Lung Cancer–Intrinsic SOX2 Expression Mediates Resistance to Checkpoint Blockade Therapy by Inducing Treg-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. In this study, 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 (Treg). CD8+ T-cell exclusion depended on Treg-mediated suppression of tumor vasculature. Depleting tumor-infiltrating Tregs via glucocorticoid-induced TNF receptor–related protein 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 patients with non–small cell lung cancer with SOX2-dependent CD8+ T-cell exclusion would benefit from the depletion of glucocorticoid-induced TNFR-related protein–positive Tregs.