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Gao F, Sun K, Wang S, Zhang X, Bai X. Lactate metabolism reprogramming in PDAC: Potential for tumor therapy. Biochim Biophys Acta Rev Cancer 2025; 1880:189373. [PMID: 40513632 DOI: 10.1016/j.bbcan.2025.189373] [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: 02/18/2025] [Revised: 06/07/2025] [Accepted: 06/10/2025] [Indexed: 06/16/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. During tumor progression, metabolic reprogramming plays a crucial role in both tumor proliferation and immune evasion. In PDAC, genetic mutations and environment limitations lead to resulting in increased lactate production through enhanced glycolysis. Elevated glycolysis is a significant metabolic feature in pancreatic cancer, leading to lactate accumulation within both the tumor cells and tumor immune microenvironment. Lactate not only promotes tumor growth and sustains its survival but also has a profound impact on the immune-suppressive phenotype switch of immune cells. Lactate promotes tumor progression through various biological processes. Pharmacological agents targeting lactate generation, accumulation and lactate-related molecular pathways show potential clinical translation value in cancer treatment.
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Affiliation(s)
- Fan Gao
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China; Shangyu People's Hospital of Shaoxing, Shaoxing University, Shaoxing 312300, Zhejiang, China
| | - Kang Sun
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Sicheng Wang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Xiaozhen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China.
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2
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Plummer R, Sodergren MH, Hodgson R, Ryan BM, Raulf N, Nicholls JP, Reebye V, Voutila J, Sinigaglia L, Meyer T, Pinato DJ, Sarker D, Basu B, Blagden S, Cook N, Jeffrey Evans TR, Yachnin J, Chee CE, Li D, El-Khoueiry A, Diab M, Huang KW, Pai M, Spalding D, Talbot T, Noel MS, Keenan B, Mahalingam D, Song MS, Grosso M, Arnaud D, Auguste A, Zacharoulis D, Storkholm J, McNeish I, Habib R, Rossi JJ, Habib NA. TIMEPOINT, a phase 1 study combining MTL-CEBPA with pembrolizumab, supports the immunomodulatory effect of MTL-CEBPA in solid tumors. Cell Rep Med 2025; 6:102041. [PMID: 40168999 PMCID: PMC12047497 DOI: 10.1016/j.xcrm.2025.102041] [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: 11/16/2023] [Revised: 03/05/2024] [Accepted: 03/03/2025] [Indexed: 04/03/2025]
Abstract
Many patients with cancer do not benefit from currently approved immune checkpoint inhibitors (ICIs), suggesting that additional immunomodulation of the immunosuppressive tumor microenvironment (TME) is required. MTL-CCAAT enhancer-binding protein alpha (CEBPA) specifically upregulates the expression of the master myeloid transcription factor, CEBPA, relieving myeloid-driven immunosuppression. Here, we report the safety, tolerability, pharmacokinetics, and efficacy of MTL-CEBPA in combination with pembrolizumab in patients with advanced solid tumors that typically show ICI resistance. Multimodal exploratory analyses of paired patient biopsies demonstrate biological changes associated with the combination treatment of MTL-CEBPA and pembrolizumab, including increased infiltration of T cell and antigen-presenting cells supporting conversion from an immune-desert toward a more immune-inflamed TME. Patients with disease stabilization demonstrate reductions in immunosuppressive myeloid cells post treatment. Collectively, these data support a role for MTL-CEBPA in reducing immunosuppression in the TME. This study was registered at ClinicalTrials.gov (NCT04105335).
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Affiliation(s)
- Ruth Plummer
- The Northern Centre for Cancer Care, Freeman Hospital, NE7 7DN Newcastle, UK
| | - Mikael H Sodergren
- Department of Surgery & Cancer, Imperial College London, W12 0NN London, UK
| | | | | | - Nina Raulf
- MiNA Therapeutics Ltd, W12 0BZ London, UK
| | - Joanna P Nicholls
- Department of Surgery & Cancer, Imperial College London, W12 0NN London, UK; MiNA Therapeutics Ltd, W12 0BZ London, UK
| | - Vikash Reebye
- Department of Surgery & Cancer, Imperial College London, W12 0NN London, UK; MiNA Therapeutics Ltd, W12 0BZ London, UK
| | | | | | - Tim Meyer
- Research Department of Oncology, UCL Cancer Institute, University College London, WC1E 6DD London, UK
| | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, W12 0NN London, UK; Department of Translational Medicine (DIMET), Università Del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Debashis Sarker
- Department of Research Oncology, Guys Hospital, Kings College London, SE1 9RT London, UK
| | - Bristi Basu
- University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, CB2 0QQ Cambridge, UK
| | - Sarah Blagden
- Department of Oncology, Oxford University, Churchill Hospital, OX3 7LE Oxford, UK
| | - Natalie Cook
- University of Manchester and The Christie NHS Foundation Trust, M20 4BX Manchester, UK
| | | | - Jeffrey Yachnin
- Centrum Kliniska Cancerstudier, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Cheng E Chee
- National University Hospital, National University Cancer Institute Singapore, Singapore 11928, Singapore
| | - Daneng Li
- Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Anthony El-Khoueiry
- Norris Comprehensive Cancer Centre, Keck Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Maria Diab
- Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
| | | | - Madhava Pai
- Department of Surgery & Cancer, Imperial College London, W12 0NN London, UK
| | - Duncan Spalding
- Department of Surgery & Cancer, Imperial College London, W12 0NN London, UK
| | - Thomas Talbot
- Department of Surgery & Cancer, Imperial College London, W12 0NN London, UK
| | - Marcus S Noel
- Medstar Georgetown University Hospital, Washington, DC 20007, USA
| | - Bridget Keenan
- University of California San Francisco, San Francisco, CA 94143, USA
| | - Devalingam Mahalingam
- Robert H Lurie Comprehensive Cancer Centre, Northwestern University, Chicago, IL 60611, USA
| | - Min-Sun Song
- Beckman Research Institute, City of Hope, CA, USA
| | | | | | | | | | - Jan Storkholm
- Department of Surgery & Cancer, Imperial College London, W12 0NN London, UK
| | - Iain McNeish
- Department of Surgery & Cancer, Imperial College London, W12 0NN London, UK
| | | | - John J Rossi
- Beckman Research Institute, City of Hope, CA, USA
| | - Nagy A Habib
- Department of Surgery & Cancer, Imperial College London, W12 0NN London, UK; MiNA Therapeutics Ltd, W12 0BZ London, UK.
