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Trawling for drivers of T cell exhaustion
Although checkpoint blockade has markedly changed the landscape of cancer therapeutics, not all tumors are responsive to immunotherapy. Here, Kim et al. studied T cell exhaustion in two distinct types of colorectal cancers (CRCs), microsatellite instability–high (MSI) CRCs that are responsive to PD-1 blockade and microsatellite stable (MSS) CRCs that are resistant to PD-1 centric therapies. Although tumor-infiltrating T cells in both types of CRCs were exhausted, they report T cell exhaustion in MSS but not MSI CRCs to be driven by VEGF-A. Using mouse models, they demonstrate that combined blockade of both PD-1 and VEGF-A makes MSS CRCs sensitive to PD-1 blockade. Their study highlights how in-depth characterization of checkpoint-resistant tumors can lead to identification of pathways to sensitize them to immunotherapy.
Abstract
Although immune checkpoint blockade therapies have demonstrated clinical efficacy in cancer treatment, harnessing this strategy is largely encumbered by resistance in multiple cancer settings. Here, we show that tumor-infiltrating T cells are severely exhausted in the microsatellite stable (MSS) colorectal cancer (CRC), a representative example of PD-1 blockade–resistant tumors. In MSS CRC, we found wound healing signature to be up-regulated and that T cell exhaustion is driven by vascular endothelial growth factor-A (VEGF-A). We report that VEGF-A induces the expression of transcription factor TOX in T cells to drive exhaustion-specific transcription program in T cells. Using a combination of in vitro, ex vivo, and in vivo mouse studies, we demonstrate that combined blockade of PD-1 and VEGF-A restores the antitumor functions of T cells, resulting in better control of MSS CRC tumors.
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