VEGF-A drives TOX-dependent T cell exhaustion in anti-PD-1-resistant microsatellite stable colorectal cancers.

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.

• Authors: Chang Gon Kim, Mi Jang, Youngun Kim, Galam Leem, Kyung Hwan Kim, Hoyoung Lee, Tae-Shin Kim, Seong Jin Choi, Hyung-Don Kim, Ji Won Han, Minsuk Kwon, Jong Hoon Kim, Andrew J Lee, Su Kyung Nam, Seok-Joo Bae, Sat Byol Lee, Sang Joon Shin, Sung Ho Park, Joong Bae Ahn, Inkyung Jung, Kang Young Lee, Su-Hyung Park, Hoguen Kim, Byung Soh Min, Eui-Cheol Shin
• Journal: Science immunology (Sci Immunol) Vol. 4 Issue 41 (11 08 2019) ISSN: 2470-9468 [Electronic] United States
• PMID: 31704735 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• High Mobility Group Proteins
• Homeodomain Proteins
• PDCD1 protein, human
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Rhox8 protein, mouse
• TOX protein, human
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Caco-2 Cells
• Colorectal Neoplasms (immunology, pathology)
• High Mobility Group Proteins (immunology)
• Homeodomain Proteins (immunology)
• Humans
• Mice
• Mice, Inbred C57BL
• Microsatellite Repeats (immunology)
• Programmed Cell Death 1 Receptor (immunology)
• T-Lymphocytes (immunology)
• Vascular Endothelial Growth Factor A (immunology)