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3
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Cheng H, Guo H, Wen C, Sun G, Tang F, Li Y. The dual role of gut microbiota in pancreatic cancer: new insights into onset and treatment. Ther Adv Med Oncol 2025; 17:17588359251324882. [PMID: 40093983 PMCID: PMC11909682 DOI: 10.1177/17588359251324882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 02/14/2025] [Indexed: 03/19/2025] Open
Abstract
Pancreatic cancer ranks among the most lethal digestive malignancies, exhibiting a steadily increasing incidence and mortality worldwide. Despite significant advances in cancer research, the 5-year survival rate remains below 10%, predominantly due to delayed diagnosis and limited therapeutic options. Concurrently, the gut microbiota-an integral component of host physiology-has emerged as a crucial player in the pathogenesis of pancreatic cancer. Mounting evidence indicates that alterations in gut microbial composition and function may influence tumor initiation, progression, and response to therapy. This review provides an in-depth examination of the intricate interplay between the gut microbiome and pancreatic cancer, highlighting potential diagnostic biomarkers and exploring microbiome-targeted therapeutic strategies to improve patient outcomes.
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Affiliation(s)
- Huijuan Cheng
- School of Life Sciences, Lanzhou University, Lanzhou, Gansu, P.R. China
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou University Second Hospital, Lanzhou, Gansu, P.R. China
| | - Hongkai Guo
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, P.R. China
| | - Chengming Wen
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, P.R. China
| | - Guodong Sun
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, P.R. China
- Department of Medical Affairs, Lanzhou University First Hospital, Lanzhou, Gansu, P.R. China
| | - Futian Tang
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou University Second Hospital, Lanzhou, Gansu, P.R. China
| | - Yumin Li
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou University Second Hospital, No. 82, Cuiyingmen, Chengguan, Lanzhou, Gansu 730000, P.R. China
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Gaikwad S, Srivastava SK. Reprogramming tumor immune microenvironment by milbemycin oxime results in pancreatic tumor growth suppression and enhanced anti-PD-1 efficacy. Mol Ther 2024; 32:3145-3162. [PMID: 39097773 PMCID: PMC11403213 DOI: 10.1016/j.ymthe.2024.07.029] [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: 02/21/2024] [Revised: 07/15/2024] [Accepted: 07/31/2024] [Indexed: 08/05/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a survival rate of 12%, and multiple clinical trials testing anti-PD-1 therapies against PDAC have failed, suggesting a need for a novel therapeutic strategy. In this study, we evaluated the potential of milbemycin oxime (MBO), an antiparasitic compound, as an immunomodulatory agent in PDAC. Our results show that MBO inhibited the growth of multiple PDAC cell lines by inducing apoptosis. In vivo studies showed that the oral administration of 5 mg/kg MBO inhibited PDAC tumor growth in both subcutaneous and orthotopic models by 49% and 56%, respectively. Additionally, MBO treatment significantly increased the survival of tumor-bearing mice by 27 days as compared to the control group. Interestingly, tumors from MBO-treated mice had increased infiltration of CD8+ T cells. Notably, depletion of CD8+ T cells significantly reduced the anti-tumor efficacy of MBO in mice. Furthermore, MBO significantly augmented the efficacy of anti-PD-1 therapy, and the combination treatment resulted in a greater proportion of active cytotoxic T cells within the tumor microenvironment. MBO was safe and well tolerated in all our preclinical toxicological studies. Overall, our study provides a new direction for the use of MBO against PDAC and highlights the potential of repurposing MBO for enhancing anti-PD-1 immunotherapy.
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Affiliation(s)
- Shreyas Gaikwad
- Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Center for Tumor Immunology and Targeted Cancer Therapy, Jerry H. Hodge School of Pharmacy, Abilene, TX 79601, USA
| | - Sanjay K Srivastava
- Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Center for Tumor Immunology and Targeted Cancer Therapy, Jerry H. Hodge School of Pharmacy, Abilene, TX 79601, USA.
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Zheng R, Liu X, Zhang Y, Liu Y, Wang Y, Guo S, Jin X, Zhang J, Guan Y, Liu Y. Frontiers and future of immunotherapy for pancreatic cancer: from molecular mechanisms to clinical application. Front Immunol 2024; 15:1383978. [PMID: 38756774 PMCID: PMC11096556 DOI: 10.3389/fimmu.2024.1383978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 04/22/2024] [Indexed: 05/18/2024] Open
Abstract
Pancreatic cancer is a highly aggressive malignant tumor, that is becoming increasingly common in recent years. Despite advances in intensive treatment modalities including surgery, radiotherapy, biological therapy, and targeted therapy, the overall survival rate has not significantly improved in patients with pancreatic cancer. This may be attributed to the insidious onset, unknown pathophysiology, and poor prognosis of the disease. It is therefore essential to identify and develop more effective and safer treatments for pancreatic cancer. Tumor immunotherapy is the new and fourth pillar of anti-tumor therapy after surgery, radiotherapy, and chemotherapy. Significant progress has made in the use of immunotherapy for a wide variety of malignant tumors in recent years; a breakthrough has also been made in the treatment of pancreatic cancer. This review describes the advances in immune checkpoint inhibitors, cancer vaccines, adoptive cell therapy, oncolytic virus, and matrix-depletion therapies for the treatment of pancreatic cancer. At the same time, some new potential biomarkers and potential immunotherapy combinations for pancreatic cancer are discussed. The molecular mechanisms of various immunotherapies have also been elucidated, and their clinical applications have been highlighted. The current challenges associated with immunotherapy and proposed strategies that hold promise in overcoming these limitations have also been discussed, with the aim of offering new insights into immunotherapy for pancreatic cancer.
