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Rostamizadeh L, Ramezani M, Monirinasab H, Rostamizadeh K, Sabzichi M, Bahavarnia SR, Osouli-Bostanabad K, Ramezani F, Molavi O. Modulating the tumor microenvironment in a mouse model of colon cancer using a combination of HIF-1α inhibitors and Toll-Like Receptor 7 agonists. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:5867-5880. [PMID: 39614894 PMCID: PMC11985627 DOI: 10.1007/s00210-024-03658-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 11/19/2024] [Indexed: 04/11/2025]
Abstract
The immunosuppressive tumor microenvironment (TME) plays a pivotal role in the response to various anticancer therapies, such as immune and chemotherapeutic agents. In this study, the synergistic effects of gene-targeting HIF-1α siRNA combined with Toll-Like Receptor 7 agonist on TME remodeling were investigated in a mouse model of colorectal cancer (CRC). A HIF-1α-specific siRNA duplex was formulated based on the ionic gelation of tripolyphosphate (TPP) with cationic chitosan (CH) as a nanoplex and evaluated in terms of size, charge, polydispersity index and gel retardation assay. MTT assay was conducted to assess the cytotoxicity of the specific siRNA duplex against CT26 cells. Hypoxic condition was generated to evaluate the gene and protein expression levels of HIF-1α, respectively. CT26 mouse model was established to assess the synergistic effect of silencing HIF-1α combined with oxaliplatin (OXA) and imiquimod (IMQ) on tumor growth. The mean diameter of the CH/siRNA nanoparticles was 243 ± 6 nm, as confirmed with Micrograph scanning electron microscope. There were no significant differences observed between the CT26 cells treated with nanoparticles alone and the untreated cells, indicating that these nanoparticles are safe and physiologically biocompatible (p ≥ 0.05). Triple combination therapy involving HIF-1α siRNA, OXA, and IMQ significantly retarded tumor growth and led to elevated levels of cytokines linked to cellular immunity (INF-γ and IL-12) compared with those in the other groups (P < 0.05). The positive correlation coefficient (r = 0.68) between tumor size and HIF-1α expression levels was statistically significant (P = 0.003). Compared with those in the control group, the expression levels of the anti-inflammatory cytokines IL-10 and IL-4 significantly decreased (P < 0.05). In conclusion, our findings suggest that inhibiting HIF-1α could serve as a rational strategy to enhance the antitumor response in the TME.
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Affiliation(s)
- Leila Rostamizadeh
- Department of Molecular Medicine, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Golgasht Avenue, Tabriz, Iran
| | - Mina Ramezani
- Faculty of Medical Science, Department of Anatomical Science, Tarbiat Modares University, Tehran, Iran
| | | | - Kobra Rostamizadeh
- Department of Psychiatry and Behavioral Sciences, Department of Pharmacology, School of Medicine, University of Washington, Seattle, WA, USA
| | - Mehdi Sabzichi
- School of Medicine, Pharmacy, and Biomedical Sciences, University of Portsmouth, White Swan Road, Portsmouth, Portsmouth PO1 2DT, UK.
| | | | - Karim Osouli-Bostanabad
- School of Medicine, Pharmacy, and Biomedical Sciences, University of Portsmouth, White Swan Road, Portsmouth, Portsmouth PO1 2DT, UK
| | - Fatemeh Ramezani
- Department of Molecular Medicine, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Golgasht Avenue, Tabriz, Iran.
| | - Ommoleila Molavi
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
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Qian J, Jiang Y, Hu H. Ginsenosides: an immunomodulator for the treatment of colorectal cancer. Front Pharmacol 2024; 15:1408993. [PMID: 38939839 PMCID: PMC11208871 DOI: 10.3389/fphar.2024.1408993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 05/23/2024] [Indexed: 06/29/2024] Open
Abstract
Ginsenosides, the primary bioactive ingredients derived from the root of Panax ginseng, are eagerly in demand for tumor patients as a complementary and alternative drug. Ginsenosides have increasingly become a "hot topic" in recent years due to their multifunctional role in treating colorectal cancer (CRC) and regulating tumor microenvironment (TME). Emerging experimental research on ginsenosides in the treatment and immune regulation of CRC has been published, while no review sums up its specific role in the CRC microenvironment. Therefore, this paper systematically introduces how ginsenosides affect the TME, specifically by enhancing immune response, inhibiting the activation of stromal cells, and altering the hallmarks of CRC cells. In addition, we discuss their impact on the physicochemical properties of the tumor microenvironment. Furthermore, we discuss the application of ginsenosides in clinical treatment as their efficacy in enhancing tumor patient immunity and prolonging survival. The future perspectives of ginsenoside as a complementary and alternative drug of CRC are also provided. This review hopes to open up a new horizon for the cancer treatment of Traditional Chinese Medicine monomers.
