CD106 in tumor-specific exhausted CD8+ T cells mediates immunosuppression by inhibiting TCR signaling

  • Cancer Res. 2024 Apr 18. doi: 10.1158/0008-5472.CAN-23-0453.
Yuto Naoi  1 ,  Takao Morinaga  2 ,  Joji Nagasaki  3 ,  Ryo Ariyasu  4 ,  Youki Ueda  5 ,  Kazuo Yamashita  6 ,  Wenhao Zhou  3 ,  Shusuke Kawashima  7 ,  Katsushige Kawase  8 ,  Akiko Honobe-Tabuchi  9 ,  Takehiro Ohnuma  9 ,  Tatsuyoshi Kawamura  9 ,  Yoshiyasu Umeda  10 ,  Yu Kawahara  11 ,  Yasuhiro Nakamura  12 ,  Yukiko Kiniwa  13 ,  Osamu Yamasaki  14 ,  Satoshi Fukushima  15 ,  Masahito Kawazu  16 ,  Yutaka Suzuki  17 ,  Hiroyoshi Nishikawa  18 ,  Toyoyuki Hanazawa  19 ,  Mizuo Ando  5 ,  Takashi Inozume  7 ,  Yosuke Togashi  3
Affiliations
  • 1. Okayama University, Japan.
  • 2. Chiba Cancer Center, Chiba, Chiba, Japan.
  • 3. Okayama University, Okayama, Japan.
  • 4. Japanese Foundation For Cancer Research, Tokyo, Japan.
  • 5. Okayama University, Okayama, Okayama, Japan.
  • 6. KOTAI Biotechnologies, Inc., Suita, Japan.
  • 7. Chiba University, Chiba, Chiba, Japan.
  • 8. Chiba Cancer Center, Chiba-shi, Chiba, Japan.
  • 9. University of Yamanashi, Yamanashi, Japan.
  • 10. Saitama Medical University, Japan.
  • 11. Chiba University, Chiba, Japan.
  • 12. Saitama Medical University, Saitama, Japan.
  • 13. Shinshu University School of Medicine, Matsumoto, Japan.
  • 14. Shimane University Hospital, Izumo city, Shimane Pref., Japan.
  • 15. Kumamoto University, Kumamoto, Kumamoto, Japan.
  • 16. Chiba Cancer Center, Chiba, Japan.
  • 17. The University of Tokyo, Kashiwa, Chiba, Japan.
  • 18. National Cancer Centre, Chuo-ku, Tokyo, Japan.
  • 19. Graduate School of Medicine, Chiba University, Chiba, Japan.
PMID: 38635899 DOI: 10.1158/0008-5472.CAN-23-0453
Abstract

T cell exhaustion is a major contributor to Immunosuppression in the tumor microenvironment (TME). Blockade of key regulators of T cell exhaustion, such as PD-1, can reinvigorate tumor-specific T cells and activate anti-tumor immunity in various types of Cancer. Here, we identified that CD106 was specifically expressed in exhausted CD8+ T cells in the TME using single-cell RNA-sequencing. High CD106 expression in the TME in clinical samples corresponded to improved response to Cancer Immunotherapy. CD106 in tumor-specific T cells suppressed anti-tumor immunity both in vitro and in vivo, and loss of CD106 in CD8+ T cells suppressed tumor growth and improved response to PD-1 blockade. Mechanistically, CD106 inhibited T-cell receptor (TCR) signaling by interacting with the TCR/CD3 complex and reducing its surface expression. Together, these findings provide insights into the immunosuppressive role of CD106 expressed in tumor-specific exhausted CD8+ T cells, identifying it as a potential biomarker and therapeutic target for Cancer Immunotherapy.

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