Cargando…
T-Cell Responses to Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses to the Colorectal Cancer Antigen, Guanylyl Cyclase C
The Gram-positive bacterium Listeria monocytogenes (Lm) is an emerging platform for cancer immunotherapy. To date, over 30 clinical trials have been initiated testing Lm cancer vaccines across a wide variety of cancers, including lung, cervical, colorectal, and pancreatic. Here, we assessed the immu...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8959893/ https://www.ncbi.nlm.nih.gov/pubmed/35355987 http://dx.doi.org/10.3389/fimmu.2022.855759 |
_version_ | 1784677263450570752 |
---|---|
author | Flickinger, John C. Singh, Jagmohan Yarman, Yanki Carlson, Robert D. Barton, Joshua R. Waldman, Scott A. Snook, Adam E. |
author_facet | Flickinger, John C. Singh, Jagmohan Yarman, Yanki Carlson, Robert D. Barton, Joshua R. Waldman, Scott A. Snook, Adam E. |
author_sort | Flickinger, John C. |
collection | PubMed |
description | The Gram-positive bacterium Listeria monocytogenes (Lm) is an emerging platform for cancer immunotherapy. To date, over 30 clinical trials have been initiated testing Lm cancer vaccines across a wide variety of cancers, including lung, cervical, colorectal, and pancreatic. Here, we assessed the immunogenicity of an Lm vaccine against the colorectal tumor antigen GUCY2C (Lm-GUCY2C). Surprisingly, Lm-GUCY2C vaccination did not prime naïve GUCY2C-specific CD8(+) T-cell responses towards the dominant H-2K(d)-restricted epitope, GUCY2C(254-262). However, Lm-GUCY2C produced robust CD8(+) T-cell responses towards Lm-derived peptides suggesting that GUCY2C(254-262) peptide may be subdominant to Lm-derived peptides. Indeed, incorporating immunogenic Lm peptides into an adenovirus-based GUCY2C vaccine previously shown to induce robust GUCY2C(254-262) immunity completely suppressed GUCY2C(254-262) responses. Comparison of immunogenic Lm-derived peptides to GUCY2C(254-262) revealed that Lm-derived peptides form highly stable peptide-MHC complexes with H-2K(d) compared to GUCY2C(254-262) peptide. Moreover, amino acid substitution at a critical anchoring residue for H-2K(d) binding, producing GUCY2C(F255Y), significantly improved stability with H-2K(d) and rescued GUCY2C(254-262) immunogenicity in the context of Lm vaccination. Collectively, these studies suggest that Lm antigens may compete with and suppress the immunogenicity of target vaccine antigens and that use of altered peptide ligands with enhanced peptide-MHC stability may be necessary to elicit robust immune responses. These studies suggest that optimizing target antigen competitiveness with Lm antigens or alternative immunization regimen strategies, such as prime-boost, may be required to maximize the clinical utility of Lm-based vaccines. |
format | Online Article Text |
id | pubmed-8959893 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89598932022-03-29 T-Cell Responses to Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses to the Colorectal Cancer Antigen, Guanylyl Cyclase C Flickinger, John C. Singh, Jagmohan Yarman, Yanki Carlson, Robert D. Barton, Joshua R. Waldman, Scott A. Snook, Adam E. Front Immunol Immunology The Gram-positive bacterium Listeria monocytogenes (Lm) is an emerging platform for cancer immunotherapy. To date, over 30 clinical trials have been initiated testing Lm cancer vaccines across a wide variety of cancers, including lung, cervical, colorectal, and pancreatic. Here, we assessed the immunogenicity of an Lm vaccine against the colorectal tumor antigen GUCY2C (Lm-GUCY2C). Surprisingly, Lm-GUCY2C vaccination did not prime naïve GUCY2C-specific CD8(+) T-cell responses towards the dominant H-2K(d)-restricted epitope, GUCY2C(254-262). However, Lm-GUCY2C produced