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Affiliation(s)
- Jianan Qian
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yanyu Jiang
- Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongyi Hu
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Pei F, He W, Duan Y, Yao Q, Zhao Y, Fan X, Liu S, Chen H, He F, Liu T, Chen J, Zheng Y, Li H, Guo X, Shi L, Ling L, Chen Y, He J, Liu M, Huang M, Bai Y, Wang J, Huang M, Huang J. PD-1 blockade enhances the effect of targeted chemotherapy on locally advanced pMMR/MSS colorectal cancer. Cancer Med 2024; 13:e7224. [PMID: 38888366 PMCID: PMC11184646 DOI: 10.1002/cam4.7224] [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: 11/14/2023] [Revised: 04/06/2024] [Accepted: 04/14/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies. METHODS In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics. RESULTS By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 × 10-8). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively). CONCLUSIONS Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation.
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Affiliation(s)
- Fengyun Pei
- Department of Colorectal Surgery, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Department of General Surgery, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Wan He
- Department of OncologyShenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology)ShenzhenChina
| | - Yinghua Duan
- Department of Traditional Chinese Medicine, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Qijun Yao
- Department of Colorectal Surgery, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Department of General Surgery, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Yandong Zhao
- Department of Pathology, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Xinjuan Fan
- Department of Pathology, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Shuai Liu
- Department of Radiation Oncology, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Haiyang Chen
- Department of Radiation Oncology, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Fang He
- Department of Radiation Oncology, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Tingzhi Liu
- Department of Hematology, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Jiaoting Chen
- Department of Hematology, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Yijia Zheng
- Department of Hematology, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Heping Li
- Department of Medical Oncology of the Eastern Hospital, The First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Xiaofang Guo
- Department of Medical Oncology of the Eastern Hospital, The First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Lishuo Shi
- Clinical Research Center, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Li Ling
- Faculty of Medical Statistics, School of Public HealthSun Yat‐sen UniversityGuangzhouChina
| | - Yaoxu Chen
- Medical Affairs3D Medicines, Inc.ShanghaiChina
| | - Jiapeng He
- Medical Affairs3D Medicines, Inc.ShanghaiChina
| | - Miao Liu
- Medical Affairs3D Medicines, Inc.ShanghaiChina
| | | | - Yuezong Bai
- Medical Affairs3D Medicines, Inc.ShanghaiChina
| | - Jianping Wang
- Department of Colorectal Surgery, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Department of General Surgery, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Guangdong Institute of GastroenterologyGuangzhouChina
| | - Meijin Huang
- Department of Colorectal Surgery, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Department of General Surgery, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Guangdong Institute of GastroenterologyGuangzhouChina
| | - Jun Huang
- Department of Colorectal Surgery, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Department of General Surgery, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Guangdong Institute of GastroenterologyGuangzhouChina
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Taniura T, Ishitobi K, Hidaka M, Harada M. Modulatory effects of supplementation of Lentinula edodes mycelia extract and l-arginine on the therapeutic efficacy of immunogenic chemotherapy in colon cancer-bearing mice. Microbiol Immunol 2024; 68:15-22. [PMID: 37964433 DOI: 10.1111/1348-0421.13101] [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: 10/19/2023] [Accepted: 11/02/2023] [Indexed: 11/16/2023]
Abstract
Some chemotherapeutic drugs can induce cancer cell death and enhance antitumor T-cell immunity in cancer-bearing hosts. Immunomodulatory reagents could augment such chemotherapy-induced effects. We previously reported that oral digestion of Lentinula edodes mycelia (L.E.M.) extract or l-arginine supplementation can augment antitumor T-cell responses in cancer-bearing mice. In this study, the effects of L.E.M. extract with or without l-arginine on the therapeutic efficacy of immunogenic chemotherapy by 5-fluorouracil (5-FU)/oxaliplatin (L-OHP) and/or cyclophosphamide (CP) are examined using two mouse colon cancer models. In MC38 and CT26 cancer models, therapy with 5-FU/L-OHP/CP significantly suppressed tumor growth, and supplementation with L.E.M. extract halved the tumor volumes. However, the modulatory effect of L.E.M. extract was not significant. In the CT26 cancer model, supplementation with L.E.M. extract and l-arginine had no clear effect on tumor growth. In contrast, their addition to chemotherapy halved the tumor volumes, although the effect was not significant. There was no difference in the cytotoxicity of tumor-specific cytotoxic T cells generated from CT26-cured mice treated by chemotherapy alone versus chemotherapy combined with L.E.M. extract/ l-arginine. These results indicate that the antitumor effects of immunogenic chemotherapy were too strong to ascertain the effects of supplementation of L.E.M. extract and l-arginine, but these reagents nonetheless have immunomodulatory effects on the therapeutic efficacy of immunogenic chemotherapy in colon cancer-bearing mice.
