한빛사 논문
Chang Gon Kim1,*, Mi Jang2,*, Youngun Kim1, Galam Leem1, Kyung Hwan Kim1, Hoyoung Lee1, Tae-Shin Kim1, Seong Jin Choi1, Hyung-Don Kim1, Ji Won Han1, Minsuk Kwon1, Jong Hoon Kim1, Andrew J. Lee3, Su Kyung Nam3, Seok-Joo Bae1, Sat Byol Lee4, Sang Joon Shin5, Sung Ho Park6, Joong Bae Ahn5, Inkyung Jung3, Kang Young Lee4, Su-Hyung Park1, Hoguen Kim2,†, Byung Soh Min4,† and Eui-Cheol Shin1,†
1 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
2 Department of Pathology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03772, Republic of Korea.
3 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
4 Department of Surgery, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03772, Republic of Korea.
5 Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03772, Republic of Korea.
6 School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea.
†Corresponding author : Eui-Cheol Shin, Byung Soh Min, Hoguen Kim
* These au thors contributed equally to this work.
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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