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<p>Lymphocyte antigen-plasminogen activator urokinase receptor domain-containing protein 6B (Lypd6b) is a newly identified molecule associated with neuromodulation. However, the role of Lypd6b in regulating the tumor microenvironment and its impact on CD8<sup>+</sup> T cell-mediated antitumor immunity remain unknown. Here, we observe that Lypd6b expression is increased significantly in colorectal cancer (CRC) tumor tissues compared to normal tissues. Lypd6b is mainly expressed in CD8<sup>+</sup> T cells in tumor tissues. <i>Lypd6b</i> knockout (<i>Lypd6b</i><sup>−/−</sup>) mice are resistant to AOM/DSS-induced tumorigenesis. Furthermore, global deficiency or CD8<sup>+</sup> cell deficiency of Lypd6b inhibits MC38 or CMT-93 tumor growth and promotes the infiltration of CD8<sup>+</sup> T cells. Mechanistically, Lypd6b deficiency promotes activation and function of CD8<sup>+</sup> T cells in anti-tumor response with increased glycolysis and reduced oxidative phosphorylation in a PI3K/mTOR/LDHA pathway-dependent manner. Notably, Lypd6b deficient CD8<sup>+</sup> T cells have a more potent antitumor effect when combined with anti-PD1 antibody. Thus, Lypd6b as a negative regulator for T cell immunity promotes CRC development, providing a molecular target with therapeutic potential in CRC.</p>

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Lypd6b depletion promotes CD8+ T cell-mediated anti-tumor immunity via metabolic reprogramming in colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月11日

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  • Ting Liu,
  • Fanxin Zeng,
  • Zuyin Li,
  • Leirong Cheng,
  • Xuanxuan Yan,
  • Haiqiang Chen,
  • Qin Liu,
  • Xue Li,
  • Zhao Li,
  • Jiaheng Yao,
  • Dan Xu,
  • Zhinan Chen,
  • Fengchao Wang,
  • Jun Wang,
  • Jinhua Zhang

摘要

Lymphocyte antigen-plasminogen activator urokinase receptor domain-containing protein 6B (Lypd6b) is a newly identified molecule associated with neuromodulation. However, the role of Lypd6b in regulating the tumor microenvironment and its impact on CD8+ T cell-mediated antitumor immunity remain unknown. Here, we observe that Lypd6b expression is increased significantly in colorectal cancer (CRC) tumor tissues compared to normal tissues. Lypd6b is mainly expressed in CD8+ T cells in tumor tissues. Lypd6b knockout (Lypd6b−/−) mice are resistant to AOM/DSS-induced tumorigenesis. Furthermore, global deficiency or CD8+ cell deficiency of Lypd6b inhibits MC38 or CMT-93 tumor growth and promotes the infiltration of CD8+ T cells. Mechanistically, Lypd6b deficiency promotes activation and function of CD8+ T cells in anti-tumor response with increased glycolysis and reduced oxidative phosphorylation in a PI3K/mTOR/LDHA pathway-dependent manner. Notably, Lypd6b deficient CD8+ T cells have a more potent antitumor effect when combined with anti-PD1 antibody. Thus, Lypd6b as a negative regulator for T cell immunity promotes CRC development, providing a molecular target with therapeutic potential in CRC.