Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4

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 i...

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Vydané v:	Genome medicine Ročník 11; číslo 1; s. 87 - 15
Hlavní autori:	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.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London BioMed Central 30.12.2019 BioMed Central Ltd Springer Nature B.V BMC
Predmet:	Adoptive T cell transfer (ACT) Antigenic determinants Antigens Antigens, Neoplasm - chemistry Antigens, Neoplasm - immunology Bioinformatics Biomedical and Life Sciences Biomedicine Blood cells Bone morphogenetic proteins Cancer Cancer immunotherapy Cancer patients Cancer Research Cancer treatment CD103 antigen CD8-Positive T-Lymphocytes - cytology CD8-Positive T-Lymphocytes - metabolism Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - immunology Colorectal Neoplasms - pathology Colorectal Neoplasms - therapy Deoxyribonucleic acid DNA DNA Mismatch Repair DNA-Binding Proteins - genetics Epitopes Epitopes - chemistry Epitopes - immunology Epitopes - pharmacology Gene expression Genetic aspects Genomes Health aspects Human Genetics Humans Immune checkpoint Immunotherapy Interferon-gamma - metabolism Low mutation burden Lymphocytes Lymphocytes T Lymphocytes, Tumor-Infiltrating - cytology Lymphocytes, Tumor-Infiltrating - drug effects Lymphocytes, Tumor-Infiltrating - metabolism Medical prognosis Medicine/Public Health Metabolomics Microfilament Proteins - genetics Mismatch repair Mismatch repair-proficient (MMR-p) Mutation Neoantigens Patients Peptides Peptides - chemical synthesis Peptides - pharmacology Pharmacy Scientific equipment industry Systems Biology T cells T-Lymphocyte Subsets - cytology T-Lymphocyte Subsets - metabolism Transcription Factors - genetics Transforming Growth Factor beta - metabolism Transforming growth factor-beta Transforming growth factors Tumor antigens Tumor immune microenvironment and immunotherapy Tumor-infiltrating lymphocytes Tumors United States Netherlands United States > US Adoptive T cell transfer (ACT) Tumor-infiltrating lymphocytes Mismatch repair-proficient (MMR-p) CMS Transforming growth factor-beta Cancer immunotherapy Neoantigen Low mutation burden
ISSN:	1756-994X, 1756-994X
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Popis
Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1756-994X 1756-994X
DOI:	10.1186/s13073-019-0697-8