radiotherapy with other forms of therapy such as anti-angiogenic therapy or immunotherapy. These strategies provide different opportunities and challenges, especially with regard to dose scheduling and timing. Addressing these issues requires insight in the interaction between the different treatment modalities. In the current review, we describe the basic principles of the effects of radiotherapy on tumor vascularization and tumor immunity and vice versa. We discuss the main strategies to combine these treatment modalities and the hurdles that have to be overcome in order to maximize therapeutic effectivity. Finally, we evaluate the outstanding questions and present future prospects of a therapeutic triad for cancer.
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Affiliation(s)
- Ruben S A Goedegebuure
- Amsterdam UMC, Location VUmc, Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Leonie K de Klerk
- Amsterdam UMC, Location VUmc, Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Adam J Bass
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.,Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Sarah Derks
- Amsterdam UMC, Location VUmc, Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Victor L J L Thijssen
- Amsterdam UMC, Location VUmc, Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands.,Amsterdam UMC, Location VUmc, Radiation Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands
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Eckert F, Schilbach K, Klumpp L, Bardoscia L, Sezgin EC, Schwab M, Zips D, Huber SM. Potential Role of CXCR4 Targeting in the Context of Radiotherapy and Immunotherapy of Cancer. Front Immunol 2018; 9:3018. [PMID: 30622535 PMCID: PMC6308162 DOI: 10.3389/fimmu.2018.03018] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 12/06/2018] [Indexed: 12/28/2022] Open
Abstract
Cancer immunotherapy has been established as standard of care in different tumor entities. After the first reports on synergistic effects with radiotherapy and the induction of abscopal effects-tumor shrinkage outside the irradiated volume attributed to immunological effects of radiotherapy-several treatment combinations have been evaluated. Different immunotherapy strategies (e.g., immune checkpoint inhibition, vaccination, cytokine based therapies) have been combined with local tumor irradiation in preclinical models. Clinical trials are ongoing in different cancer entities with a broad range of immunotherapeutics and radiation schedules. SDF-1 (CXCL12)/CXCR4 signaling has been described to play a major role in tumor biology, especially in hypoxia adaptation, metastasis and migration. Local tumor irradiation is a known inducer of SDF-1 expression and release. CXCR4 also plays a major role in immunological processes. CXCR4 antagonists have been approved for the use of hematopoietic stem cell mobilization from the bone marrow. In addition, several groups reported an influence of the SDF-1/CXCR4 axis on intratumoral immune cell subsets and anti-tumor immune response. The aim of this review is to merge the knowledge on the role of SDF-1/CXCR4 in tumor biology, radiotherapy and immunotherapy of cancer and in combinatorial approaches.
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Affiliation(s)
- Franziska Eckert
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
| | - Karin Schilbach
- Department of General Pediatrics/Pediatric Oncology, University Hospital Tuebingen, Tuebingen, Germany
| | - Lukas Klumpp
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany.,Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
| | - Lilia Bardoscia
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany.,Department of Radiation Oncology, University of Brescia, Brescia, Italy
| | - Efe Cumhur Sezgin
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.,Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University Hospital and University Tuebingen, Tuebingen, Germany
| | - Daniel Zips
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
| | - Stephan M Huber
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
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45
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Patel RB, Baniel CC, Sriramaneni RN, Bradley K, Markovina S, Morris ZS. Combining brachytherapy and immunotherapy to achieve in situ tumor vaccination: A review of cooperative mechanisms and clinical opportunities. Brachytherapy 2018; 17:995-1003. [PMID: 30078541 PMCID: PMC8292980 DOI: 10.1016/j.brachy.2018.07.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 07/06/2018] [Indexed: 12/22/2022]
Abstract
As immunotherapies continue to emerge as a standard component of treatment for a variety of cancers, the imperative for testing these in combination with other standard cancer therapies grows. Radiation therapy may be a particularly well-suited partner for many immunotherapies. By modulating immune tolerance and functional immunogenicity at a targeted tumor site, radiation therapy may serve as a method of in situ tumor vaccination. In situ tumor vaccination is a therapeutic strategy that seeks to convert a patient's own tumor into a nidus for enhanced presentation of tumor-specific antigens in a way that will stimulate and diversify an antitumor T cell response. The mechanisms whereby radiation may impact immunotherapy are diverse and include its capacity to simultaneously elicit local inflammation, temporary local depletion of suppressive lymphocyte lineages, enhanced tumor cell susceptibility to immune response, and immunogenic tumor cell death. Emerging data suggest that each of these mechanisms may display a distinct dose-response profile, making it challenging to maximize each of these effects using external beam radiation. Conversely, the highly heterogenous and conformal dose distribution achieved with brachytherapy may be optimal for enhancing the immunogenic capacity of radiation at a tumor site while minimizing off-target antagonistic effects on peripheral immune cells. Here, we review the immunogenic effects of radiation, summarize the clinical rationale and data supporting the use of radiation together with immunotherapies, and discuss the rationale and urgent need for further preclinical and clinical investigation specifically of brachytherapy in combination with immunotherapies. Harnessing these immunomodulatory effects of brachytherapy may offer solutions to overcome obstacles to the efficacy of immunotherapies in immunologically "cold" tumors while potentiating greater response in the context of immunologically "hot" tumors.