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Affiliation(s)
- Rui Zheng
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Xiaobin Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yufu Zhang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Yan’an University, Yan’an, Shaanxi, China
| | - Yongxian Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yaping Wang
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Shutong Guo
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Xiaoyan Jin
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Jing Zhang
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yuehong Guan
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yusi Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
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Persky J, Cruz SM, Darrow MA, Judge SJ, Li Y, Bold RJ, Karnezis AN, Matsukuma KE, Qi L, Canter RJ. Characterization of natural killer and cytotoxic T-cell immune infiltrates in pancreatic ductal adenocarcinoma. J Surg Oncol 2024; 129:885-892. [PMID: 38196111 PMCID: PMC10980567 DOI: 10.1002/jso.27581] [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: 12/19/2023] [Accepted: 12/22/2023] [Indexed: 01/11/2024]
Abstract
BACKGROUND AND OBJECTIVES Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor response to systemic therapies, including immunotherapy. Given the immunotherapeutic potential of natural killer (NK) cells, we evaluated intratumoral NK cell infiltrates along with cytotoxic T cells in PDAC to determine their association with patient outcomes. METHODS We analyzed tumors from 93 PDAC patients treated from 2012 to 2020. Predictor variables included tumor-infiltrating lymphocytes (TILs), T-cell markers (CD3, CD8, CD45RO), NK marker (NKp46), and NK inhibitory marker (major histocompatibility complex class I [MHC-I]) by immunohistochemistry. Primary outcome variables were recurrence-free survival (RFS) and overall survival (OS). RESULTS Mean TILs, CD3, and NKp46 scores were 1.3 ± 0.63, 20.6 ± 17.5, and 3.1 ± 3.9, respectively. Higher expression of CD3 and CD8 was associated with higher OS, whereas NK cell infiltration was not associated with either RFS or OS. There was a tight positive correlation between MHC-I expression and all T-cell markers, but not with NKp46. CONCLUSIONS Overall NK cell infiltrates were low in PDAC and did not predict clinical outcomes, whereas T-cell infiltrates did. Further characterization of the immune infiltrate in PDAC, including inhibitory signals and suppressive cell types, may yield better biomarkers of prognosis and immune targeting in this refractory disease.
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Affiliation(s)
- Julia Persky
- Division of Surgical Oncology, UC Davis Comprehensive Cancer Center, Sacramento, CA
| | - Sylvia M. Cruz
- Division of Surgical Oncology, UC Davis Comprehensive Cancer Center, Sacramento, CA
| | - Morgan, A. Darrow
- Department of Pathology and Laboratory Medicine, UC Davis Medical Center, Sacramento, CA
| | - Sean J. Judge
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Yueju Li
- Division of Biostatistics, Department of Public Health Sciences, UC Davis
| | - Richard J. Bold
- Division of Surgical Oncology, UC Davis Comprehensive Cancer Center, Sacramento, CA
| | - Anthony N. Karnezis
- Department of Pathology and Laboratory Medicine, UC Davis Medical Center, Sacramento, CA
| | - Karen E. Matsukuma
- Department of Pathology and Laboratory Medicine, UC Davis Medical Center, Sacramento, CA
| | - Lihong Qi
- Division of Biostatistics, Department of Public Health Sciences, UC Davis
| | - Robert J. Canter
- Division of Surgical Oncology, UC Davis Comprehensive Cancer Center, Sacramento, CA
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Chai Y, Huang Z, Shen X, Lin T, Zhang Y, Feng X, Mao Q, Liang Y. Microbiota Regulates Pancreatic Cancer Carcinogenesis through Altered Immune Response. Microorganisms 2023; 11:1240. [PMID: 37317214 PMCID: PMC10221276 DOI: 10.3390/microorganisms11051240] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 06/16/2023] Open
Abstract
The microbiota is present in many parts of the human body and plays essential roles. The most typical case is the occurrence and development of cancer. Pancreatic cancer (PC), one of the most aggressive and lethal types of cancer, has recently attracted the attention of researchers. Recent research has revealed that the microbiota regulates PC carcinogenesis via an altered immune response. Specifically, the microbiota, in several sites, including the oral cavity, gastrointestinal tract, and pancreatic tissue, along with the numerous small molecules and metabolites it produces, influences cancer progression and treatment by activating oncogenic signaling, enhancing oncogenic metabolic pathways, altering cancer cell proliferation, and triggering chronic inflammation that suppresses tumor immunity. Diagnostics and treatments based on or in combination with the microbiota offer novel insights to improve efficiency compared with existing therapies.
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Affiliation(s)
- Yihan Chai
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
| | - Zhengze Huang
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
| | - Xuqiu Shen
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
| | - Tianyu Lin
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
| | - Yiyin Zhang
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
| | - Xu Feng
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
| | - Qijiang Mao
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Hangzhou 310016, China
- Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310028, China
| | - Yuelong Liang
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
- Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310028, China
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8
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Yu L, He R, Cui Y. Characterization of tumor microenvironment and programmed death-related genes to identify molecular subtypes and drug resistance in pancreatic cancer. Front Pharmacol 2023; 14:1146280. [PMID: 37007021 PMCID: PMC10063807 DOI: 10.3389/fphar.2023.1146280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 03/09/2023] [Indexed: 03/19/2023] Open
Abstract
Background: Immunotherapy has been a key option for the treatment of many types of cancer. A positive response to immunotherapy is heavily dependent on tumor microenvironment (TME) interaction. However, in pancreatic adenocarcinoma (PAAD), the association between TME mode of action and immune cell infiltration and immunotherapy, clinical outcome remained unknown.Methods: We systematically evaluated 29 TME genes in PAAD signature. Molecular subtypes of distinct TME signatures in PAAD were characterized by consensus clustering. After this, we comprehensively analyzed their clinical features, prognosis, and immunotherapy/chemotherapy response using correlation analysis, Kaplan-Meier curves analysis, ssGSEA analysis. 12 programmed cell death (PCD) patterns were acquired from previous study. Differentially expressed genes (DEGs) were acquired based on differential analysis. Key genes affecting overall survival (OS) of PAAD were screened by COX regression analysis and used to develop a RiskScore evaluation model. Finally, we assessed the value of RiskScore in predicting prognosis and treatment response in PAAD.Results: We identified 3 patterns of TME-associated molecular subtypes (C1, C2, C3), and observed that clinicopathological characteristics, prognosis, pathway features and immune features, immunotherapy/chemosensitivity of patients were correlated with the TME related subtypes. C1 subtype was more sensitive to the four chemotherapeutic drugs. PCD patterns were more likely to occur at C2 or C3. At the same time, we also detected 6 key genes that could affect the prognosis of PAAD, and 5 genes expressions were closely associated to methylation level. Low-risk patients with high immunocompetence had favorable prognostic results and high immunotherapy benefit. Patients in the high-risk group were more sensitive to chemotherapeutic drugs. RiskScore related to TME was an independent prognostic factor for PAAD.Conclusion: Collectively, we identified a prognostic signature of TME in PAAD patients, which could help elucidate the specific mechanism of action of TME in tumors and help to explore more effective immunotherapy strategies.
