Journal
GENOME MEDICINE
Volume 11, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13073-019-0697-8
Keywords
Mismatch repair-proficient (MMR-p); Tumor-infiltrating lymphocytes; Transforming growth factor-beta; Cancer immunotherapy; Adoptive T cell transfer (ACT); Low mutation burden; Neoantigen; CMS
Categories
Funding
- KWF Bas Mulder Award UL [2015-7664]
- ZonMw Veni grant [016.176.l44]
- Fight Colorectal Cancer-Michael's Mission-AACR Fellowship in Young Onset
- Late-Stage Colorectal Cancer Research 2015 [15-40-1645-DEMI]
- LUMC PhD fellowship
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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-beta 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-beta pathway to reinforce T cell reactivity in this patient group.
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