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Affiliation(s)
- Ravi B Patel
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Claire C Baniel
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Raghava N Sriramaneni
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Kristin Bradley
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Stephanie Markovina
- Department of Radiation Oncology, Washington University in St Louis, St Louis, MO
| | - Zachary S Morris
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
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Martinez-Zubiaurre I, Chalmers AJ, Hellevik T. Radiation-Induced Transformation of Immunoregulatory Networks in the Tumor Stroma. Front Immunol 2018; 9:1679. [PMID: 30105016 PMCID: PMC6077256 DOI: 10.3389/fimmu.2018.01679] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 07/09/2018] [Indexed: 12/27/2022] Open
Abstract
The implementation of novel cancer immunotherapies in the form of immune checkpoint blockers represents a major advancement in the treatment of cancer, and has renewed enthusiasm for identifying new ways to induce antitumor immune responses in patients. Despite the proven efficacy of neutralizing antibodies that target immune checkpoints in some refractory cancers, many patients do not experience therapeutic benefit, possibly owing to a lack of antitumor immune recognition, or to the presence of dominant immunosuppressive mechanisms in the tumor microenvironment (TME). Recent developments in this field have revealed that local radiotherapy (RT) can transform tumors into in situ vaccines, and may help to overcome some of the barriers to tumor-specific immune rejection. RT has the potential to ignite tumor immune recognition by generating immunogenic signals and releasing neoantigens, but the multiple immunosuppressive forces in the TME continue to represent important barriers to successful tumor rejection. In this article, we review the radiation-induced changes in the stromal compartments of tumors that could have an impact on tumor immune attack. Since different RT regimens are known to mediate strikingly different effects on the multifarious elements of the tumor stroma, special emphasis is given to different RT schedules, and the time after treatment at which the effects are measured. A better understanding of TME remodeling following specific RT regimens and the window of opportunity offered by RT will enable optimization of the design of novel treatment combinations.
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Affiliation(s)
- Inigo Martinez-Zubiaurre
- Department of Clinical Medicine, Faculty of Health Sciences, UiT the Arctic University of Norway, Tromsø, Norway
| | - Anthony J Chalmers
- Institute of Cancer Sciences, Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, United Kingdom
| | - Turid Hellevik
- Department of Radiation Oncology, University Hospital of Northern Norway, Tromsø, Norway
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Wennerberg E, Vanpouille-Box C, Bornstein S, Yamazaki T, Demaria S, Galluzzi L. Immune recognition of irradiated cancer cells. Immunol Rev 2018; 280:220-230. [PMID: 29027232 DOI: 10.1111/imr.12568] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Ionizing irradiation has been extensively employed for the clinical management of solid tumors, with therapeutic or palliative intents, for decades. Until recently, radiation therapy (RT) was believed to mediate antineoplastic activity mostly (if not only) as a consequence of cancer cell-intrinsic effects. Indeed, the macromolecular damage imposed to malignant cells by RT initiates one or multiple signal transduction cascades that drive a permanent proliferative arrest (cellular senescence) or regulated cell death. Both these phenomena show a rather linear dose-response correlation. However, RT also mediates consistent immunological activity, not only as an "on-target effect" originating within irradiated cancer cells, but also as an "off-target effect" depending on the interaction between RT and stromal, endothelial, and immune components of the tumor microenvironment. Interestingly, the immunological activity of RT does not exhibit linear dose-response correlation. Here, we discuss the mechanisms whereby RT alters the capacity of the immune system to recognize and eliminate irradiated cancer cells, either as an "on-target" or as on "off-target" effect. In particular, we discuss the antagonism between the immunostimulatory and immunosuppressive effects of RT as we delineate combinatorial strategies to boost the former at the expenses of the latter.
