학술논문
Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4.
Document Type
Article
Author
van den Bulk, Jitske; Verdegaal, Els M. E.; Ruano, Dina; Ijsselsteijn, Marieke E.; Visser, Marten; van der Breggen, Ruud; Duhen, Thomas; van der Ploeg, Manon; de Vries, Natasja L.; Oosting, Jan; Peeters, Koen C. M. J.; Weinberg, Andrew D.; Farina-Sarasqueta, Arantza; van der Burg, Sjoerd H.; de Miranda, Noel F. C. C.
Source
Subject
*COLORECTAL cancer
*T cells
*BLOOD cells
*INTERLEUKIN-21
*T cell receptors
*CYTOTOXIC T cells
*CANCER patients
*IMMUNITY
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Language
ISSN
1756-994X
Abstract
Background: The efficacy of checkpoint blockade immunotherapies in colorectal cancer is currently restricted to a minority of patients diagnosed with mismatch repair-deficient tumors having high mutation burden. However, this observation does not exclude the existence of neoantigen-specific T cells in colorectal cancers with low mutation burden and the exploitation of their anti-cancer potential for immunotherapy. Therefore, we investigated whether autologous neoantigen-specific T cell responses could also be observed in patients diagnosed with mismatch repair-proficient colorectal cancers. Methods: Whole-exome and transcriptome sequencing were performed on cancer and normal tissues from seven colorectal cancer patients diagnosed with mismatch repair-proficient tumors to detect putative neoantigens. Corresponding neo-epitopes were synthesized and tested for recognition by in vitro expanded T cells that were isolated from tumor tissues (tumor-infiltrating lymphocytes) and from peripheral mononuclear blood cells stimulated with tumor material. Results: Neoantigen-specific T cell reactivity was detected to several neo-epitopes in the tumor-infiltrating lymphocytes of three patients while their respective cancers expressed 15, 21, and 30 non-synonymous variants. Cell sorting of tumor-infiltrating lymphocytes based on the co-expression of CD39 and CD103 pinpointed the presence of neoantigen-specific T cells in the CD39+CD103+ T cell subset. Strikingly, the tumors containing neoantigen-reactive TIL were classified as consensus molecular subtype 4 (CMS4), which is associated with TGF-β pathway activation and worse clinical outcome. Conclusions: We have detected neoantigen-targeted reactivity by autologous T cells in mismatch repair-proficient colorectal cancers of the CMS4 subtype. These findings warrant the development of specific immunotherapeutic strategies that selectively boost the activity of neoantigen-specific T cells and target the TGF-β pathway to reinforce T cell reactivity in this patient group. [ABSTRACT FROM AUTHOR]