CD103 and CD39 coexpression identifies neoantigen-specific cytotoxic T cells in colorectal cancers with low mutation burden
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 Whol...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-02-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/2/e005887.full |
| _version_ | 1797899492498866176 |
|---|---|
| author | Sjoerd H van der Burg Rebekka Duhen Thomas Duhen Marieke E Ijsselsteijn Ruud van der Breggen Koen C M J Peeters Noel F C C de Miranda Els M E Verdegaal Dina Ruano Manon van der Ploeg Jitske van den Bulk Arantza Fariña-Sarasqueta |
| author_facet | Sjoerd H van der Burg Rebekka Duhen Thomas Duhen Marieke E Ijsselsteijn Ruud van der Breggen Koen C M J Peeters Noel F C C de Miranda Els M E Verdegaal Dina Ruano Manon van der Ploeg Jitske van den Bulk Arantza Fariña-Sarasqueta |
| author_sort | Sjoerd H van der Burg |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T08:29:38Z |
| format | Article |
| id | doaj.art-a80924796f3f43ca978f61b4c5f9bebf |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-10T08:29:38Z |
| publishDate | 2023-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-a80924796f3f43ca978f61b4c5f9bebf2023-02-23T03:30:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-02-0111210.1136/jitc-2022-005887CD103 and CD39 coexpression identifies neoantigen-specific cytotoxic T cells in colorectal cancers with low mutation burdenSjoerd H van der Burg0Rebekka Duhen1Thomas Duhen2Marieke E Ijsselsteijn3Ruud van der Breggen4Koen C M J Peeters5Noel F C C de Miranda6Els M E Verdegaal7Dina Ruano8Manon van der Ploeg9Jitske van den Bulk10Arantza Fariña-Sarasqueta11Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The NetherlandsAff238 grid.415337.7Earle A. Chiles Research Institute, Providence Cancer Center Portland OR USAAff239 AgonOx, Inc. Portland OR USA3 Pathology, Leiden University Medical Center, Leiden, The Netherlands3 Pathology, Leiden University Medical Center, Leiden, The Netherlands6 Surgery, Leiden University Medical Center, Leiden, The NetherlandsPathology, Leiden University Medical Centre, Leiden, The NetherlandsDepartment of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The NetherlandsPathology, Leiden University Medical Centre, Leiden, The NetherlandsDepartment of Pathology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Pathology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Pathology, Leiden University Medical Center, Leiden, The NetherlandsBackground 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.https://jitc.bmj.com/content/11/2/e005887.full |
| spellingShingle | Sjoerd H van der Burg Rebekka Duhen Thomas Duhen Marieke E Ijsselsteijn Ruud van der Breggen Koen C M J Peeters Noel F C C de Miranda Els M E Verdegaal Dina Ruano Manon van der Ploeg Jitske van den Bulk Arantza Fariña-Sarasqueta CD103 and CD39 coexpression identifies neoantigen-specific cytotoxic T cells in colorectal cancers with low mutation burden Journal for ImmunoTherapy of Cancer |
| title | CD103 and CD39 coexpression identifies neoantigen-specific cytotoxic T cells in colorectal cancers with low mutation burden |
| title_full | CD103 and CD39 coexpression identifies neoantigen-specific cytotoxic T cells in colorectal cancers with low mutation burden |
| title_fullStr | CD103 and CD39 coexpression identifies neoantigen-specific cytotoxic T cells in colorectal cancers with low mutation burden |
| title_full_unstemmed | CD103 and CD39 coexpression identifies neoantigen-specific cytotoxic T cells in colorectal cancers with low mutation burden |
| title_short | CD103 and CD39 coexpression identifies neoantigen-specific cytotoxic T cells in colorectal cancers with low mutation burden |
| title_sort | cd103 and cd39 coexpression identifies neoantigen specific cytotoxic t cells in colorectal cancers with low mutation burden |
| url | https://jitc.bmj.com/content/11/2/e005887.full |
| work_keys_str_mv | AT sjoerdhvanderburg cd103andcd39coexpressionidentifiesneoantigenspecificcytotoxictcellsincolorectalcancerswithlowmutationburden AT rebekkaduhen cd103andcd39coexpressionidentifiesneoantigenspecificcytotoxictcellsincolorectalcancerswithlowmutationburden AT thomasduhen cd103andcd39coexpressionidentifiesneoantigenspecificcytotoxictcellsincolorectalcancerswithlowmutationburden AT mariekeeijsselsteijn cd103andcd39coexpressionidentifiesneoantigenspecificcytotoxictcellsincolorectalcancerswithlowmutationburden AT ruudvanderbreggen cd103andcd39coexpressionidentifiesneoantigenspecificcytotoxictcellsincolorectalcancerswithlowmutationburden AT koencmjpeeters cd103andcd39coexpressionidentifiesneoantigenspecificcytotoxictcellsincolorectalcancerswithlowmutationburden AT noelfccdemiranda cd103andcd39coexpressionidentifiesneoantigenspecificcytotoxictcellsincolorectalcancerswithlowmutationburden AT elsmeverdegaal cd103andcd39coexpressionidentifiesneoantigenspecificcytotoxictcellsincolorectalcancerswithlowmutationburden AT dinaruano cd103andcd39coexpressionidentifiesneoantigenspecificcytotoxictcellsincolorectalcancerswithlowmutationburden AT manonvanderploeg cd103andcd39coexpressionidentifiesneoantigenspecificcytotoxictcellsincolorectalcancerswithlowmutationburden AT jitskevandenbulk cd103andcd39coexpressionidentifiesneoantigenspecificcytotoxictcellsincolorectalcancerswithlowmutationburden AT arantzafarinasarasqueta cd103andcd39coexpressionidentifiesneoantigenspecificcytotoxictcellsincolorectalcancerswithlowmutationburden |