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

Abstract Tumor cell–intrinsic signaling pathways can drastically affect the tumor immune microenvironment, 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 and T-cell infiltration creating “cold” tumors. However, clinical evidence suggests that excluding cytotoxic T cells from the tumor core also mediates immune evasion. Here, we find that tumor cell–intrinsic SOX2 signaling in non-small cell lung cancer induces the exclusion of cytotoxic T cells from the tumor core and promotes resistance to checkpoint blockade therapy. Mechanistically, tumor cell–intrinsic SOX2 expression upregulates CCL2 in tumor cells, resulting in increased recruitment of regulatory T cells. CD8+ T-cell exclusion depended 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, when combined with checkpoint blockade therapy, reduced tumor growth. These results show that tumor cell–intrinsic SOX2 expression in lung cancer serves as a mechanism of immunotherapy resistance and provide evidence to support future studies investigating whether NSCLC patients with SOX2-dependent CD8+ T-cell exclusion would benefit from the depletion of GITR+ Tregs.