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Affiliation(s)
- Takahito Taniura
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Shimane, Japan
| | - Kazunari Ishitobi
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Shimane, Japan
| | - Masaaki Hidaka
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Shimane, Japan
| | - Mamoru Harada
- Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan
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Nguyen HPQ, Bae WK, Park MS, Chung IJ, Nam TK, Jeong JU, Uong TNT, Cho D, Kim SK, Yoon M. Intensified NK cell therapy in combination with low-dose chemoradiotherapy against human colorectal cancer. Cancer Immunol Immunother 2023; 72:4089-4102. [PMID: 37801126 PMCID: PMC10992501 DOI: 10.1007/s00262-023-03545-w] [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: 08/04/2023] [Accepted: 09/07/2023] [Indexed: 10/07/2023]
Abstract
The therapeutic potential of adoptive natural Killer (NK) cells immunotherapy in combination with chemoradiotherapy, the main treatment modality for colorectal cancer (CRC), has not yet been explored. Here, we aimed to investigate the efficacy of NK cells to potentiate primary tumor control and improve survival outcomes, especially in combination with low-dose chemoradiotherapy. Ex vivo activated NK cells (> 90% purity) from healthy donors were obtained. NK cells were administered intravenously to the CRC-bearing mice and intensified in vivo in combination with low-dose 5-fluorouracil (0.5 mg/kg or 1 mg/Kg) and irradiated tumors with low doses (2 Gy or 4 Gy). Real-time NK cell cytotoxicity demonstrated a synergistic killing effect of a combination of low-dose chemoradiotherapy, mainly through NKp30 and NKG2D, showing a decrease in NK cell degranulation after blocking NKG2D and NKp30. In vivo tumor characteristics after combination treatment showed decreased CD112, CD155, MICA, and MICB expression. Under the combination strategy, 70% of the mice had free lung metastasis and 90% without secondary gross tumors, indicating suppressed distant metastasis to lung and axillary regions. This combination therapy resulted in significantly synergistic antitumor activity against primary solid tumors compared to chemoradiotherapy only. Furthermore, the intensified NK cell administration showed significantly better primary tumor control and survival outcomes than the non-intensified NK cell administration in a human colorectal HT-29 model treated with low-dose chemoradiotherapy. Optimized NK cell therapy combined with low-dose chemoradiotherapy can provide effective therapeutic potential for intractable cold human colorectal cancer.
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Affiliation(s)
- Huy Phuoc Quang Nguyen
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
- Department of Biomedical Science, Chonnam National University Graduate School, Gwangju, Republic of Korea
| | - Woo Kyun Bae
- Immunotherapy Innovation Center, Chonnam National University Medical School, Hwasun, Republic of Korea.
- Department of Hematology and Oncology, Chonnam National University Medical School and Hwasun Hospital, Hwasun, Republic of Korea.
| | - Myong Suk Park
- Department of Hematology and Oncology, Chonnam National University Medical School and Hwasun Hospital, Hwasun, Republic of Korea
| | - Ik-Joo Chung
- Immunotherapy Innovation Center, Chonnam National University Medical School, Hwasun, Republic of Korea
- Department of Hematology and Oncology, Chonnam National University Medical School and Hwasun Hospital, Hwasun, Republic of Korea
| | - Taek-Keun Nam
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Jae-Uk Jeong
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Tung Nguyen Thanh Uong
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
- Department of Biomedical Science, Chonnam National University Graduate School, Gwangju, Republic of Korea
| | - Duck Cho
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sang-Ki Kim
- Department of Companion and Laboratory Animal Science, Kongju National University, Yesan, Republic of Korea
| | - Meesun Yoon
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea.
