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Neoantigen-specific stem cell memory-like CD4(+) T cells mediate CD8(+) T cell-dependent immunotherapy of MHC class II-negative solid tumors

CD4(+) T cells play key roles in a range of immune responses, either as direct effectors or through accessory cells, including CD8(+) T lymphocytes. In cancer, neoantigen (NeoAg)-specific CD8(+) T cells capable of direct tumor recognition have been extensively studied, whereas the role of NeoAg-spec...

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Autores principales: Brightman, Spencer E., Becker, Angelica, Thota, Rukman R., Naradikian, Martin S., Chihab, Leila, Zavala, Karla Soria, Ramamoorthy Premlal, Ashmitaa Logandha, Griswold, Ryan Q., Dolina, Joseph S., Cohen, Ezra E. W., Miller, Aaron M., Peters, Bjoern, Schoenberger, Stephen P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382322/
https://www.ncbi.nlm.nih.gov/pubmed/37400675
http://dx.doi.org/10.1038/s41590-023-01543-9
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author Brightman, Spencer E.
Becker, Angelica
Thota, Rukman R.
Naradikian, Martin S.
Chihab, Leila
Zavala, Karla Soria
Ramamoorthy Premlal, Ashmitaa Logandha
Griswold, Ryan Q.
Dolina, Joseph S.
Cohen, Ezra E. W.
Miller, Aaron M.
Peters, Bjoern
Schoenberger, Stephen P.
author_facet Brightman, Spencer E.
Becker, Angelica
Thota, Rukman R.
Naradikian, Martin S.
Chihab, Leila
Zavala, Karla Soria
Ramamoorthy Premlal, Ashmitaa Logandha
Griswold, Ryan Q.
Dolina, Joseph S.
Cohen, Ezra E. W.
Miller, Aaron M.
Peters, Bjoern
Schoenberger, Stephen P.
author_sort Brightman, Spencer E.
collection PubMed
description CD4(+) T cells play key roles in a range of immune responses, either as direct effectors or through accessory cells, including CD8(+) T lymphocytes. In cancer, neoantigen (NeoAg)-specific CD8(+) T cells capable of direct tumor recognition have been extensively studied, whereas the role of NeoAg-specific CD4(+) T cells is less well understood. We have characterized the murine CD4(+) T cell response against a validated NeoAg (CLTC(H129>Q)) expressed by the MHC-II-deficient squamous cell carcinoma tumor model (SCC VII) at the level of single T cell receptor (TCR) clonotypes and in the setting of adoptive immunotherapy. We find that the natural CLTC(H129>Q)-specific repertoire is diverse and contains TCRs with distinct avidities as measured by tetramer-binding assays and CD4 dependence. Despite these differences, CD4(+) T cells expressing high or moderate avidity TCRs undergo comparable in vivo proliferation to cross-presented antigen from growing tumors and drive similar levels of therapeutic immunity that is dependent on CD8(+) T cells and CD40L signaling. Adoptive cellular therapy (ACT) with NeoAg-specific CD4(+) T cells is most effective when TCR-engineered cells are differentiated ex vivo with IL-7 and IL-15 rather than IL-2 and this was associated with both increased expansion as well as the acquisition and stable maintenance of a T stem cell memory (T(SCM))-like phenotype in tumor-draining lymph nodes (tdLNs). ACT with T(SCM)-like CD4(+) T cells results in lower PD-1 expression by CD8(+) T cells in the tumor microenvironment and an increased frequency of PD-1(+)CD8(+) T cells in tdLNs. These findings illuminate the role of NeoAg-specific CD4(+) T cells in mediating antitumor immunity via providing help to CD8(+) T cells and highlight their therapeutic potential in ACT.
