The immune suppressive tumor microenvironment affects efficacy of radio-immunotherapy in breast-to-brain metastasis

The tumor microenvironment in brain metastases is characterized by high myeloid cell content with immune-suppressive and cancer-permissive functions. Moreover, brain metastases induce the recruitment of lymphocytes. Despite their presence, T cell-directed therapies fail to elicit effective anti-tumor immune responses. Here we seek to evaluate the applicability of radio-immunotherapy to modulate tumor immunity and overcome inhibitory effects that diminish anti-cancer activity. Radiotherapy-induced immune modulation resulted in an increase in cytotoxic T cell numbers and prevented the induction of lymphocyte-mediated immune suppression. Radio-immunotherapy led to significantly improved tumor control with prolonged median survival in experimental breast-to-brain metastases. However, long-term efficacy was not observed. Recurrent brain metastases showed accumulation of blood-borne PD-L1+ myeloid cells after radio-immunotherapy indicating the establishment of an immune-suppressive environment to counteract re-activated T cell responses. This finding was further supported by transcriptional analyses indicating a crucial role for monocyte-derived macrophages in mediating immune-suppression and regulating T cell function. Therefore, selective targeting of immune suppressive functions of myeloid cells is expected to be critical for improved therapeutic efficacy of radio-immunotherapy in brain metastases. RNA-Seq of FACS purified myeloid and lymphoid cells out of a syngeneic breast-to-brain metastasis (infl. Monocytes, monocyte-derived macrophages, microglia, CD4+, CD8+, B220+ cells) and their normal cellular counterparts (healthy microglia, peripheral blood monocytes, blood CD4, CD8, and B220 cells)