- Department of Biomedical Science, Chonnam National University Graduate School, Gwangju, Republic of Korea.
- Immunotherapy Innovation Center, Chonnam National University Medical School, Hwasun, Republic of Korea.
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Wang L, Chelakkot VS, Newhook N, Tucker S, Hirasawa K. Inflammatory cell death induced by 5-aminolevulinic acid-photodynamic therapy initiates anticancer immunity. Front Oncol 2023; 13:1156763. [PMID: 37854679 PMCID: PMC10581343 DOI: 10.3389/fonc.2023.1156763] [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: 02/01/2023] [Accepted: 09/07/2023] [Indexed: 10/20/2023] Open
Abstract
Background Inflammatory cell death is a form of programmed cell death (PCD) that induces inflammatory mediators during the process. The production of inflammatory mediators during cell death is beneficial in standard cancer therapies as it can break the immune silence in cancers and induce anticancer immunity. Photodynamic therapy (PDT) is a cancer therapy with photosensitizer molecules and light sources to destroy cancer cells, which is currently used for treating different types of cancers in clinical settings. In this study, we investigated if PDT using 5-aminolevulinic (5-ALA-PDT) causes inflammatory cell death and, subsequently, increases the immunogenicity of cancer cells. Methods Mouse breast cancer (4T1) and human colon cancer (DLD-1) cells were treated with 5-ALA for 4 hours and then irradiated with a light source. PCD induction was measured by western blot analysis and FACS. Morphological changes were determined by transmission electron microscopy (TEM). BALB/c mice were injected with cell-free media, supernatant of freeze/thaw cells or supernatant of PDT cells intramuscular every week for 4 weeks and then challenged with 4T1 cells at the right hind flank of BALB/c. Tumor growth was monitored for 12 days. Results We found that 5-ALA-PDT induces inflammatory cell death, but not apoptosis, in 4T1 cells and DLD-1 cells in vitro. Moreover, when mice were pretreated with 5-ALA-PDT culture supernatant, the growth of 4T1 tumors was significantly suppressed compared to those pretreated with freeze and thaw (F/T) 4T1 culture supernatant. Conclusion These results indicate that 5-ALA-PDT induces inflammatory cell death which promotes anticancer immunity in vivo.
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Affiliation(s)
- Lingyan Wang
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Vipin Shankar Chelakkot
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Nick Newhook
- Medical Laboratories, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Stephanie Tucker
- Medical Laboratories, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Kensuke Hirasawa
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
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Fernández Moro C, Geyer N, Harrizi S, Hamidi Y, Söderqvist S, Kuznyecov D, Tidholm Qvist E, Salmonson Schaad M, Hermann L, Lindberg A, Heuchel RL, Martín-Bernabé A, Dhanjal S, Navis AC, Villard C, Del Valle AC, Bozóky L, Sparrelid E, Dirix L, Strell C, Östman A, Schmierer B, Vermeulen PB, Engstrand J, Bozóky B, Gerling M. An idiosyncratic zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver. Nat Commun 2023; 14:5024. [PMID: 37596278 PMCID: PMC10439160 DOI: 10.1038/s41467-023-40688-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 07/31/2023] [Indexed: 08/20/2023] Open
Abstract
A perimetastatic capsule is a strong positive prognostic factor in liver metastases, but its origin remains unclear. Here, we systematically quantify the capsule's extent and cellular composition in 263 patients with colorectal cancer liver metastases to investigate its clinical significance and origin. We show that survival improves proportionally with increasing encapsulation and decreasing tumor-hepatocyte contact. Immunostaining reveals the gradual zonation of the capsule, transitioning from benign-like NGFRhigh stroma at the liver edge to FAPhigh stroma towards the tumor. Encapsulation correlates with decreased tumor viability and preoperative chemotherapy. In mice, chemotherapy and tumor cell ablation induce capsule formation. Our results suggest that encapsulation develops where tumor invasion into the liver plates stalls, representing a reparative process rather than tumor-induced desmoplasia. We propose a model of metastases growth, where the efficient tumor colonization of the liver parenchyma and a reparative liver injury reaction are opposing determinants of metastasis aggressiveness.