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Affiliation(s)
- Liang Yu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Risheng He
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yunfu Cui
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
- *Correspondence: Yunfu Cui,
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9
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Mansouri S, Daniel L, Amhis N, Leveille M, Boudreau JE, Alkayyal AA, Collin Y, Tai LH. Perioperative oncolytic virotherapy to counteract surgery-induced immunosuppression and improve outcomes in pancreatic ductal adenocarcinoma. Front Oncol 2023; 13:1071751. [PMID: 36874130 PMCID: PMC9978493 DOI: 10.3389/fonc.2023.1071751] [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: 10/17/2022] [Accepted: 01/30/2023] [Indexed: 02/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a high fatality cancer with one of the worst prognoses in solid tumors. Most patients present with late stage, metastatic disease and are not eligible for potentially curative surgery. Despite complete resection, the majority of surgical patients will recur within the first two years following surgery. Postoperative immunosuppression has been described in different digestive cancers. While the underlying mechanism is not fully understood, there is compelling evidence to link surgery with disease progression and cancer metastasis in the postoperative period. However, the idea of surgery-induced immunosuppression as a facilitator of recurrence and metastatic spread has not been explored in the context of pancreatic cancer. By surveying the existing literature on surgical stress in mostly digestive cancers, we propose a novel practice-changing paradigm: alleviate surgery-induced immunosuppression and improve oncological outcome in PDAC surgical patients by administering oncolytic virotherapy in the perioperative period.
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Affiliation(s)
- Sarah Mansouri
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC, Canada.,Department of Surgery, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Lauren Daniel
- Department of Surgery, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Nawal Amhis
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC, Canada.,Department of Surgery, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Maxime Leveille
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Jeanette E Boudreau
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Almohanad A Alkayyal
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia.,Immunology Research Program, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Yves Collin
- Department of Surgery, Université de Sherbrooke, Sherbrooke, QC, Canada.,Research Center of the Centre hospitalier universitaire de Sherbrooke (CHUS), Sherbrooke, QC, Canada
| | - Lee-Hwa Tai
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC, Canada.,Research Center of the Centre hospitalier universitaire de Sherbrooke (CHUS), Sherbrooke, QC, Canada
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10
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Binda C, Gibiino G, Sbrancia M, Coluccio C, Cazzato M, Carloni L, Cucchetti A, Ercolani G, Sambri V, Fabbri C. Microbiota in the Natural History of Pancreatic Cancer: From Predisposition to Therapy. Cancers (Basel) 2022; 15:cancers15010001. [PMID: 36611999 PMCID: PMC9817971 DOI: 10.3390/cancers15010001] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/28/2022] [Accepted: 12/13/2022] [Indexed: 12/29/2022] Open
Abstract
Early microbiome insights came from gut microbes and their role among intestinal and extraintestinal disease. The latest evidence suggests that the microbiota is a true organ, capable of several interactions throughout the digestive system, attracting specific interest in the biliopancreatic district. Despite advances in diagnostics over the last few decades and improvements in the management of this disease, pancreatic cancer is still a common cause of cancer death. Microbiota can influence the development of precancerous disease predisposing to pancreatic cancer (PC). At the same time, neoplastic tissue shows specific characteristics in terms of diversity and phenotype, determining the short- and long-term prognosis. Considering the above information, a role for microbiota has also been hypothesized in the different phases of the PC approach, providing future revolutionary therapeutic insights. Microbiota-modulating therapies could open new issues in the therapeutic landscape. The aim of this narrative review is to assess the most updated evidence on microbiome in all the steps regarding pancreatic adenocarcinoma, from early development to response to antineoplastic therapy and long-term prognosis.
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Affiliation(s)
- Cecilia Binda
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì-Cesena, Italy
| | - Giulia Gibiino
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì-Cesena, Italy
- Correspondence: ; Tel.: +39-3488609557
| | - Monica Sbrancia
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì-Cesena, Italy
| | - Chiara Coluccio
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì-Cesena, Italy
| | - Maria Cazzato
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì-Cesena, Italy
| | - Lorenzo Carloni
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì-Cesena, Italy
- Department of Medical and Surgical Sciences—DIMEC, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences—DIMEC, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
- General and Oncologic Surgery, Morgagni—Pierantoni Hospital, AUSL Romagna, 47121 Forlì, Italy
| | - Giorgio Ercolani
- Department of Medical and Surgical Sciences—DIMEC, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
- General and Oncologic Surgery, Morgagni—Pierantoni Hospital, AUSL Romagna, 47121 Forlì, Italy
| | - Vittorio Sambri
- Department of Medical and Surgical Sciences—DIMEC, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
- Microbiology Unit, Hub Laboratory, AUSL della Romagna, 47121 Cesena, Italy
| | - Carlo Fabbri
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì-Cesena, Italy
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11
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Teramatsu K, Oono T, Oyama K, Fujimori N, Murakami M, Yasumori S, Ohno A, Matsumoto K, Takeno A, Nakata K, Nakamura M, Ogawa Y. Circulating CD8+CD122+ T cells as a prognostic indicator of pancreatic cancer. BMC Cancer 2022; 22:1134. [PMCID: PMC9636831 DOI: 10.1186/s12885-022-10207-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022] Open
Abstract
Abstract
Purpose
The distribution of tissue infiltrating lymphocytes has been shown to affect the prognosis of patients with pancreatic cancer in some previous studies. However, the role of peripheral lymphocytes in pancreatic cancer remains debated. The purpose of this study was to analyze the peripheral subtypes of T lymphocytes, and establish their association with the prognosis of patients with pancreatic cancer.
