Abstract
Glioma evolution is associated with disease progression and therapeutic resistance. We recently identified a group of MAPK-driven glioma with CDKN2A homozygous deletion that are low-grade and immune enriched, characterized by the presence of antigen presenting cells (APCs) and activated cytotoxic CD8⁺ T cells. Over time, however, these tumors can progress to aggressive, higher-grade tumors. While low-grade tumors may be amenable to immunotherapeutic strategies, it is unknown how the tumor and its microenvironment evolve. To investigate this, we tested human tumors before and after progression within the same patients (n=7) over time (longitudinally) and across patients (n=21) using transcriptomic and proteomic approaches. In neoplastic cells, genetic evolution was accompanied by increased tumor cell proliferation and differentially expressed genes were enriched for telomere organization and maintenance (RTEL1, TERC, HSP90) and response to hypoxia (VEGFA, VEGFC, HIF1A). In parallel, the immune response became predominantly immunosuppressive, marked by an expansion of immunosuppressive macrophages, a reduction in APCs, including dendritic cells, and transcriptional reprogramming of T cells. At progression, T cells displayed increased exhaustion, diminished cytotoxicity (reduced GZMA), and enhanced expression of immunosuppressive mediators (IL-10 and TGF-β). Using spatial proteomics and spatial transcriptomics, we investigated factors potentially driving tumor–immune co-evolution. With disease progression, reductions in APCs and activated CD8 T cells were associated with altered cell-cell signaling. CXCL16–CXCR6 signaling between APCs and T cells was decreased and CXCL14, a chemokine implicated in recruitment of both CD8 T cells and APCs to tumors, was decreased. Indeed, CXCL14 expression correlated with an increased CD11c expressing population of antigen presenting cells. Thus, tumor progression is accompanied by a coordinated evolution of both tumor and immune compartments, driven in part by changes in cell-cell communication within the tumor microenvironment. Ongoing studies are investigating how targeting these communication pathways within the tumor microenvironment may alter tumor evolution.