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Affiliation(s)
- Carlos Fernández Moro
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, 14186, Sweden
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, 14186, Stockholm, Sweden
| | - Natalie Geyer
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Sara Harrizi
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Yousra Hamidi
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Sara Söderqvist
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Danyil Kuznyecov
- Department of Clinical Genetics, Pathology and Molecular Diagnostics, Medicinsk Service, Skåne University Hospital, 22185, Lund, Sweden
| | - Evelina Tidholm Qvist
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, 14186, Sweden
| | | | - Laura Hermann
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Amanda Lindberg
- Department of Immunology, Genetics and Pathology, Uppsala University, 75185, Uppsala, Sweden
| | - Rainer L Heuchel
- Pancreatic Cancer Research Laboratory, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14183, Hudinge, Sweden
| | | | - Soniya Dhanjal
- CRISPR Functional Genomics, SciLifeLab and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17165, Solna, Sweden
| | - Anna C Navis
- CRISPR Functional Genomics, SciLifeLab and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17165, Solna, Sweden
| | - Christina Villard
- Department of Medicine Huddinge, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Andrea C Del Valle
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Lorand Bozóky
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Ernesto Sparrelid
- Department of Clinical Science, Intervention and Technology, Division of Surgery, Karolinska Institutet, Karolinska University Hospital, 14152, Stockholm, Sweden
| | - Luc Dirix
- Translational Cancer Research Unit (GZA Hospitals and University of Antwerp), Antwerp, Belgium
| | - Carina Strell
- Department of Immunology, Genetics and Pathology, Uppsala University, 75185, Uppsala, Sweden
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, 5020, Bergen, Norway
| | - Arne Östman
- Department of Oncology-Pathology, Karolinska Institutet, 17176, Solna, Sweden
| | - Bernhard Schmierer
- CRISPR Functional Genomics, SciLifeLab and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17165, Solna, Sweden
| | - Peter B Vermeulen
- Translational Cancer Research Unit (GZA Hospitals and University of Antwerp), Antwerp, Belgium
| | - Jennie Engstrand
- Department of Clinical Science, Intervention and Technology, Division of Surgery, Karolinska Institutet, Karolinska University Hospital, 14152, Stockholm, Sweden
| | - Béla Bozóky
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, 14186, Sweden
| | - Marco Gerling
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden.
- Theme Cancer, Karolinska University Hospital, 17 176, Solna, Sweden.
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8
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Jeong KY. Challenges to addressing the unmet medical needs for immunotherapy targeting cold colorectal cancer. World J Gastrointest Oncol 2023; 15:215-224. [PMID: 36908316 PMCID: PMC9994045 DOI: 10.4251/wjgo.v15.i2.215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/18/2022] [Accepted: 01/09/2023] [Indexed: 02/14/2023] Open
Abstract
With the establishment of the immune surveillance mechanism since the 1950s, attempts have been made to activate the immune system for cancer treatment through the discovery of various cytokines or the development of antibodies up to now. The fruits of these efforts have contributed to the recognition of the 3rd generation of anticancer immunotherapy as the mainstream of cancer treatment. However, the limitations of cancer immunotherapy are also being recognized through the conceptual establishment of cold tumors recently, and colorectal cancer (CRC) has become a major issue from this therapeutic point of view. Here, it is emphasized that non-clinical strategies to overcome the immunosuppressive environment and clinical trials based on these basic investigations are being made on the journey to achieve better treatment outcomes for the treatment of cold CRC.