Methods
Blood and tissue samples were collected from patients with metastatic pancreatic cancer (n = 54), resectable pancreatic cancer (n = 12), and benign pancreatic cysts (n = 52) between April 2019 and January 2022 and analyzed.
Results
Patients with metastatic pancreatic cancer had a larger proportion of both tumor-suppressive and tumor-promoting cells than those with benign pancreatic cysts. In addition, the proportion of peripheral CD4+ T cells positively correlated with the survival of patients with metastatic pancreatic cancer, and the proportion of peripheral CD8+CD122+ T cells was associated with early mortality (< 90 days). After chemotherapy, CD8+CD122+ T cells decreased in patients who had a partial response or stable disease. Moreover, by analyzing resected specimens, we first proved that the existence of CD8+CD122+ T cells in a tumor microenvironment (TME) depends on their proportion in peripheral blood.
Conclusion
Circulating CD8+CD122+ T cells can be a prognostic indicator in patients with pancreatic cancer.
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12
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Fujiwara K, Shao Y, Niu N, Zhang T, Herbst B, Henderson M, Muth S, Zhang P, Zheng L. Direct identification of HLA class I and class II-restricted T cell epitopes in pancreatic cancer tissues by mass spectrometry. J Hematol Oncol 2022; 15:154. [PMID: 36284347 PMCID: PMC9597957 DOI: 10.1186/s13045-022-01373-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 10/11/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Identifying T cell epitopes on pancreatic ductal adenocarcinoma (PDAC) associated antigens or neoantigens has been a challenge. In this study, we attempted to identify PDAC T cell epitopes by mass spectrometry (MS). METHODS We isolated HLA class I (HLA-I) and HLA class II (HLA-II)-restricted peptides, respectively, from tissues of human PDAC by using the pan-HLA-I or pan-HLA-II affinity purification column and identified T cell epitopes by peptidome analysis with MS. RESULTS Through peptidome analysis, we identified T cell epitopes shared by multiple patients with different HLA types and those containing sequences of both anti-HLA-I and HLA-II antibodies-affinity purified peptides. The identified epitopes bound non-matched HLA molecules and induced T cell response in peripheral T cells from both HLA-type matched and non-matched patients. Peptides containing both HLA class I and class II epitopes were able to induce polyfunctional cytokine responses in peripheral T cells. CONCLUSIONS T cell epitopes in PDAC can be discovered by the MS approach and can be designed into vaccine and TCR-T cell therapies for both HLA-type matched and non-matched patients.
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Affiliation(s)
- Kenji Fujiwara
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,Department of Surgery, Kimura Hospital, Fukuoka, Japan
| | - Yingkuan Shao
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Nan Niu
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Tengyi Zhang
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Brian Herbst
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Mackenzie Henderson
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Stephen Muth
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.,The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Pingbo Zhang
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
| | - Lei Zheng
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. .,The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. .,The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. .,The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. .,Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
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13
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He YG, Huang XB, Li YM, Li J, Peng XH, Huang W, Tang YC, Zheng L. Efficacy and safety of laparoscopic radical resection following neoadjuvant therapy for pancreatic ductal adenocarcinoma: A retrospective study. World J Gastrointest Oncol 2022; 14:1785-1797. [PMID: 36187398 PMCID: PMC9516639 DOI: 10.4251/wjgo.v14.i9.1785] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/16/2022] [Accepted: 08/15/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Multiple studies have demonstrated that neoadjuvant chemotherapy (NACT) can prolong the overall survival of pancreatic ductal adenocarcinoma (PDAC) patients. However, most studies have focused on open surgery following NACT. AIM To investigate the efficacy and safety of laparoscopic radical resection following NACT for PDAC. METHODS We retrospectively analyzed the clinical data of 15 patients with pathologically confirmed PDAC who received NACT followed by laparoscopic radical surgery in our hospital from December 2019 to April 2022. All patients underwent abdominal contrast-enhanced computed tomography (CT) and positron emission tomography-CT before surgery to accurately assess tumor stage and exclude distant metastasis. RESULTS All 15 patients with pancreatic cancer were successfully converted to surgical resection after NACT, including 8 patients with pancreatic head cancer and 7 patients with pancreatic body and tail cancer. Among them, 13 patients received the nab-paclitaxel plus gemcitabine regimen (gemcitabine 1000 mg/m2 plus nab-paclitaxel 125 mg/m2 on days 1, 8, and 15 every 4 wk) and 2 patients received the modified FOLFIRINOX regimen (intravenous oxaliplatin 68 mg/m2, irinotecan 135 mg/m2, and leucovorin 400 mg/m2 on day 1 and fluorouracil 400 mg/m2 on day 1, followed by 46-h continuous infusion of fluorouracil 2400 mg/m2). After each treatment cycle, abdominal CT, tumor markers, and circulating tumor cell counts were reviewed to evaluate the treatment efficacy. All 15 patients achieved partial remission. The surgical procedures included laparoscopic pancreaticoduodenectomy (LPD, n = 8) and laparoscopic radical antegrade modular pancreatosplenectomy (L-RAMPS, n = 7). None of them were converted to a laparotomy. One patient with pancreatic head carcinoma was found to have portal vein involvement during the operation, and LPD combined with vascular resection and reconstruction was performed. The amount of blood loss and operation times of L-RAMPS vs LPD were 435.71 ± 32.37 mL vs 343.75 ± 145.01 mL and 272.52 ± 49.14 min vs 444.38 ± 68.63 min, respectively. The number of dissected lymph nodes was 16.87 ± 4.10, and 3 patients had positive lymph nodes. One patient developed grade B postoperative pancreatic fistula (POPF) after L-RAMPS, and one patient experienced jaundice after LPD. None of the patients died after surgery. As of April 2022, progressive disease was noted in 4 patients, 2 patients had liver metastasis, and one had both liver metastasis and lymph node metastasis and died during the follow-up period. CONCLUSION Laparoscopic radical resection of PDAC after NACT is safe and effective if it is performed by a surgeon with rich experience in LPD and in a large center of pancreatic surgery.
