TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells.

Immunotherapies against brain metastases have shown clinical benefits mainly when applied to locally asymptomatic patients. It is currently unclear why responses to this therapy drop in symptomatic brain metastases, since the use of corticoids is not consistently involved. We report here that a subpopulation within STAT3+ brain metastasis-associated astrocytes is responsible to block the anti-tumor activity of infiltrating CD8+ T cells. The underlying molecular crosstalk involving astrocyte-secreted TIMP1 signaling on CD63+ CD8+ T cells proves a strong immunomodulatory role of astrocytes in the context of brain metastases. By using genetic and pharmacologic approaches applied not only to mouse models, but also to alive human brain metastases we conclude that a combined immunotherapy blocking this local immunosuppressive hub could benefit patients with symptomatic brain metastases. Furthermore, the detection of TIMP1 in the CSF provides a biomarker to select patients for this therapeutic approach. Our findings uncover the importance of dissecting the heterogeneity within the microenvironment at the functional level and the emerging cellular networks to improve the efficacy of organ-specific therapies in metastasis.