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Affiliation(s)
- Erik Wennerberg
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | | | - Sophia Bornstein
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Takahiro Yamazaki
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Sandra Demaria
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.,Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.,Sandra and Edward Meyer Cancer Center, New York, NY, USA.,Université Paris Descartes/Paris V, Paris, France
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48
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Yang J, Yan J, Liu B. Targeting VEGF/VEGFR to Modulate Antitumor Immunity. Front Immunol 2018; 9:978. [PMID: 29774034 PMCID: PMC5943566 DOI: 10.3389/fimmu.2018.00978] [Citation(s) in RCA: 440] [Impact Index Per Article: 62.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 04/19/2018] [Indexed: 12/15/2022] Open
Abstract
In addition to the crucial role in promoting the growth of tumor vessels, vascular endothelial growth factor (VEGF) is also immunosuppressive. VEGF can inhibit the function of T cells, increase the recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and hinder the differentiation and activation of dendritic cells (DCs). Recent studies have investigated the role of antiangiogenic agents in antitumor immunity, especially in recent 3 years. Therefore, it is necessary to update the role of targeting VEGF/VEGFR in antitumor immunity. In this review, we focus on the latest clinical and preclinical findings on the modulatory role of antiangiogenic agents targeting VEGF/VEGFR in immune cells, including effector T cells, Tregs, MDSCs, DCs, tumor-associated macrophages, and mast cells. Our review will be potentially helpful for the development of combinations of angiogenesis inhibitors with immunological modulators.
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Affiliation(s)
- Ju Yang
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, China
| | - Jing Yan
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, China
| | - Baorui Liu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, China
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49
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Chishti AA, Baumstark-Khan C, Koch K, Kolanus W, Feles S, Konda B, Azhar A, Spitta LF, Henschenmacher B, Diegeler S, Schmitz C, Hellweg CE. Linear Energy Transfer Modulates Radiation-Induced NF-kappa B Activation and Expression of its Downstream Target Genes. Radiat Res 2018; 189:354-370. [PMID: 29369006 DOI: 10.1667/rr14905.1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Nuclear factor kappaB (NF-κB) is a central transcription factor in the immune system and modulates cell survival in response to radiotherapy. Activation of NF-κB was shown to be an early step in the cellular response to ultraviolet A (UVA) and ionizing radiation exposure in human cells. NF-κB activation by the genotoxic stress-dependent sub-pathway after exposure to different radiation qualities had been evaluated to a very limited extent. In addition, the resulting gene expression profile, which shapes the cellular and tissue response, is unknown. Therefore, in this study the activation of NF-κB after exposure to low- and high-linear energy transfer (LET) radiation and the expression of its target genes were analyzed in human embryonic kidney (HEK) cells. The activation of NF-κB via canonical and genotoxic stress-induced pathways was visualized by the cell line HEK-pNF-κB-d2EGFP/Neo L2 carrying the destabilized enhanced green fluorescent protein (d2EGFP) as reporter. The NF-κB-dependent d2EGFP expression after irradiation with X rays and heavy ions was evaluated by flow cytometry. Because of differences in the extent of NF-κB activation after irradiation with X rays (significant NF-κB activation for doses >4 Gy) and heavy ions (significant NF-κB activation at doses as low as 1 Gy), it was expected that radiation quality (LET) played an important role in the cellular radiation response. In addition, the relative biological effectiveness (RBE) of NF-κB activation and reduction of cellular survival were compared for heavy ions having a broad LET range (∼0.3-9,674 keV/μm). Furthermore, the effect of LET on NF-κB target gene expression was analyzed by real-time reverse transcriptase quantitative PCR (RT-qPCR). The maximal RBE for NF-κB activation and cell killing occurred at an LET value of 80 and 175 keV/μm, respectively. There was a dose-dependent increase in expression of NF-κB target genes NF-κB1A and CXCL8. A qPCR array of 84 NF-κB target genes revealed that TNF and a set of CXCL genes (CXCL1, CXCL2, CXCL8, CXCL10), CCL2, VCAM1, CD83, NF-κB1, NF-κB2 and NF-κBIA were strongly upregulated after exposure to X rays and neon ions (LET 92 keV/μm). After heavy-ion irradiations, it was noted that the expression of NF-κB target genes such as chemokines and CD83 was highest at an LET value that coincided with the LET resulting in maximal NF-κB activation, whereas expression of the NF-κB inhibitory gene NFKBIA was induced transiently by all radiation qualities investigated. Taken together, these findings clearly demonstrate that NF-κB activation and NF-κB-dependent gene expression by heavy ions are highest in the LET range of ∼50-200 keV/μm. The upregulated chemokines and cytokines (CXCL1, CXCL2, CXCL10, CXCL8/IL-8 and TNF) could be important for cell-cell communication among hit as well as nonhit cells (bystander effect).