robust CD8(+) T-cell responses towards Lm-derived peptides suggesting that GUCY2C(254-262) peptide may be subdominant to Lm-derived peptides. Indeed, incorporating immunogenic Lm peptides into an adenovirus-based GUCY2C vaccine previously shown to induce robust GUCY2C(254-262) immunity completely suppressed GUCY2C(254-262) responses. Comparison of immunogenic Lm-derived peptides to GUCY2C(254-262) revealed that Lm-derived peptides form highly stable peptide-MHC complexes with H-2K(d) compared to GUCY2C(254-262) peptide. Moreover, amino acid substitution at a critical anchoring residue for H-2K(d) binding, producing GUCY2C(F255Y), significantly improved stability with H-2K(d) and rescued GUCY2C(254-262) immunogenicity in the context of Lm vaccination. Collectively, these studies suggest that Lm antigens may compete with and suppress the immunogenicity of target vaccine antigens and that use of altered peptide ligands with enhanced peptide-MHC stability may be necessary to elicit robust immune responses. These studies suggest that optimizing target antigen competitiveness with Lm antigens or alternative immunization regimen strategies, such as prime-boost, may be required to maximize the clinical utility of Lm-based vaccines. Frontiers Media S.A. 2022-03-09 /pmc/articles/PMC8959893/ /pubmed/35355987 http://dx.doi.org/10.3389/fimmu.2022.855759 Text en Copyright © 2022 Flickinger, Singh, Yarman, Carlson, Barton, Waldman and Snook https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Flickinger, John C. Singh, Jagmohan Yarman, Yanki Carlson, Robert D. Barton, Joshua R. Waldman, Scott A. Snook, Adam E. T-Cell Responses to Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses to the Colorectal Cancer Antigen, Guanylyl Cyclase C |
title | T-Cell Responses to Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses to the Colorectal Cancer Antigen, Guanylyl Cyclase C |
title_full | T-Cell Responses to Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses to the Colorectal Cancer Antigen, Guanylyl Cyclase C |
title_fullStr | T-Cell Responses to Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses to the Colorectal Cancer Antigen, Guanylyl Cyclase C |
title_full_unstemmed | T-Cell Responses to Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses to the Colorectal Cancer Antigen, Guanylyl Cyclase C |
title_short | T-Cell Responses to Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses to the Colorectal Cancer Antigen, Guanylyl Cyclase C |
title_sort | t-cell responses to immunodominant listeria epitopes limit vaccine-directed responses to the colorectal cancer antigen, guanylyl cyclase c |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8959893/ https://www.ncbi.nlm.nih.gov/pubmed/35355987 http://dx.doi.org/10.3389/fimmu.2022.855759 |
work_keys_str_mv | AT flickingerjohnc tcellresponsestoimmunodominantlisteriaepitopeslimitvaccinedirectedresponsestothecolorectalcancerantigenguanylylcyclasec AT singhjagmohan tcellresponsestoimmunodominantlisteriaepitopeslimitvaccinedirectedresponsestothecolorectalcancerantigenguanylylcyclasec AT yarmanyanki tcellresponsestoimmunodominantlisteriaepitopeslimitvaccinedirectedresponsestothecolorectalcancerantigenguanylylcyclasec AT carlsonrobertd tcellresponsestoimmunodominantlisteriaepitopeslimitvaccinedirectedresponsestothecolorectalcancerantigenguanylylcyclasec AT bartonjoshuar tcellresponsestoimmunodominantlisteriaepitopeslimitvaccinedirectedresponsestothecolorectalcancerantigenguanylylcyclasec AT waldmanscotta tcellresponsestoimmunodominantlisteriaepitopeslimitvaccinedirectedresponsestothecolorectalcancerantigenguanylylcyclasec AT snookadame tcellresponsestoimmunodominantlisteriaepitopeslimitvaccinedirectedresponsestothecolorectalcancerantigenguanylylcyclasec |