Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4
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...
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doaj-1053242894a246058058f9231a19524f2021-01-03T12:05:21ZengBMCGenome Medicine1756-994X2019-12-0111111510.1186/s13073-019-0697-8Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4Jitske van den Bulk0Els M. E. Verdegaal1Dina Ruano2Marieke E. Ijsselsteijn3Marten Visser4Ruud van der Breggen5Thomas Duhen6Manon van der Ploeg7Natasja L. de Vries8Jan Oosting9Koen C. M. J. Peeters10Andrew D. Weinberg11Arantza Farina-Sarasqueta12Sjoerd H. van der Burg13Noel F. C. C. de Miranda14Pathology, LUMCMedical Oncology, Oncode Institute, LUMCPathology, LUMCPathology, LUMCMedical Oncology, Oncode Institute, LUMCPathology, LUMCEarle A. Chiles InstitutePathology, LUMCImmunohematology and Blood Transfusion, LUMCPathology, LUMCSurgery, LUMCEarle A. Chiles InstitutePathology, LUMCMedical Oncology, Oncode Institute, LUMCPathology, LUMCAbstract 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.https://doi.org/10.1186/s13073-019-0697-8Mismatch repair-proficient (MMR-p)Tumor-infiltrating lymphocytesTransforming growth factor-betaCancer immunotherapyAdoptive T cell transfer (ACT)Low mutation burden |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jitske van den Bulk Els M. E. Verdegaal Dina Ruano Marieke E. Ijsselsteijn Marten Visser Ruud van der Breggen Thomas Duhen Manon van der Ploeg Natasja L. de Vries Jan Oosting Koen C. M. J. Peeters Andrew D. Weinberg Arantza Farina-Sarasqueta Sjoerd H. van der Burg Noel F. C. C. de Miranda |
spellingShingle |
Jitske van den Bulk Els M. E. Verdegaal Dina Ruano Marieke E. Ijsselsteijn Marten Visser Ruud van der Breggen Thomas Duhen Manon van der Ploeg Natasja L. de Vries Jan Oosting Koen C. M. J. Peeters Andrew D. Weinberg Arantza Farina-Sarasqueta Sjoerd H. van der Burg Noel F. C. C. de Miranda Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4 Genome Medicine Mismatch repair-proficient (MMR-p) Tumor-infiltrating lymphocytes Transforming growth factor-beta Cancer immunotherapy Adoptive T cell transfer (ACT) Low mutation burden |
author_facet |
Jitske van den Bulk Els M. E. Verdegaal Dina Ruano Marieke E. Ijsselsteijn Marten Visser Ruud van der Breggen Thomas Duhen Manon van der Ploeg Natasja L. de Vries Jan Oosting Koen C. M. J. Peeters Andrew D. Weinberg Arantza Farina-Sarasqueta Sjoerd H. van der Burg Noel F. C. C. de Miranda |
author_sort |
Jitske van den Bulk |
title |
Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4 |
title_short |
Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4 |
title_full |
Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4 |
title_fullStr |
Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4 |
title_full_unstemmed |
Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4 |
title_sort |
neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4 |
publisher |
BMC |
series |
Genome Medicine |
issn |
1756-994X |
publishDate |
2019-12-01 |
description |
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. |
topic |
Mismatch repair-proficient (MMR-p) Tumor-infiltrating lymphocytes Transforming growth factor-beta Cancer immunotherapy Adoptive T cell transfer (ACT) Low mutation burden |
url |
https://doi.org/10.1186/s13073-019-0697-8 |
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