Lung cancer-intrinsic SOX2 expression mediates resistance to checkpoint blockade therapy by inducing Treg-dependent CD8 + T cell exclusion
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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 affect myeloid cell infiltration and downstream T cell infiltration. Clinical evidence suggests that the exclusion of cytotoxic T cells from the tumor core likewise mediates resistance. Here, we find that tumor cell-intrinsic SOX2 expression 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 (GITR) restored CD8 + T cell infiltration and reduced tumor growth in combination with checkpoint blockade therapy.
Significance
We identified tumor cell-intrinsic SOX2 expression in lung cancer as a mechanism of resistance to immunotherapy. SOX2 expression increases regulatory T cell populations in the TME, negatively affecting the tumor vasculature and blunting CD8 + T cell infiltration into the tumor core. This effect could be reverted by targeting regulatory T cells with anti-GITR therapy.
