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<p>Clear cell renal cell carcinoma (ccRCC) is characterized by abundant infiltration of CD8⁺ T cells; however, the clinical benefit from immune checkpoint inhibitors (ICI) remains limited. To clarify this paradox, we systematically investigated the functional states of CD8⁺ T cells in ccRCC, with a particular focus on exhaustion-associated subsets and their potential link to ICI responsiveness. By integrating six publicly available bulk and single-cell RNA sequencing datasets with independent institutional validation cohorts, we found that the majority of tumor-infiltrating CD8⁺ T cells exhibited an exhausted phenotype, characterized by elevated expression of canonical exhaustion markers. Importantly, we identified CD8⁺ T cells with high LIM domain–containing protein 2 (LIMD2) expression that co-express canonical exhaustion markers and are enriched in ICI responders. Single-cell transcriptomic analyses further supported markedly increased LIMD2 expression within CD8⁺ Tex cells from patients achieving clinical benefit. Multiplex immunofluorescence showed LIMD2 protein predominantly localized to CD8A⁺ T cells, co-expressed with exhaustion markers, and significantly enriched in tumor tissues of responders. Collectively, these findings indicate that CD8⁺ Tex cells with high LIMD2 expression are associated with ICI responses in ccRCC, positioning LIMD2 as a candidate predictive biomarker to refine patient stratification and inform immunotherapy optimization.</p>

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LIMD2 is associated with an exhausted CD8⁺ T cell state linked to ICI response in clear cell renal cell carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月4日

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  • Junfeng Zhang,
  • Qingyan Peng,
  • Xiaolong Xiang,
  • Fuzhong Liu,
  • Xiangdong Jiang,
  • Hongwei Nie,
  • Xing Bi,
  • Ting Pan,
  • kailing Li,
  • Peng Chen,
  • Shuai Yuan,
  • Su Chen

摘要

Clear cell renal cell carcinoma (ccRCC) is characterized by abundant infiltration of CD8⁺ T cells; however, the clinical benefit from immune checkpoint inhibitors (ICI) remains limited. To clarify this paradox, we systematically investigated the functional states of CD8⁺ T cells in ccRCC, with a particular focus on exhaustion-associated subsets and their potential link to ICI responsiveness. By integrating six publicly available bulk and single-cell RNA sequencing datasets with independent institutional validation cohorts, we found that the majority of tumor-infiltrating CD8⁺ T cells exhibited an exhausted phenotype, characterized by elevated expression of canonical exhaustion markers. Importantly, we identified CD8⁺ T cells with high LIM domain–containing protein 2 (LIMD2) expression that co-express canonical exhaustion markers and are enriched in ICI responders. Single-cell transcriptomic analyses further supported markedly increased LIMD2 expression within CD8⁺ Tex cells from patients achieving clinical benefit. Multiplex immunofluorescence showed LIMD2 protein predominantly localized to CD8A⁺ T cells, co-expressed with exhaustion markers, and significantly enriched in tumor tissues of responders. Collectively, these findings indicate that CD8⁺ Tex cells with high LIMD2 expression are associated with ICI responses in ccRCC, positioning LIMD2 as a candidate predictive biomarker to refine patient stratification and inform immunotherapy optimization.