VEGF-A drives TOX-dependent T cell exhaustion in anti-PD-1-resistant microsatellite stable colorectal cancers
Chang Gon Kim1, Mi Jang2, Youngun Kim1
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
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.
Insights
Microsatellite stable colorectal cancer (CRC) shows T cell exhaustion driven by vascular endothelial growth factor-A (VEGF-A). Combining PD-1 and VEGF-A blockade restores T cell function and improves CRC tumor control.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Immune checkpoint blockade (ICB) therapies are effective in cancer treatment but face resistance.
- Microsatellite stable (MSS) colorectal cancer (CRC) is a major challenge due to PD-1 blockade resistance.
- Tumor-infiltrating T cells in MSS CRC exhibit severe exhaustion.
Purpose of the Study:
- To investigate the mechanisms of T cell exhaustion in MSS CRC.
- To identify therapeutic strategies to overcome PD-1 blockade resistance in MSS CRC.
Main Methods:
- Analysis of tumor-infiltrating T cells in MSS CRC.
- Investigating the role of vascular endothelial growth factor-A (VEGF-A) and transcription factor TOX in T cell exhaustion.
- In vitro, ex vivo, and in vivo mouse studies combining PD-1 and VEGF-A blockade.
Main Results:
- A wound healing signature is upregulated in MSS CRC.
- VEGF-A drives T cell exhaustion by inducing TOX expression and an exhaustion-specific transcription program.
- Combined PD-1 and VEGF-A blockade restores anti-tumor T cell functions.
- Combined blockade leads to improved control of MSS CRC tumors in mouse models.
Conclusions:
- VEGF-A is a key driver of T cell exhaustion in PD-1 blockade-resistant MSS CRC.
- Combined PD-1 and VEGF-A blockade represents a promising therapeutic strategy for MSS CRC.
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