AI Article Synopsis
- Human colorectal cancer-derived cancer-associated fibroblasts (CAFs) can cross-present neoantigens, which enhances their ability to interact with tumor-specific CD8+ T cells compared to normal fibroblasts.
- The study utilized advanced genetic techniques and assays to identify the molecular mechanisms involved, particularly highlighting the role of the lysosomal protease cathepsin S.
- Results showed that interaction between CAFs and CD8+ T cells can lead to reduced T cell activation and increased exhaustion, suggesting that CAFs may negatively impact tumor immunity.
Article Abstract
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8915372 | PMC |
| http://dx.doi.org/10.1136/jitc-2021-003591 | DOI Listing |
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Article Synopsis
- Human colorectal cancer-derived cancer-associated fibroblasts (CAFs) can cross-present neoantigens, which enhances their ability to interact with tumor-specific CD8+ T cells compared to normal fibroblasts.
- The study utilized advanced genetic techniques and assays to identify the molecular mechanisms involved, particularly highlighting the role of the lysosomal protease cathepsin S.
- Results showed that interaction between CAFs and CD8+ T cells can lead to reduced T cell activation and increased exhaustion, suggesting that CAFs may negatively impact tumor immunity.
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May 2022
Department of Surgery, National Defense Medical College, Tokorozawa, Japan.
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- The tumor microenvironment, particularly the desmoplastic reaction (DR), significantly influences cancer aggressiveness, with different DR types impacting patient prognosis in colorectal cancer (CRC).
- In a study of 1,497 patients, those with Immature-type DR had the worst relapse-free survival, and cancer-associated fibroblasts (CAFs) from this DR type enhanced tumor growth and spread in experiments.
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