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

Content Provider	Europe PMC
Author	Lu, Tong Zhang, Jiayu Lu, Shiqi Yang, Fa Gan, Lunbiao Wu, Xinjie Song, Hongtao Liu, Shaojie Xu, Chao Han, Donghui Yang, Bo Wen, Weihong Qin, Weijun Yang, Lijun
Abstract	BackgroundImmune 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.MethodsWe 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.ResultsHigh 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.ConclusionENhigh 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.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00262-023-03372-z.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC10198862&blobtype=pdf
ISSN	03407004
Journal	Cancer Immunology, Immunotherapy [Cancer Immunol Immunother]
Volume Number	72
DOI	10.1007/s00262-023-03372-z
PubMed Central reference number	PMC10198862
Issue Number	6
PubMed reference number	36646951
e-ISSN	14320851
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2023-01-16
Publisher Place	Berlin/Heidelberg
Access Restriction	Open
Rights License	Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2023
Subject Keyword	Endosialin/CD248/TEM-1 Clear cell renal cell carcinoma Tumor-derived pericyte CD8+ T cell ICB therapy
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Cancer Research Immunology Oncology