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Affiliation(s)
- Yong-Gang He
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Xiao-Bing Huang
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Yu-Ming Li
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Jing Li
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Xue-Hui Peng
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Wen Huang
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Yi-Chen Tang
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Lu Zheng
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
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14
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Zhu ZG, Chen L, Miao DL, Jin Y, Wu Q. Integrated analysis of senescence-associated genes in pancreatic ductal adenocarcinoma. Front Genet 2022; 13:941389. [PMID: 36046234 PMCID: PMC9420911 DOI: 10.3389/fgene.2022.941389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/21/2022] [Indexed: 01/10/2023] Open
Abstract
Background: Cellular senescence plays a critical role in the occurrence and development, and immune modulation of cancer. This research primarily investigated the role of senescence-associated genes (SAGs) in the survival and tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC). Methods: From the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database, the gene expression profiles and clinical data of PDAC samples were downloaded. SAGs in the TCGA cohort were used to build a novel prognostic model and validated in the ICGC cohort. The relationship of signature with the immune landscape, tumor mutational burden (TMB), as well as the sensitivity of different therapies, was explored. Moreover, a nomogram was developed to predict the overall survival of PDAC patients. Results: A prognostic signature was constructed on basis of three SAGs, and patients in the low-risk score group had a longer survival time. The accuracy of the signature to distinguish different score groups was confirmed through principal component analysis (PCA) and the Receiver operator curves curve. The mRNA expression of the three signature genes was also verified in normal pancreatic and PDAC cell lines by RT-qPCR. The signature could independently predict the prognosis of PDAC patients and had broad applicability. Meanwhile, the nomogram predicted that 1- and 3-years survival rates were in good agreement with the observed overall survival rates. Low-risk patients had lower tumor mutational burden, and low-TMB patients had a better prognosis. Low- and high-risk patients exhibit distinct immune cell infiltration and immune checkpoint changes. By further analyzing the risk score, patients in the low-risk group were more responsive to immunotherapy and a variety of commonly used chemotherapeutic drugs. Conclusion: The prognostic signature can well predict the prognosis and assess the possibility of immunotherapy in personalized PDAC treatment.
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15
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Gupta VK, Pandey S, Lavania S. Targeting IRAK4 Signaling in PDAC: Turning the "Cold" Tumors to "Hot" Ones. Gastroenterology 2022; 162:1837-1839. [PMID: 35358509 DOI: 10.1053/j.gastro.2022.03.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 03/25/2022] [Indexed: 12/02/2022]
Affiliation(s)
- Vineet Kumar Gupta
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
| | - Somnath Pandey
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
| | - Shweta Lavania
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
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16
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A Potential Prognostic Marker PRDM1 in Pancreatic Adenocarcinoma. JOURNAL OF ONCOLOGY 2022; 2022:1934381. [PMID: 35607327 PMCID: PMC9123419 DOI: 10.1155/2022/1934381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/24/2022] [Indexed: 11/18/2022]
Abstract
Pancreatic adenocarcinoma (PAAD) is a major threat to people's health. PRDM1 is a transcription factor with multiple functions, and its functions have been validated in a variety of tumors; however, there are few studies reported on PRDM1 in PAAD. Using the GEPIA2 database, this research found that PRDM1 expression in PAAD was significantly higher than that in normal pancreatic tissue. The Kaplan-Meier Plotter database showed that high expression of PRDM1 in PAAD has a poor prognosis, suggesting that PRDM1 may be a potential prognostic marker in PAAD. The cBioPortal database shows that the expression of PRDM1 in PAAD is significantly correlated with its methylation degree. Further analysis on the coexpressed genes of PRDM1 in PAAD was performed by using LinkedOmics database to explore potential mechanisms. Based on gene enrichment analysis, PRDM1 was implicated in many pathways involved in tumor progression. In the construction of a PPI network of PRDM1 and its coexpressed gene protein via the STRING database, we found that PRDM1 may be involved in the pathogenesis and development of PAAD. TIMER database suggested that a high level of PRDM1 has a significant positive correlation with macrophages, neutrophils, and DCs. Potential methylation sites of PRDM1 were found through DNMIVD database, and MethSurv database explored eight sites which were significantly related with the prognosis of PAAD. In conclusion, PRDM1 may work as a prognostic marker or even provide a potential therapeutic strategy in PAAD.
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17
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Kim SI, Chaurasiya S, Sivanandam V, Kang S, Park AK, Lu J, Yang A, Zhang Z, Bagdasarian IA, Woo Y, Morgan JT, Yin Z, Fong Y, Warner SG. Priming stroma with a vitamin D analog to optimize viroimmunotherapy for pancreatic cancer. Mol Ther Oncolytics 2022; 24:864-872. [PMID: 35317522 PMCID: PMC8914466 DOI: 10.1016/j.omto.2022.02.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 02/19/2022] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer resistance to immunotherapies is partly due to deficits in tumor-infiltrating immune cells and stromal density. Combination therapies that modify stroma and recruit immune cells are needed. Vitamin D analogs such as calcipotriol (Cal) decrease fibrosis in pancreas stroma, thus allowing increased chemotherapy delivery. OVs infect, replicate in, and kill cancer cells and recruit immune cells to immunodeficient microenvironments. We investigated whether stromal modification with Cal would enhance oncolytic viroimmunotherapy using recombinant orthopoxvirus, CF33. We assessed effect of Cal on CF33 replication using pancreas ductal adenocarcinoma (PDAC) cell lines and in vivo flank orthotopic models. Proliferation assays showed that Cal did not alter viral replication. Less replication was seen in cell lines whose division was slowed by Cal, but this appeared proportional to cell proliferation. Three-dimensional in vitro models demonstrated decreased myofibroblast integrity after Cal treatment. Cal increased vascular lumen size and immune cell infiltration in subcutaneous models of PDAC and increased viral delivery and replication. Cal plus serial OV dosing in the syngeneic Pan02 model caused more significant tumor abrogation than other treatments. Cal-treated tumors had less dense fibrosis, enhanced immune cell infiltration, and decreased T cell exhaustion. Calcipotriol is a possible adjunct for CF33-based oncolytic viroimmunotherapy against PDAC.
