Search

Your search keyword '"Low mutation burden"' showing total 2 results
Start Over Descriptor "Low mutation burden" Topic antigens, neoplasm
2 results on '"Low mutation burden"'

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

Author

van den Bulk J, Verdegaal EME, Ruano D, Ijsselsteijn ME, Visser M, van der Breggen R, Duhen T, van der Ploeg M, de Vries NL, Oosting J, Peeters KCMJ, Weinberg AD, Farina-Sarasqueta A, van der Burg SH, and de Miranda NFCC

Subjects
Antigens, Neoplasm chemistry, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes metabolism, Colorectal Neoplasms immunology, Colorectal Neoplasms therapy, DNA Mismatch Repair, DNA-Binding Proteins genetics, Epitopes chemistry, Epitopes immunology, Epitopes pharmacology, Humans, Immunotherapy, Interferon-gamma metabolism, Lymphocytes, Tumor-Infiltrating cytology, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating metabolism, Microfilament Proteins genetics, Mutation, Peptides chemical synthesis, Peptides pharmacology, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets metabolism, Transcription Factors genetics, Transforming Growth Factor beta metabolism, Antigens, Neoplasm immunology, Colorectal Neoplasms pathology
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.

Published
2019
Full Text
View/download PDF

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

Author

Marieke E. Ijsselsteijn, Els M. E. Verdegaal, Noel F C C de Miranda, Arantza Farina-Sarasqueta, Ruud van der Breggen, Dina Ruano, Andrew D. Weinberg, Natasja L. de Vries, Jitske van den Bulk, Sjoerd H. van der Burg, Jan Oosting, Koen C. M. J. Peeters, Marten Visser, Thomas Duhen, and Manon van der Ploeg

Subjects
Colorectal cancer, Adoptive T cell transfer (ACT), medicine.medical_treatment, lcsh:Medicine, Cancer immunotherapy, CD8-Positive T-Lymphocytes, DNA Mismatch Repair, Tumor-infiltrating lymphocytes, Epitopes, T-Lymphocyte Subsets, Transforming Growth Factor beta, Genetics (clinical), biology, integumentary system, CMS, Mismatch repair-proficient (MMR-p), Microfilament Proteins, Cell sorting, DNA-Binding Proteins, Transforming growth factor-beta, medicine.anatomical_structure, Molecular Medicine, Immunotherapy, Colorectal Neoplasms, lcsh:QH426-470, T cell, Low mutation burden, Interferon-gamma, Lymphocytes, Tumor-Infiltrating, Antigens, Neoplasm, Genetics, medicine, Humans, Molecular Biology, business.industry, Research, lcsh:R, Cancer, Transforming growth factor beta, medicine.disease, lcsh:Genetics, Mutation, Cancer research, biology.protein, business, Neoantigen, Peptides, Transcription Factors
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.

Published
2019

Catalog

Books, media, physical & digital resources
See catalog results