Blockade of immune checkpoints e.g., by anti-PD1 or anti-PDL1 reactivates T cells and reinstates tumor cell killing by cytotoxic T cells. immune cells together with brain-resident cell-types, such as astrocytes, microglia, and neurons, form a highly complex and dynamic TME that affects tumor cell survival and modulates the mode of immune responses that are elicited by brain metastatic tumor cells. In this review, we will summarize recent findings on heterotypic interactions within the brain metastatic TME and highlight specific functions of brain-resident and recruited cells at different rate-limiting actions of the metastatic cascade. Based on the insight from recent studies, we will discuss new opportunities and challenges for TME-targeted and immunotherapies for BrM. (SCI) (48), further underpinning the context-dependent outcome of cellular interactions. In line with this obtaining, microglia-mediated blockade of an A1 astrocyte conversion was shown to be neuro-protective in a mouse model of sporadic Parkinson’s Disease (49). There is also evidence that RA are regulated by distinct T cell subsets in neuro-inflammatory conditions such as stroke, which then potentiates neurological recovery (50). While our understanding of astrocyte function in neurodegenerative disorders is usually steadily increasing, we are just at the beginning to decipher the underlying mechanisms of pro- or anti-tumor functions of astrocytes in BrM (51, 52). Induction of astrogliosis is Triisopropylsilane an early event during metastatic colonization and outgrowth. This early reaction is usually attributed to neuro-protection by delineating metastatic foci from the normal brain parenchyma. Valiente et al. proposed that early contacts between tumor cells and astrocytes lead to tumor cell death and clearance of the majority of tumor cells that enter the brain. In order to successfully colonize the brain, tumor cells have to acquire traits to block pro-apoptotic stimuli from astrocytes (53) (Physique 1; Box 2). On the other hand, there is accumulating Triisopropylsilane evidence that astrocytes promote distinct steps of the metastatic cascade, including initial seeding and support of tumor outgrowth (54C56). Moreover, astrocytes have been shown to protect tumor cells from chemotherapy (57). This process was shown to be Rabbit Polyclonal to TSC2 (phospho-Tyr1571) dependent on gap junction formation (57, 58). The importance of direct cellular connections between astrocytes and breast- or lung brain metastatic tumor cells via gap junctions was further exhibited by Chen et al. (59). In this context, gap junction formation was mediated by connexin43 (Cx43) and protocadherin (Pcdh7) and activated the innate immune response pathway cGAS-Sting (Cyclic GMP-AMP synthase-stimulator of interferon genes) leading to secretion of tumor-supportive cytokines such as IFN and TNF (Physique 1; Box 3). Functional co-option of RA by melanoma cells was further exemplified by Schwartz et al. (60). The authors exhibited in a melanoma brain metastasis model that astrogliosis is usually exploited by the tumor cells to support their growth (60). Astrocytes are also emerging as critical modulators of immune responses in BrM by interacting with brain-resident and recruited inflammatory cells. Priego et al. Triisopropylsilane recently proposed an important role of astrocytes in the modulation of innate and acquired immunity in BrM (61). The authors identified a subpopulation of RA with high STAT3 activation levels associated with BrM of different primary origin. STAT3 activation was shown to affect microglia and T cell functions, likely leading to the establishment of an immunosuppressive microenvironment (Physique 1; Box 5). CD74+ TAMs were previously shown to generate an immunosuppressive milieu by reducing the Triisopropylsilane secretion of IFN in glioma (62). More recently it was exhibited in BrM that CD74+.