Interrogating the immune-modulating roles of radiation therapy for a rational combination with immune-checkpoint inhibitors in treating pancreatic cancer
| Autor: | Nathan L. Cheadle, Michael Wichroski, Kenji Fujiwara, Brian Herbst, Keyu Li, Lei Zheng, MacKenzie Zarecki, Hao Jing, Stephen Muth, Neolle Jurcak, Elaine Bigelow, May Tun Saung, Jordan Blum, Alex B. Blair, Jennifer Koenitzer, Ding Ding, Linda Chen, Annie A. Wu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
tumors
0301 basic medicine Cancer Research Combination therapy medicine.medical_treatment Immunology gastroenterology Adenocarcinoma Mice 03 medical and health sciences 0302 clinical medicine Immune system Pancreatic cancer medicine Animals Humans Immunology and Allergy Immune Checkpoint Inhibitors RC254-282 radiotherapy Neoadjuvant therapy Pharmacology business.industry Neoplasms. Tumors. Oncology. Including cancer and carcinogens Basic Tumor Immunology Immunotherapy medicine.disease Blockade Radiation therapy Disease Models Animal 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research Molecular Medicine Female Pancreas business Carcinoma Pancreatic Ductal |
| Zdroj: | Journal for Immunotherapy of Cancer Journal for ImmunoTherapy of Cancer, Vol 8, Iss 2 (2020) |
| ISSN: | 2051-1426 |
| Popis: | BackgroundRadiation therapy (RT) has the potential to enhance the efficacy of immunotherapy, such as checkpoint inhibitors, which has dramatically altered the landscape of treatments for many cancers, but not yet for pancreatic ductal adenocarcinoma (PDAC). Our prior studies demonstrated that PD ligand-1 and indoleamine 2,3-dioxygenase 1 (IDO1) were induced on tumor epithelia of PDACs following neoadjuvant therapy including RT, suggesting RT may prime PDAC for PD-1 blockade antibody (αPD-1) or IDO1 inhibitor (IDO1i) treatments. In this study, we investigated the antitumor efficacy of the combination therapies with radiation and PD-1 blockade or IDO1 inhibition or both.MethodsWe developed and used a mouse syngeneic orthotopic model of PDAC suitable for hypofractionated RT experiments.ResultsThe combination therapy of αPD-1 and RT improved survival. The dual combination of RT/IDO1i and triple combination of RT/αPD-1/IDO1i did not improve survival compared with RT/αPD-1, although all of these combinations offer similar local tumor control. RT/αPD-1 appeared to result in the best systemic interferon-γ response compared with other treatment groups and the highest local expression of immune-activation genes, including Cd28 and Icos.ConclusionOur RT model allows examining the immune-modulatory effects of RT alone and in combination with immune-checkpoint inhibitors in the pancreas/local microenvironment. This study highlights the importance of choosing the appropriate immune-modulatory agents to be combined with RT to tip the balance toward antitumor adaptive immune responses. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|