Scholarlink

<p>T cell exhaustion is a major barrier to effective cancer immunotherapy. Although immune checkpoint blockade can reinvigorate exhausted T cells, not all patients achieve long-term responses, partly due to the refractory nature of terminally exhausted T cells. Beyond persistent antigen stimulation, the environmental drivers of exhaustion remain to be thoroughly characterized. Here we identify CD47 upregulation in tumor-infiltrating exhausted CD8<sup>+</sup> T cells in both human and murine tumors. We reveal a novel role for the extracellular matrix protein thrombospondin-1 (TSP-1) in engaging CD47 on T cells to promote exhaustion. This interaction activates calcineurin–NFAT signaling, inducing upregulation of TOX and expression of inhibitory receptors, and impairing effector function during tumor progression. Importantly, disrupting the TSP-1–CD47 axis prevents T cell exhaustion and enhances tumor control. Our findings identify a novel pathway promoting T cell dysfunction and suggest that targeting the TSP-1–CD47 axis is a promising strategy to enhance T cell immunity and immunotherapy efficacy.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Thrombospondin-1–CD47 signaling contributes to the development of T cell exhaustion in cancer

  • 期刊论文

  • 发表日期：

    2025年11月17日

查看全文
  • Chien-Huan Weng,
  • Anais Assouvie,
  • Lauren Dong,
  • Jean-Christophe Beltra,
  • Sadna Budhu,
  • Levi Mangarin,
  • Yacine Marouf,
  • Lucia Morgado-Palacin,
  • Cailian Liu,
  • Sébastien Monette,
  • Jonathan F. Khan,
  • Isabell Schulze,
  • Dmitriy Zamarin,
  • Linda Hamadene,
  • Fadi Samaan,
  • Daniel Hirschhorn,
  • Stephane Pourpe,
  • David Schröder,
  • Roberta Zappasodi,
  • Pamela M. Holland,
  • Niroshana Anandasabapathy,
  • E. John Wherry,
  • Jedd D. Wolchok,
  • Taha Merghoub

摘要

T cell exhaustion is a major barrier to effective cancer immunotherapy. Although immune checkpoint blockade can reinvigorate exhausted T cells, not all patients achieve long-term responses, partly due to the refractory nature of terminally exhausted T cells. Beyond persistent antigen stimulation, the environmental drivers of exhaustion remain to be thoroughly characterized. Here we identify CD47 upregulation in tumor-infiltrating exhausted CD8+ T cells in both human and murine tumors. We reveal a novel role for the extracellular matrix protein thrombospondin-1 (TSP-1) in engaging CD47 on T cells to promote exhaustion. This interaction activates calcineurin–NFAT signaling, inducing upregulation of TOX and expression of inhibitory receptors, and impairing effector function during tumor progression. Importantly, disrupting the TSP-1–CD47 axis prevents T cell exhaustion and enhances tumor control. Our findings identify a novel pathway promoting T cell dysfunction and suggest that targeting the TSP-1–CD47 axis is a promising strategy to enhance T cell immunity and immunotherapy efficacy.