Kim and Jang et al. showed increased vascular endothelial growth factor-A (VEGF-A) expression in plasma and tumor cells of patients with microsatellite-stable (MSS) vs. -unstable colorectal cancer (CRC). VEGF-A induced DNA-binding factor TOX to drive the exhaustion-related transcription program, including PD-1, TIM3, LAG3, and TIGIT, most notably by sparse tumor-specific VEGFR2+ MSS-CRC tumor-infiltrating CD8+ T cells (TILs). Silencing TOX in TILs reduced exhaustion marker expression and restored IFNγ and TNFα responses in vitro. Dual blockade of PD-1 and VEGF-A revitalized anti-MSS-CRC tumor activity in vitro, ex vivo, and in mice.
Contributed by Paula Hochman
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.