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Affiliation(s)
- Sang-In Kim
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Shyambabu Chaurasiya
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Venkatesh Sivanandam
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Seonah Kang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Anthony K Park
- Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Jianming Lu
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Annie Yang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Zhifang Zhang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Isabella A Bagdasarian
- Department of Bioengineering, University of California, Riverside, Riverside, CA 92521, USA
| | - Yanghee Woo
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.,Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Joshua T Morgan
- Department of Bioengineering, University of California, Riverside, Riverside, CA 92521, USA
| | - Zhirong Yin
- Pathology Core, Department of Pathology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Yuman Fong
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.,Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Susanne G Warner
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.,Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
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18
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Rajpurohit T, Bhattacharya S. Moving Towards Dawn: KRas Signaling and Treatment in Pancreatic Ductal Adenocarcinoma. Curr Mol Pharmacol 2022; 15:904-928. [PMID: 35088684 DOI: 10.2174/1874467215666220128161647] [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: 07/26/2021] [Revised: 10/20/2021] [Accepted: 11/17/2021] [Indexed: 12/24/2022]
Abstract
"Pancreatic ductal adenocarcinoma (PDAC)" is robust, nearly clueless, and all-around deadly among all tumors. Below 10 %, the general 5-year endurance period has remained adamantly unaltered in the last 30 years, regardless of enormous clinical and therapeutic endeavors. The yearly number of deaths is more than the number of recently analyzed cases. Not a classic one, but "Carbohydrate Antigen CA19- 9" remains the prevailing tool for diagnosis. MicroRNAs and non-invasive techniques are now incorporated for the effective prognosis of PDAC than just CA19-9. Mutated "Rat sarcoma virus Ras" conformation "V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog KRas" is 95 % accountable for PDAC, and its active (GTP-bound) formation activates signaling cascade comprising "Rapidly accelerated fibrosarcoma Raf"/"Mitogen-activated protein kinase MEK"/ "Extracellular signal-regulated kinase ERK" with "Phosphoinositide 3-kinase PI3K"/ "protein kinase B Akt"/ "mammalian target of rapamycin mTOR" pathways. KRas has acquired the label of 'undruggable' since the crosstalk in the nexus of pathways compensates for Raf and PI3K signaling cascade blocking. It is arduous to totally regulate KRascoordinated PDAC with traditional medicaments like "gemcitabine GEM" plus nabpaclitaxel/ FOLFIRINOX. For long-haul accomplishments aiming at KRas, future endeavors should be directed to combinatorial methodologies to adequately block KRas pathways at different standpoints. Currently they are contributing to healing PDAC. In this review article, we outline the function of KRas in carcinogenesis in PDAC, its signaling cascade, former techniques utilized in hindering Kras, current and future possibilities for targeting Kras.
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Affiliation(s)
- Tarun Rajpurohit
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra 425405, India
| | - Sankha Bhattacharya
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra 425405, India
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19
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Sammallahti H, Kokkola A, Rezasoltani S, Ghanbari R, Asadzadeh Aghdaei H, Knuutila S, Puolakkainen P, Sarhadi VK. Microbiota Alterations and Their Association with Oncogenomic Changes in Pancreatic Cancer Patients. Int J Mol Sci 2021; 22:12978. [PMID: 34884776 PMCID: PMC8658013 DOI: 10.3390/ijms222312978] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is an aggressive disease with a high mortality and poor prognosis. The human microbiome is a key factor in many malignancies, having the ability to alter host metabolism and immune responses and participate in tumorigenesis. Gut microbes have an influence on physiological functions of the healthy pancreas and are themselves controlled by pancreatic secretions. An altered oral microbiota may colonize the pancreas and cause local inflammation by the action of its metabolites, which may lead to carcinogenesis. The mechanisms behind dysbiosis and PC development are not completely clear. Herein, we review the complex interactions between PC tumorigenesis and the microbiota, and especially the question, whether and how an altered microbiota induces oncogenomic changes, or vice versa, whether cancer mutations have an impact on microbiota composition. In addition, the role of the microbiota in drug efficacy in PC chemo- and immunotherapies is discussed. Possible future scenarios are the intentional manipulation of the gut microbiota in combination with therapy or the utilization of microbial profiles for the noninvasive screening and monitoring of PC.
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Affiliation(s)
- Heidelinde Sammallahti
- Department of Pathology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland;
- Department of Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland; (A.K.); (P.P.)
| | - Arto Kokkola
- Department of Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland; (A.K.); (P.P.)
| | - Sama Rezasoltani
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box 1985717411, Iran;
| | - Reza Ghanbari
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Science, Tehran P.O. Box 1411713135, Iran;
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box 1985717411, Iran;
| | - Sakari Knuutila
- Department of Pathology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland;
| | - Pauli Puolakkainen
- Department of Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland; (A.K.); (P.P.)
| | - Virinder Kaur Sarhadi
- Department of Oral and Maxillofacial Diseases, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland;
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20
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Multiplex Quantitative Analysis of Tumor-Infiltrating Lymphocytes, Cancer-Associated Fibroblasts, and CD200 in Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13215501. [PMID: 34771664 PMCID: PMC8583434 DOI: 10.3390/cancers13215501] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 10/27/2021] [Accepted: 10/29/2021] [Indexed: 11/16/2022] Open
Abstract
Pancreatic cancer is marked by a desmoplastic tumor microenvironment and low tumor immunogenicity, making it difficult for immunotherapy drugs to improve outcomes for patients. Tumor-infiltrating lymphocytes (TILs) and cancer-associated fibroblasts (CAFs) are seen in the tumor microenvironment of patients with pancreatic ductal adenocarcinoma (PDAC). In this work, we sought to characterize the expression levels and potential prognostic value of TILs (CD4, CD8, and CD20) and CAFs (Thy-1, FAP, and SMA) in a large retrospective cohort of PDAC patients. Additionally, we investigated the expression levels and prognostic significance of CD200, an immunoinhibitory protein that has shown interest as a potential target for immune checkpoint blockade. We measured the expression levels of these seven proteins with multiplexed immunofluorescence staining and quantitative immunofluorescence (QIF). We found CD8 and FAP to be independent predictors of progression-free survival and overall survival. CD200 was found to be heterogeneously expressed in both the tumor and stromal compartments of PDAC, with the majority of patients having positive stromal expression and negative tumor expression. This work demonstrates the potential clinical utility of CD8 and FAP in PDAC patients, and it sheds light on the expression patterns of CD200 in pancreatic cancer as the protein is being tested as a target for immune checkpoint blockade.