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Affiliation(s)
- Keun-Yeong Jeong
- Research and Development Center, PearlsinMires, Seoul 03690, South Korea
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9
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Ibrahim D, Abozied N, Abdel Maboud S, Alzamami A, Alturki NA, Jaremko M, Alanazi MK, Alhuthali HM, Seddek A. Therapeutic potential of bone marrow mesenchymal stem cells in cyclophosphamide-induced infertility. Front Pharmacol 2023; 14:1122175. [PMID: 37033609 PMCID: PMC10073512 DOI: 10.3389/fphar.2023.1122175] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 01/26/2023] [Indexed: 04/11/2023] Open
Abstract
Cancer is a deadly disease characterized by abnormal cell proliferation. Chemotherapy is one technique of cancer treatment. Cyclophosphamide (CYP) is the most powerful chemotherapy medication, yet it has serious adverse effects. It is an antimitotic medicine that regulates cell proliferation and primarily targets quickly dividing cells, and it has been related to varying levels of infertility in humans. In the current study, we assessed the biochemical, histological, and microscopic evaluations of testicular damage following cyclophosphamide administration. Further, we have explored the potential protective impact of mesenchymal stem cell (MSCs) transplantation. The biochemical results revealed that administration of cyclophosphamide increased serum concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), while it decreased serum concentrations of free testosterone hormone (TH), testicular follicle-stimulating hormone, luteinizing hormone, and free testosterone hormone concentrations, testicular total antioxidant capacity (TAC), and testicular activity of superoxide dismutase (SOD) enzyme. The histology and sperm examinations revealed that cyclophosphamide induced destruction to the architectures of several tissues in the testes, which drastically reduced the Johnsen score as well as the spermatogenesis process. Surprisingly, transplantation of mesenchymal stem cell after cyclophosphamide administration altered the deterioration effect of cyclophosphamide injury on the testicular tissues, as demonstrated by biochemical and histological analysis. Our results indicated alleviation of serum and testicular sex hormones, as well as testicular oxidative stress markers (total antioxidant capacity and superoxide dismutase activity), and nearly restored the normal appearance of the testicular tissues, Johnsen score, and spermatogenesis process. In conclusion, our work emphasizes the protective pharmacological use of mesenchymal stem cell to mitigate the effects of cyclophosphamide on testicular tissues that impair the spermatogenesis process following chemotherapy. These findings indicate that transferring mesenchymal stem cell to chemotherapy patients could significantly improve spermatogenesis.
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Affiliation(s)
- Dalia Ibrahim
- The Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
- *Correspondence: Dalia Ibrahim,
| | - Nadia Abozied
- The Department of Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Samar Abdel Maboud
- The Department of Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Ahmad Alzamami
- Clinical Laboratory Science Department, College of Applied Medical Science, Shaqra University, AlQuwayiyah, Saudi Arabia
| | - Norah A. Alturki
- Clinical Laboratory Science Department, College of Applied Medical Science, King Saud University, Riyadh, Saudi Arabia
| | - Mariusz Jaremko
- Smart-Health Initiative and Red Sea Research Center, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
| | - Maram Khalil Alanazi
- Pharm.D, Scientific Office and Regulatory Affair Department, Dallah Pharma Company, Riyadh, Saudi Arabia
| | - Hayaa M. Alhuthali
- Department of Clinical laboratory sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Asmaa Seddek
- The Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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10
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Ishitobi K, Kotani H, Iida Y, Taniura T, Notsu Y, Tajima Y, Harada M. A modulatory effect of L-arginine supplementation on anticancer effects of chemoimmunotherapy in colon cancer-bearing aged mice. Int Immunopharmacol 2022; 113:109423. [DOI: 10.1016/j.intimp.2022.109423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 10/21/2022] [Accepted: 10/31/2022] [Indexed: 11/10/2022]
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11
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Thermodynamic stability of cisplatin-loaded polymeric micelles and the phenotypic switching of the tumor-associated macrophages induced by combination of cisplatin-loaded micelles and Anti-PD-L1 antibody. Int J Pharm 2022; 622:121860. [PMID: 35654378 DOI: 10.1016/j.ijpharm.2022.121860] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 05/13/2022] [Accepted: 05/22/2022] [Indexed: 12/13/2022]
Abstract
Chemotherapy is an effective anti-tumor treatment. Some anticancer chemotherapeutic drugs can not only induce cell death, but can also elicit antitumor immune responses. Here, the stability of cisplatin-loaded polymeric micelles (CDDP-PMs), pharmacokinetic drug-drug interactions of CDDP and anti-PD-L1 antibody (aPD-L1) in vivo and the alteration of the tumor microenvironment by combination of CDDP-PMs and aPD-L1 were evaluated. CDDP-PMs were fabricated by coordinated complexation and self-assembly method for tumor targeting. CDDP-PMs with higher mass ratio of copolymer have higher thermodynamic stability. The pharmacokinetic study showed that the CDDP and aPD-L1 were metabolized and cleared by two different pathways, suggesting that there is almost no risk of potential drug interactions between CDDP and aPD-L1 and the combination of aPD-L1 and CDDP- PMs may not alter the tissue distribution of CDDP. In vivo antitumor test showed that the tumor growth inhibition rates of CDDP-PMs combined with medium-dose aPD-L1 and CDDP-PMs combined with high-dose PD-L1 were 89.41% and 93.16%, respectively and therapeutic efficacy can be further increased by increasing the dose of aPD-L1 in co-administration group. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between them and holds great potential to offer better safety and antitumor efficacy profiles.
