Lung cancer-intrinsic SOX2 expression mediates resistance to checkpoint blockade therapy by inducing Treg cell-dependent CD8+ T cell exclusion

Tumor-intrinsic signaling pathways can drastically affect the tumor immune microenvironment (TME), promoting tumor progression and resistance to immunotherapy by excluding immune cell populations from the tumor. Several tumor-cell intrinsic pathways have been reported to modulate myeloid cell infiltration and subsequent T cell recruitment. Clinical evidence suggests that excluding cytotoxic T cells from the tumor core mediates resistance to immunotherapy. Here, we find that tumor cell-intrinsic SOX2 expression in non-small cell lung cancer induces the exclusion of cytotoxic T cells from the tumor core and promotes resistance to checkpoint blockade therapy. CD8+ T cell exclusion was dependent on regulatory T cell-mediated suppression of tumor vasculature. Depleting tumor-infiltrating regulatory T cells via Glucocorticoid-Induced TNFR-Related protein (GITR) restored CD8+ T cell infiltration and, combined with checkpoint blockade therapy, reduced tumor growth. Comparison of gene expression in three replicates each of the KPS2.SIY (expressing SIY-GFP and Sox2) and KPCt.SIY (expressing SIY-GFP) cells derived from the mouse lung adenocarcinoma KP parental cell line driven by KrasG12D and Trp53-/- deletion.