Antigen-presenting astrocytes play a role in modulating immune responses in brain metastasis

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Yael Zait1, Lea Monteran1, Yeela Scharff1, Elia Balouka1, Sameeha Mittwali2, Gali Yanovich-Arad2, Marva Langer1, Nour Ershaid1, Hila Doron1, Omer Adler1, Shlomit Yust Katz3, Tami Gaiger2, Leeat Keren2, Yaron Carmi and Neta Erez1
 

1 Department of Pathology, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel.

2 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

3 Neuro-Oncology Unit, Davidoff Cancer Center at Rabin Medical Center and Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel.

 

The main cause of cancer mortality is metastasis to distant organs, frequently to brain, encompassing grim prognosis. Despite progress in targeted and immune therapies, brain metastasis (BrM) response rates to therapy are low and improved therapeutic concepts are urgently needed. The tumor microenvironment (TME) plays a pivotal role in facilitating metastasis. Therefore, to effectively combat or prevent brain metastatic relapse, it is critical to deepen our understanding of the unique brain microenvironment.
We recently discovered a novel subpopulation of astrocytes and found that they are capable of presenting antigenic peptides to CD4+ helper T cells via their expression of major histocompatibility complex type II (MHC-II), as well as co-stimulatory molecules, typically expressed only by professional antigen presenting cells (APCs). Expression of MHC-II in astrocytes was previously suggested in Parkinson’s disease, but was not previously reported in cancer. Intrigued by these unexpected findings, we validated the expression of MHC-II and co-stimulatory molecules in this subpopulation of antigen-presenting astrocytes (apAstrocytes) in mouse and in human brain metastasis, and characterized their function. Importantly, we found that apAstrocytes can uptake tumor antigen, interact with, and affect T cell activity, leading to cytotoxic killing activity. Moreover, we found that MHC-II expression in astrocytes was induced by IFNg signaling, but inhibited by secreted factors from brain-metastasizing cancer cells. Expression of MHC-II in astrocytes inversely correlated with brain metastatic burden, suggesting that apAstrocytes play an important role in shaping the immune response in brain metastasis. Importantly, specific targeting of MHC-II in astrocytes in vivo resulted in enhanced metastatic burden and reduced T cell activation. 

 

Our findings provide novel insights on astrocyte function, highlight stromal-immune interactions in the brain metastatic landscape and implicate apAstrocytes as novel players in shaping anti-tumor immunity. This knowledge can be harnessed to improve the efficacy of immune therapies for treatment of brain metastasis