Interrogating the immune-modulating roles of radiation therapy for a rational combination with immune-checkpoint inhibitors in treating pancreatic cancer

Background Radiation 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 (alpha PD-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. Methods We developed and used a mouse syngeneic orthotopic model of PDAC suitable for hypofractionated RT experiments. Results The combination therapy of alpha PD-1 and RT improved survival. The dual combination of RT/IDO1i and triple combination of RT/alpha PD-1/IDO1i did not improve survival compared with RT/alpha PD-1, although all of these combinations offer similar local tumor control. RT/alpha PD-1 appeared to result in the best systemic interferon-gamma response compared with other treatment groups and the highest local expression of immune-activation genes, includingCd28andIcos. Conclusion Our 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.