CD103 and CD39 coexpression identifies neoantigen-specific cytotoxic T cells in colorectal cancers with low mutation burden. Issue 2 (15th February 2023)

• Record Type: Journal Article
• 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
• Is Part Of: Journal for immunotherapy of cancer. Volume 11:Issue 2(2023)
• Publication Date: 2023-02-15
• Subjects: Immunotherapy -- Lymphocytes, Tumor-Infiltrating -- Gastrointestinal Neoplasms -- Antigens -- CD8-Positive T-Lymphocytes; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2022-005887
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: Expression 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 design: Whole-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. Results: Neoantigen-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. Conclusion: Coexpression 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.