CD103 and CD39 coexpression identifies neoantigen-specific cytotoxic T cells in colorectal cancers with low mutation burden

BackgroundExpression of CD103 and CD39 has been found to pinpoint tumor-reactive CD8+ T cells in a variety of solid cancers. We aimed to investigate whether these markers specifically identify neoantigen-specific T cells in colorectal cancers (CRCs) with low mutation burden.Experimental designWhole-...

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Published in:Journal for immunotherapy of cancer Vol. 11; no. 2; p. e005887
Main Authors: van den Bulk, Jitske, van der Ploeg, Manon, Ijsselsteijn, Marieke E, Ruano, Dina, van der Breggen, Ruud, Duhen, Rebekka, Peeters, Koen C M J, Fariña-Sarasqueta, Arantza, Verdegaal, Els M E, van der Burg, Sjoerd H, Duhen, Thomas, de Miranda, Noel F C C
Format: Journal Article
Language:English
Published: England BMJ Publishing Group Ltd 01.02.2023
BMJ Publishing Group LTD
BMJ Publishing Group
Series:Original research
Subjects:
Antigens
Basic Tumor Immunology
Cancer
CD8-Positive T-Lymphocytes
Colorectal cancer
Colorectal Neoplasms
Cytotoxicity
Gastrointestinal Neoplasms
Humans
Immunotherapy
Lymphocytes
Lymphocytes, Tumor-Infiltrating
Mutation
Patients
Pharmacy
Rectum
T cell receptors
T-Lymphocyte Subsets - pathology
T-Lymphocytes, Cytotoxic
Tumors
Netherlands
United Kingdom > UK
United States > US
Basel Switzerland
Massachusetts
England
Switzerland
CD8-Positive T-Lymphocytes
Antigens
Gastrointestinal Neoplasms
Lymphocytes, Tumor-Infiltrating
Immunotherapy
ISSN:2051-1426, 2051-1426
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Summary:BackgroundExpression of CD103 and CD39 has been found to pinpoint tumor-reactive CD8+ T cells in a variety of solid cancers. We aimed to investigate whether these markers specifically identify neoantigen-specific T cells in colorectal cancers (CRCs) with low mutation burden.Experimental designWhole-exome and RNA sequencing of 11 mismatch repair-proficient (MMR-proficient) CRCs and corresponding healthy tissues were performed to determine the presence of putative neoantigens. In parallel, tumor-infiltrating lymphocytes (TILs) were cultured from the tumor fragments and, in parallel, CD8+ T cells were flow-sorted from their respective tumor digests based on single or combined expression of CD103 and CD39. Each subset was expanded and subsequently interrogated for neoantigen-directed reactivity with synthetic peptides. Neoantigen-directed reactivity was determined by flow cytometric analyses of T cell activation markers and ELISA-based detection of IFN-γ and granzyme B release. Additionally, imaging mass cytometry was applied to investigate the localization of CD103+CD39+ cytotoxic T cells in tumors.ResultsNeoantigen-directed reactivity was only encountered in bulk TIL populations and CD103+CD39+ (double positive, DP) CD8+ T cell subsets but never in double-negative or single-positive subsets. Neoantigen-reactivity detected in bulk TIL but not in DP CD8+ T cells could be attributed to CD4+ T cells. CD8+ T cells that were located in direct contact with cancer cells in tumor tissues were enriched for CD103 and CD39 expression.ConclusionCoexpression of CD103 and CD39 is characteristic of neoantigen-specific CD8+ T cells in MMR-proficient CRCs with low mutation burden. The exploitation of these subsets in the context of adoptive T cell transfer or engineered T cell receptor therapies is a promising avenue to extend the benefits of immunotherapy to an increasing number of CRC patients.
Bibliography:Original research
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ISSN:2051-1426
2051-1426
DOI:10.1136/jitc-2022-005887