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spelling pubmed-103823222023-07-30 Neoantigen-specific stem cell memory-like CD4(+) T cells mediate CD8(+) T cell-dependent immunotherapy of MHC class II-negative solid tumors Brightman, Spencer E. Becker, Angelica Thota, Rukman R. Naradikian, Martin S. Chihab, Leila Zavala, Karla Soria Ramamoorthy Premlal, Ashmitaa Logandha Griswold, Ryan Q. Dolina, Joseph S. Cohen, Ezra E. W. Miller, Aaron M. Peters, Bjoern Schoenberger, Stephen P. Nat Immunol Article CD4(+) T cells play key roles in a range of immune responses, either as direct effectors or through accessory cells, including CD8(+) T lymphocytes. In cancer, neoantigen (NeoAg)-specific CD8(+) T cells capable of direct tumor recognition have been extensively studied, whereas the role of NeoAg-specific CD4(+) T cells is less well understood. We have characterized the murine CD4(+) T cell response against a validated NeoAg (CLTC(H129>Q)) expressed by the MHC-II-deficient squamous cell carcinoma tumor model (SCC VII) at the level of single T cell receptor (TCR) clonotypes and in the setting of adoptive immunotherapy. We find that the natural CLTC(H129>Q)-specific repertoire is diverse and contains TCRs with distinct avidities as measured by tetramer-binding assays and CD4 dependence. Despite these differences, CD4(+) T cells expressing high or moderate avidity TCRs undergo comparable in vivo proliferation to cross-presented antigen from growing tumors and drive similar levels of therapeutic immunity that is dependent on CD8(+) T cells and CD40L signaling. Adoptive cellular therapy (ACT) with NeoAg-specific CD4(+) T cells is most effective when TCR-engineered cells are differentiated ex vivo with IL-7 and IL-15 rather than IL-2 and this was associated with both increased expansion as well as the acquisition and stable maintenance of a T stem cell memory (T(SCM))-like phenotype in tumor-draining lymph nodes (tdLNs). ACT with T(SCM)-like CD4(+) T cells results in lower PD-1 expression by CD8(+) T cells in the tumor microenvironment and an increased frequency of PD-1(+)CD8(+) T cells in tdLNs. These findings illuminate the role of NeoAg-specific CD4(+) T cells in mediating antitumor immunity via providing help to CD8(+) T cells and highlight their therapeutic potential in ACT. Nature Publishing Group US 2023-07-03 2023 /pmc/articles/PMC10382322/ /pubmed/37400675 http://dx.doi.org/10.1038/s41590-023-01543-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Brightman, Spencer E.
Becker, Angelica
Thota, Rukman R.
Naradikian, Martin S.
Chihab, Leila
Zavala, Karla Soria
Ramamoorthy Premlal, Ashmitaa Logandha
Griswold, Ryan Q.
Dolina, Joseph S.
Cohen, Ezra E. W.
Miller, Aaron M.
Peters, Bjoern
Schoenberger, Stephen P.
Neoantigen-specific stem cell memory-like CD4(+) T cells mediate CD8(+) T cell-dependent immunotherapy of MHC class II-negative solid tumors
title Neoantigen-specific stem cell memory-like CD4(+) T cells mediate CD8(+) T cell-dependent immunotherapy of MHC class II-negative solid tumors
title_full Neoantigen-specific stem cell memory-like CD4(+) T cells mediate CD8(+) T cell-dependent immunotherapy of MHC class II-negative solid tumors
title_fullStr Neoantigen-specific stem cell memory-like CD4(+) T cells mediate CD8(+) T cell-dependent immunotherapy of MHC class II-negative solid tumors
title_full_unstemmed Neoantigen-specific stem cell memory-like CD4(+) T cells mediate CD8(+) T cell-dependent immunotherapy of MHC class II-negative solid tumors
title_short Neoantigen-specific stem cell memory-like CD4(+) T cells mediate CD8(+) T cell-dependent immunotherapy of MHC class II-negative solid tumors
title_sort neoantigen-specific stem cell memory-like cd4(+) t cells mediate cd8(+) t cell-dependent immunotherapy of mhc class ii-negative solid tumors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382322/
https://www.ncbi.nlm.nih.gov/pubmed/37400675
http://dx.doi.org/10.1038/s41590-023-01543-9
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