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Affiliation(s)
- Arif Ali Chishti
- a German Aerospace Centre (DLR), Institute of Aerospace Medicine, Radiation Biology Department, Linder Höhe, D-51147 Köln, Germany
| | - Christa Baumstark-Khan
- a German Aerospace Centre (DLR), Institute of Aerospace Medicine, Radiation Biology Department, Linder Höhe, D-51147 Köln, Germany
| | - Kristina Koch
- a German Aerospace Centre (DLR), Institute of Aerospace Medicine, Radiation Biology Department, Linder Höhe, D-51147 Köln, Germany
| | - Waldemar Kolanus
- b Life and Medical Sciences (LIMES) Institute, University of Bonn, Karlrobert-Kreiten-Straße 13, 53115 Bonn, Germany
| | - Sebastian Feles
- a German Aerospace Centre (DLR), Institute of Aerospace Medicine, Radiation Biology Department, Linder Höhe, D-51147 Köln, Germany
| | - Bikash Konda
- a German Aerospace Centre (DLR), Institute of Aerospace Medicine, Radiation Biology Department, Linder Höhe, D-51147 Köln, Germany
| | - Abid Azhar
- c The Karachi Institute of Biotechnology and Genetic Engineering, University of Karachi, Karachi-75270, Pakistan
| | - Luis F Spitta
- a German Aerospace Centre (DLR), Institute of Aerospace Medicine, Radiation Biology Department, Linder Höhe, D-51147 Köln, Germany
| | - Bernd Henschenmacher
- a German Aerospace Centre (DLR), Institute of Aerospace Medicine, Radiation Biology Department, Linder Höhe, D-51147 Köln, Germany
| | - Sebastian Diegeler
- a German Aerospace Centre (DLR), Institute of Aerospace Medicine, Radiation Biology Department, Linder Höhe, D-51147 Köln, Germany
| | - Claudia Schmitz
- a German Aerospace Centre (DLR), Institute of Aerospace Medicine, Radiation Biology Department, Linder Höhe, D-51147 Köln, Germany
| | - Christine E Hellweg
- a German Aerospace Centre (DLR), Institute of Aerospace Medicine, Radiation Biology Department, Linder Höhe, D-51147 Köln, Germany
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50
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Jackson DG. Hyaluronan in the lymphatics: The key role of the hyaluronan receptor LYVE-1 in leucocyte trafficking. Matrix Biol 2018; 78-79:219-235. [PMID: 29425695 DOI: 10.1016/j.matbio.2018.02.001] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 01/31/2018] [Accepted: 02/01/2018] [Indexed: 12/25/2022]
Abstract
LYVE-1, a close relative of the leucocyte receptor, CD44, is the main receptor for hyaluronan (HA) in lymphatic vessel endothelium and a widely used marker for distinguishing between blood and lymphatic vessels. Enigmatic for many years because of its anomalous HA-binding characteristics, the function of LYVE-1 has just recently been identified as that of a lymphatic docking receptor for dendritic cells, selectively engaging with their surface HA glycocalyx to regulate entry to peripheral lymphatics and migration to downstream lymph nodes for immune activation. Furthermore, LYVE-1 mediates the trafficking of macrophages, and is also exploited by HA-encapsulated Group A streptococci for lymphatic invasion and host dissemination. Consistent with a role in lymphatic trafficking, the interaction of LYVE-1 with HA and its degradation products can also activate intracellular signalling pathways for endothelial junctional retraction and lymphatic endothelial proliferation. Here we outline the latest findings on the receptor in the context of its peculiar biochemical properties and speculate on how the interaction of LYVE-1 with different HA sizes and conformations might variably influence cell function as a consequence of avidity and receptor crosslinking. Finally, we evaluate evidence that LYVE-1 can also bind growth factors and associate with kinase-linked growth factor receptors and conclude on how the LYVE-1·HA axis may be exploited as a target to either block inflammation or tissue allograft rejection, or potentiate vaccine and drug delivery.
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Affiliation(s)
- David G Jackson
- University of Oxford, MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
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