Modulation of Microglia and T Cell Interactions in Malignant Glioma

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ABSTRACT Immunotherapy has revolutionized cancer treatment by reversing the immune suppression of cytotoxic anti- tumor CD8+ effector T cells. However, glioblastoma patients have profound lymphopenia and immune checkpoint inhibition treatment does not restore T cell immune function. Extensive characterization by our group has demonstrated that glioblastoma is fundamentally different relative to other malignancies in its preferential enrichment of innate immune cells such as macrophages and microglia that are recruited to the tumor microenvironment. These innate immune cells are tumor supportive. In a genetically-engineered mouse model (GEMM) of glioblastoma we recapitulated lympophenia using a CD8 knockout (KO) background, and found marked enrichment of PD-1 expressing macrophages in the murine glioma microenvironment – similar to observations made in human glioblastoma patients. We evaluated the effect of anti-PD-1 Ab delivered intravenously in glioblastoma-bearing wild-type mice and in the CD8 KO background and found therapeutic benefit even in the absence of the CD8 effector T cell. Both peripheral monocyte-derived macrophages and resident microglia were reduced within the glioblastoma microenvironment in mice treated with the anti-PD-1 Ab. As such, our overall study hypothesis is that anti-PD-1 exerts therapeutic immune modulatory effects against glioblastoma through innate immunity in the central nervous system (CNS). This proposal will address multiple crucial questions to the field including: 1) Does the anti-PD-1 Ab cross into the CNS to exert a therapeutic effect; 2) what immune cells, other than the CD8 T cell, are contributing to the therapeutic effect of this agent; 3) are the immune cells that are mediating the therapeutic effect arising from the periphery or are they intrinsic to the CNS; and 4) how does the glioblastoma immune microenvironment change in response to treatment? To address these questions, we will use contemporary murine models of glioma that closely approximate human glioblastoma and manipulate both the innate and adaptive immune systems to dissect the impact and importance of each in the context of anti-PD-1 treatment. Validation will be carried out using data from human subjects treated with anti-PD-1. By clarifying the mechanistic role of anti-PD-1 therapeutic activity, we may identify the subset of glioblastoma patients that are capable of responding to this type of strategy. This is a significant area of unmet need if glioblastoma patients are to benefit from immunotherapy. These studies may also reveal that anti-PD-1 treatment has a dual role on both the innate and adaptive immune system and when one arm is not operational this agent toggles its modulatory properties to the dominant immune arm.