Back to Search
Start Over
Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4.
- Source :
- Genome Medicine; 12/30/2019, Vol. 11 Issue 1, p1-15, 15p
- Publication Year :
- 2019
-
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<superscript>+</superscript>CD103<superscript>+</superscript> 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]
Details
- Language :
- English
- ISSN :
- 1756994X
- Volume :
- 11
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Genome Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 140956484
- Full Text :
- https://doi.org/10.1186/s13073-019-0697-8