Abstract PL04-03: Germline and microbiome variants impact immunotherapy efficacy through modulation of myeloid cells

Abstract

Abstract Most cancers express tumor antigens that can be recognized by T cells of the host. The fact that cancers become clinically relevant and grow nonetheless implies that immune escape must occur to allow cancer outgrowth. We have observed two major phenotypes of human melanoma metastases based on gene expression profiling and confirmatory assays. One subgroup of patients has a T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN signature. In contrast, the other major subset lacks this phenotype and appears to display immune “exclusion”. Factors that influence the degree of spontaneous immune infiltration are being investigated, as sources of inter-patient heterogeneity. These include tumor cell-intrinsic oncogenic events, the composition of the gut microbiota, and polymorphisms in immune regulatory genes. We now know that each of these dimensions can be functionally important. The first tumor cell-intrinsic oncogenic pathway identified that mediates immune exclusion is the Wnt/β-catenin pathway. Tumors with active β-catenin fail to recruit Batf3-lineage dendritic cells into the tumor site. Regarding the commensal microbiota, mouse models identified commensal Bifidobacterium as one key component that augments spontaneous anti-tumor immunity and increases efficacy of anti-PD-L1 therapy in vivo. Similar analyses in human cancer patients revealed bacteria sequences enriched in anti-PD-1 responders, and also bacteria sequences enriched in non-responders. Fecal transfer into germ-free mice has confirmed a causal role for the gut microbiota in regulating immunotherapy efficacy. Recent experiments have revealed that one major mechanism by which gut microbes impact on distant ani-tumor immunity is through modulation of immune-regulatory myeloid cells, ie the M1/M2 ratio and MDSCs. Regarding germline variants, our first identified SNP connected to immune cell infiltration is in the PKCδ gene. Loss of function variants are associated with greater immune cell infiltration. PKCδ knockout hosts show improved immune-mediated tumor control and anti-PD-L1 efficacy, but with comparable T cell priming. However, activated T cell accumulation in the tumor microenvironment increases overtime, which is associated with a shift from M2 to M1. Myeloid cell-specific PKCδKO mice using LysM-Cre Tg mice recapitulate the phenotype. Thus, in each of these 3 instances, tumor and host factors impact on anti-tumor immunity by modulating myeloid cell participation—Batf3-DCs, MDSCs, and M1/M2 cells. Citation Format: Thomas F. Gajewski. Germline and microbiome variants impact immunotherapy efficacy through modulation of myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr PL04-03.