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12
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Li T, Tian Y, Wang Y, Cui Z, He Z, Wu X, Zhang Y, Jiang H. Kiss1 Inhibits the Proliferation of Nasopharyngeal Carcinoma Cells Via Activation of the LKB1/AMPK Pathway. Front Oncol 2022; 11:724251. [PMID: 35117986 PMCID: PMC8804215 DOI: 10.3389/fonc.2021.724251] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 12/24/2021] [Indexed: 12/31/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a cancer that occurs in the nasopharynx. Infinite proliferation and distant metastasis are the main characteristics of NPC cells, and the main reason for the current failure of malignant tumor treatment. In this study, by integrating the immunohistochemical, cell transfection, western blot and real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis, we observed that the expression of KISS1 and its receptor gene (KISS1R) negatively related with the proliferation of NPC cells. Overexpression of the KISS1 genes in cells reduced cell proliferation, slow down the cell cycle, and increased apoptosis. Additionally, overexpression of these genes significantly increased Liver Kinase B1 (LKB1), phosphorylation of LKB1 and AMPK, indicated by Western blotting. Together, all of these results suggested for the first time that KISS1 and KISS1R suppress the proliferation of NPC cells by activating the LKB1/AMPK pathway, thus revealing a viable indicator for diagnosis of NPC in clinical practice.
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Affiliation(s)
- Tingting Li
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yong Tian
- Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical Collage, Bengbu, China
| | - Yixuan Wang
- General Surgery, Po Cheung Hospital, Bozhou, China
| | - Zhen Cui
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Zelai He
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xiao Wu
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yajun Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Hao Jiang
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
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13
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Abstract
The immune tumor microenvironment (TME) of colorectal cancer (CRC) is a crucial contributor to disease biology, making it an important target for therapeutic intervention. The diversity of immune cell populations within various subsets of CRC has led to the discovery that immune characterization of the TME has both prognostic and predictive value for patients. The convergence of improved molecular and cellular characterization of CRC along with the widespread use of immunotherapy in solid tumors has led to a revolution in the approach to clinical care. Monoclonal antibodies (mAbs) which target key immune checkpoints, such as programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), have demonstrated remarkable clinical activity in microsatellite instability-high (MSI-H) CRCs and are now used in routine practice. The observation that MSI-H cancers are highly infiltrated with immune cells and carry a high neoantigen load led to the successful targeting of these cancers with immunotherapy. More recently, the Food and Drug Administration (FDA) approved a PD-1 inhibitor for microsatellite stable (MSS) cancers with high tumor mutation burden. However, the anti-tumor activity of immunotherapy is rare in the majority of CRC. While immune cell characterization does provide prognostic value in these patients, these observations have not yet led to therapeutic interventions. By delineating factors that predict efficacy, resistance, and therapeutic targets, ongoing research will inform the development of effective combination strategies for the vast majority of MSS CRC and immunotherapy-resistant MSI-H cancers.
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Affiliation(s)
- Parul Agarwal
- Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, United States
| | - Dung T Le
- Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, United States.
