Enhanced antigen cross-presentation in human colorectal cancer-associated fibroblasts through upregulation of the lysosomal protease cathepsin S.

Autor:	Harryvan TJ; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands., Visser M; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., de Bruin L; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Plug L; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands., Griffioen L; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Mulder A; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., van Veelen PA; Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands., van der Heden van Noort GJ; Department of Cell & Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Jongsma ML; Department of Cell & Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Meeuwsen MH; Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands., Wiertz EJ; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands., Santegoets SJ; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Hardwick JC; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands., Van Hall T; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Neefjes J; Department of Cell & Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Van der Burg SH; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Hawinkels LJ; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands., Verdegaal EM; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands e.m.e.verdegaal@lumc.nl.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Mar; Vol. 10 (3).
DOI:	10.1136/jitc-2021-003591
Abstrakt:	Background: Cross-presentation of exogenous antigens in HLA-class I molecules by professional antigen presenting cells (APCs) is crucial for CD8+ T cell function. Recent murine studies show that several non-professional APCs, including cancer-associated fibroblasts (CAFs) also possess this capacity. Whether human CAFs are able to cross-present exogenous antigen, which molecular pathways are involved in this process and how this ultimately affects tumor-specific CD8+ T cell function is unknown. Methods: In this study, we investigated the ability of human colorectal cancer (CRC)-derived CAFs to cross-present neoantigen-derived synthetic long peptides (SLPs), corresponding to tumor-derived mutant peptides, and how this affects tumor-specific T-cell function. Processing of the SLP was studied by targeting components of the cross-presentation machinery through CRISPR/Cas9 and siRNA-mediated genetic ablation to identify the key molecules involved in fibroblast-mediated cross-presentation. Multispectral flow cytometry and killing assays were performed to study the effect of fibroblast cross-presentation on T cell function. Results: Here, we show that human CRC-derived CAFs display an enhanced capacity to cross-present neoantigen-derived SLPs when compared with normal colonic fibroblasts. Cross-presentation of antigens by fibroblasts involved the lysosomal protease cathepsin S. Cathepsin S expression by CAFs was detected in situ in human CRC tissue, was upregulated in ex vivo cultured CRC-derived CAFs and showed increased expression in normal fibroblasts after exposure to CRC-conditioned medium. Cognate interaction between CD8+ T cells and cross-presenting CAFs suppressed T cell function, reflected by decreased cytotoxicity, reduced activation (CD137) and increased exhaustion (TIM3, LAG3 and CD39) marker expression. Conclusion: These data indicate that CAFs may directly suppress tumor-specific T cell function in an antigen-dependent fashion in human CRC. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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