Journal
EMBO MOLECULAR MEDICINE
Volume 13, Issue 5, Pages -Publisher
WILEY
DOI: 10.15252/emmm.202013412
Keywords
brain cancer; checkpoint inhibitors; microglia; tumor microenvironment; tumor‐ associated macrophages
Categories
Funding
- German Federal Ministry of Health
- Ministry of Higher Education, Research and the Arts of the State of Hesse (HMWK)
- LOEWE Center Frankfurt Cancer Institute (FCI)
- German Cancer Aid (Max-Eder Junior Group Leader Program) [70111752]
- German Research Foundation [SE2234/3-1]
- Beug Foundation for Metastasis Research
- Dr. Bodo Sponholz Foundation
- Projekt DEAL
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The tumor microenvironment in brain metastases is characterized by high myeloid cell content associated with immune suppressive and cancer-permissive functions. Radio-immunotherapy resulted in an increase in cytotoxic T-cell numbers and prevented the induction of lymphocyte-mediated immune suppression. However, long-term efficacy was not observed.
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.
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