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Intraductal Papillary Mucinous Carcinoma Versus Conventional Pancreatic Ductal Adenocarcinoma: A Comprehensive Review of Clinical-Pathological Features, Outcomes, and Molecular Insights. Int J Mol Sci 2021; 22:ijms22136756. [PMID: 34201897 PMCID: PMC8268881 DOI: 10.3390/ijms22136756] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 06/18/2021] [Accepted: 06/20/2021] [Indexed: 12/18/2022] Open
Abstract
Intraductal papillary mucinous neoplasms (IPMN) are common and one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC). PDAC derived from an IPMN is called intraductal papillary mucinous carcinoma (IPMC) and defines a subgroup of patients with ill-defined specificities. As compared to conventional PDAC, IPMCs have been associated to clinical particularities and favorable pathological features, as well as debated outcomes. However, IPMNs and IPMCs include distinct subtypes of precursor (gastric, pancreato-biliary, intestinal) and invasive (tubular, colloid) lesions, also associated to specific characteristics. Notably, consistent data have shown intestinal IPMNs and associated colloid carcinomas, defining the “intestinal pathway”, to be associated with less aggressive features. Genomic specificities have also been uncovered, such as mutations of the GNAS gene, and recent data provide more insights into the mechanisms involved in IPMCs carcinogenesis. This review synthetizes available data on clinical-pathological features and outcomes associated with IPMCs and their subtypes. We also describe known genomic hallmarks of these lesions and summarize the latest data about molecular processes involved in IPMNs initiation and progression to IPMCs. Finally, potential implications for clinical practice and future research strategies are discussed.
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Phan T, Nguyen VH, Buettner R, Morales C, Yang L, Wong P, Tsai W, Salazar MD, Gil Z, Diamond DJ, Rabinowitz JD, Rosen S, Melstrom LG. Inhibition of de novo pyrimidine synthesis augments Gemcitabine induced growth inhibition in an immunocompetent model of pancreatic cancer. Int J Biol Sci 2021; 17:2240-2251. [PMID: 34239352 PMCID: PMC8241727 DOI: 10.7150/ijbs.60473] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 05/18/2021] [Indexed: 12/13/2022] Open
Abstract
Leflunomide (Lef) is an agent used in autoimmune disorders that interferes with DNA synthesis. De Novo pyrimidine synthesis is a mechanism of Gemcitabine (Gem) resistance in pancreatic cancer. This study aims to assess the efficacy and changes in the tumor microenvironment of Lef monotherapy and in combination with Gem, in a syngeneic mouse model of pancreatic cancer. Methods: MTS proliferation assays were conducted to assess growth inhibition by Gem (0-20 nM), Lef (0-40 uM) and Gem+Lef in KPC (KrasLSL.G12D/+;p53R172H/+; PdxCretg/+) cells in vitro. An in vivo heterotopic KPC model was used and cohorts were treated with: PBS (control), Gem (75 mg/kg/q3d), Lef (40 mg/kg/d), or Gem+Lef. At d28 post-treatment, tumor burden, proliferation index (Ki67), and vascularity (CD31) were measured. Changes in the frequency of peripheral and intratumoral immune cell subsets were evaluated via FACS. Liquid chromatography-mass spectrometry was used for metabolomics profiling. Results: Lef inhibits KPC cell growth and synergizes with Gem in vitro (P<0.05; Combination Index 0.44 (<1 indicates synergy). In vivo, Lef alone and in combination with Gem delays KPC tumor progression (P<0.001). CTLA-4+T cells are also significantly decreased in tumors treated with Lef, Gem or in combination (Gem+Lef) compared to controls (P<0.05). Combination therapy also decreased the Ki67 and vascularity (P<0.01). Leflunomide inhibits de novo pyrimidine synthesis both in vitro (p<0.0001) and in vivo (p<0.05). Conclusions: In this study, we demonstrated that Gem+Lef inhibits pancreatic cancer growth, decrease T cell exhaustion, vascularity and as proof of principle inhibits de novo pyrimidine synthesis. Further characterization of changes in adaptive immunity are necessary to characterize the mechanism of tumor growth inhibition and facilitate translation to a clinical trial.
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Affiliation(s)
- Thuy Phan
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010
| | - Vu H. Nguyen
- Department of Hematology, City of Hope National Medical Center, Duarte, CA 91010
| | - Ralf Buettner
- Department of Hematology, City of Hope National Medical Center, Duarte, CA 91010
| | - Corey Morales
- Department of Hematology, City of Hope National Medical Center, Duarte, CA 91010
| | - Lifeng Yang
- Lewis Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, NJ 08544
| | - Paul Wong
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010
| | - Weiman Tsai
- Department of Hematology, City of Hope National Medical Center, Duarte, CA 91010
| | | | - Ziv Gil
- Rambam Medical Center, Israel
| | - Don J Diamond
- Department of Hematology, City of Hope National Medical Center, Duarte, CA 91010
| | - Joshua D. Rabinowitz
- Lewis Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, NJ 08544
| | - Steven Rosen
- Department of Hematology, City of Hope National Medical Center, Duarte, CA 91010
| | - Laleh G. Melstrom
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010
- ✉ Corresponding author: Laleh Melstrom MD, City of Hope National Medical Center, Department of Surgery and Immuno-oncology, 1500 E Duarte Road, Duarte, CA 91010. E-mail: ; Phone: 626 218 0282; Fax: 626 218 1113
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