Endosialin-positive tumor-derived pericytes promote tumor progression through impeding the infiltration of CD8+ T cells in clear cell renal cell carcinoma

Cancer Immunol Immunother. 2023 Jun;72(6):1739-1750. doi: 10.1007/s00262-023-03372-z. Epub 2023 Jan 16.

Abstract

Background: Immune checkpoint blockade (ICB) therapy can be effective against clear cell renal cell carcinoma (ccRCC), but many patients show no benefit. Tumor-derived pericytes (TDPs) may promote tumor progression by influencing T cells and are an immunotherapy target; however, they may comprise functionally distinct subtypes. We aimed to identify markers of tumor-promoting TDPs and develop TDP-targeting strategies to enhance ICB therapy effectiveness against ccRCC.

Methods: We analyzed the relationship between endosialin (EN) expression and cytotoxic T-lymphocyte (CTL) infiltration in ccRCC tumor samples using flow cytometry and in a ccRCC-bearing mice inhibited for EN via knockout or antibody-mediated blockade. The function of ENhigh TDPs in CTL infiltration and tumor progression was analyzed using RNA-sequencing (RNA-seq) data from ccRCC tissue-derived TDPs and single-cell RNA-seq (scRNA-seq) data from an online database. The role of EN in TDP proliferation and migration and in CTL infiltration was examined in vitro. Finally, we examined the anti-tumor effect of combined anti-EN and anti-programmed death 1 (PD-1) antibodies in ccRCC-bearing mice.

Results: High EN expression was associated with low CTL infiltration in ccRCC tissues, and inhibition of EN significantly increased CTL infiltration in ccRCC-bearing mice. RNA-seq and scRNA-seq analyses indicated that high EN expression represented the TDP activation state. EN promoted TDP proliferation and migration and impeded CTL infiltration in vitro. Finally, combined treatment with anti-EN and anti-PD-1 antibodies synergistically enhanced anti-tumor efficacy.

Conclusion: ENhigh TDPs are in an activated state and inhibit CTL infiltration into ccRCC tissues. Combined treatment with anti-EN and anti-PD-1 antibodies may improve ICB therapy effectiveness against ccRCC.

Keywords: CD8+ T cell; Clear cell renal cell carcinoma; Endosialin/CD248/TEM-1; ICB therapy; Tumor-derived pericyte.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Renal Cell*
  • DNA-Binding Proteins / metabolism
  • Kidney Neoplasms*
  • Mice
  • Pericytes / metabolism
  • Pericytes / pathology
  • Tumor Microenvironment

Substances

  • DNA-Binding Proteins
  • CD248 protein, human
  • CD248 protein, mouse