| | - Patrick M Boland
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
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14
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Pramil E, Dillard C, Escargueil AE. Colorectal Cancer and Immunity: From the Wet Lab to Individuals. Cancers (Basel) 2021; 13:cancers13071713. [PMID: 33916641 PMCID: PMC8038567 DOI: 10.3390/cancers13071713] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/27/2021] [Accepted: 03/30/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Tackling the current dilemma of colorectal cancer resistance to immunotherapy is puzzling and requires novel therapeutic strategies to emerge. However, characterizing the intricate interactions between cancer and immune cells remains difficult because of the complexity and heterogeneity of both compartments. Developing rationales is intellectually feasible but testing them can be experimentally challenging and requires the development of innovative procedures and protocols. In this review, we delineated useful in vitro and in vivo models used for research in the field of immunotherapy that are or could be applied to colorectal cancer management and lead to major breakthroughs in the coming years. Abstract Immunotherapy is a very promising field of research and application for treating cancers, in particular for those that are resistant to chemotherapeutics. Immunotherapy aims at enhancing immune cell activation to increase tumor cells recognition and killing. However, some specific cancer types, such as colorectal cancer (CRC), are less responsive than others to the current immunotherapies. Intrinsic resistance can be mediated by the development of an immuno-suppressive environment in CRC. The mutational status of cancer cells also plays a role in this process. CRC can indeed be distinguished in two main subtypes. Microsatellite instable (MSI) tumors show a hyper-mutable phenotype caused by the deficiency of the DNA mismatch repair machinery (MMR) while microsatellite stable (MSS) tumors show a comparatively more “stable” mutational phenotype. Several studies demonstrated that MSI CRC generally display good prognoses for patients and immunotherapy is considered as a therapeutic option for this type of tumors. On the contrary, MSS metastatic CRC usually presents a worse prognosis and is not responsive to immunotherapy. According to this, developing new and innovative models for studying CRC response towards immune targeted therapies has become essential in the last years. Herein, we review the in vitro and in vivo models used for research in the field of immunotherapy applied to colorectal cancer.
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Affiliation(s)
- Elodie Pramil
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; (E.P.); (C.D.)
- Alliance Pour la Recherche en Cancérologie—APREC, Tenon Hospital, F-75012 Paris, France
| | - Clémentine Dillard
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; (E.P.); (C.D.)
- Alliance Pour la Recherche en Cancérologie—APREC, Tenon Hospital, F-75012 Paris, France
| | - Alexandre E. Escargueil
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; (E.P.); (C.D.)
- Correspondence: ; Tel.: +33-(0)1-49-28-46-44
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15
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Taniura T, Iida Y, Kotani H, Ishitobi K, Tajima Y, Harada M. Immunogenic chemotherapy in two mouse colon cancer models. Cancer Sci 2020; 111:3527-3539. [PMID: 32816355 PMCID: PMC7541014 DOI: 10.1111/cas.14624] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/12/2020] [Accepted: 08/17/2020] [Indexed: 01/18/2023] Open
Abstract
Aside from the induction of cell death, some anticancer chemotherapeutic drugs can modulate antitumor immune responses. In this study, we examined the anticancer effects of 5‐fluorouracil (5‐FU) and oxaliplatin (L‐OHP), which are standard chemotherapeutic drugs for colon cancer, combined with cyclophosphamide (CP) in two mouse colon cancer models (CT26 and MC38 colon adenocarcinoma models). In the CT26 model, two injections of 5‐FU/L‐OHP and CP significantly suppressed the growth of subcutaneously established CT26 tumors compared with either 5‐FU/L‐OHP or CP, without a significant loss of body weight. The anticancer effect was weakened in nude mice. Cured mice acquired protective immunity against CT26, and CT26‐specific cytotoxic T cells (CTLs) were induced from their spleen cells. Analysis of tumor‐infiltrating immune cells revealed that 5‐FU/L‐OHP treatment with or without CP increased the proportion of CD8+ T cells at tumor sites. The 5‐FU/L‐OHP treatment decreased the proportion of granulocytic myeloid‐derived suppressor cells (MDSCs) and increased monocytic MDSCs in tumor sites, whereas the addition of CP treatment reversed these changes. In the MC38 model, although significant anticancer effects of the triple combination therapy were seen, additional treatment with anti‐PD‐1 antibody increased the number of cured mice. These mice exhibited protective immunity against MC38, and MC38‐specific CTLs were generated from their spleen cells. Together, these results indicate that the antitumor effects of the combination of 5‐FU/L‐OHP and CP mainly depend on host T cells; moreover, the therapeutic efficacy can be effectively boosted by immune checkpoint blockade.
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Affiliation(s)
- Takahito Taniura
- Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, Shimane, Japan
| | - Yuichi Iida
- Department of Immunology, Faculty of Medicine, Shimane University, Shimane, Japan
| | - Hitoshi Kotani
- Department of Immunology, Faculty of Medicine, Shimane University, Shimane, Japan
| | - Kazunari Ishitobi
- Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, Shimane, Japan
| | - Yoshitsugu Tajima
- Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, Shimane, Japan
| | - Mamoru Harada
- Department of Immunology, Faculty of Medicine, Shimane University, Shimane, Japan
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