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The immune suppressive microenvironment affects efficacy of radio‐immunotherapy in brain metastasis

Authors: Niesel, Katja; Schulz, Michael; Anthes, Julian; Alekseeva, Tijna; Macas, Jadranka; Salamero‐Boix, Anna; Möckl, Aylin; Oberwahrenbrock, Timm; Lolies, Marco; Stein, Stefan; Plate, Karl H; Reiss, Yvonne; Rödel, Franz; Sevenich, Lisa

Online: https://onlinelibrary.wiley.com/doi/10.15252/emmm.202013412

Issue: EMBO Mol Med . 2021 May 7;13(5):e13412.


The tumor microenvironment in brain metastases is characterized by high myeloid cell content associated 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 metastasis. 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.