High-Dose per Fraction Radiotherapy Induces Both Anti-Tumor Immunity and Immunosuppressive Responses in Prostate Tumors.

PURPOSE The use of high-dose per fraction radiotherapy (RT) delivered as stereotactic body radiotherapy is a standard of care for prostate cancer. It is hypothesized that high-dose RT may enhance or suppress tumor-reactive immunity. The objective of this study is to assess both anti-tumor and immunosuppressive effects induced by high-dose RT in prostate cancer co-clinical models, and ultimately, to test if a combination of RT with targeted immunotherapy can enhance anti-tumor immunity. EXPERIMENTAL DESIGN We studied the effects of high-dose per fraction RT with and without anti-Gr-1 using syngeneic murine allograft prostate cancer models. The dynamic change of immune populations, including tumor-infiltrating lymphocytes (TIL), T-regulatory cells (Treg), and myeloid-derived suppressive cells (MDSC) was evaluated using flow cytometry and immunohistochemistry. RESULTS Co-clinical prostate cancer models demonstrated that high-dose per fraction RT induced a rapid increase of tumor-infiltrating MDSCs and a subsequent rise of CD8 TILs and circulating CD8 T effector memory cells. These radiation-induced CD8 TILs were more functionally potent than those from non-irradiated controls. While systemic depletion of MDSCs by anti-Gr-1 effectively prevented MDSC tumor infiltration, it did not enhance RT-induced anti-tumor immunity due to a compensatory expansion of Treg-mediated immune suppression. CONCLUSIONS In allograft prostate cancer models, high-dose RT induced an early rise of MDSCs, followed by a transient increase of functionally active CD8 TILs. However, systemic depletion of MDSC did not augment the anti-tumor efficacy of high-dose RT due to a compensatory Treg response, indicating blocking both MDSC and Treg might be necessary to enhance RT-induced anti-tumor immunity.