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Plexin-A4 Mediates Cytotoxic T-cell Trafficking and Exclusion in Cancer
Cytotoxic T cell (CTL) infiltration of the tumor carries the potential to limit cancer progression, but their exclusion by the immunosuppressive tumor microenvironment hampers the efficiency of immunotherapy. Here, we show that expression of the axon guidance molecule Plexin-A4 (Plxna4) in CTLs, esp...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612191/ https://www.ncbi.nlm.nih.gov/pubmed/34815265 http://dx.doi.org/10.1158/2326-6066.CIR-21-0061 |
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author | Celus, Ward Oliveira, Ana I. Rivis, Silvia Van Acker, Heleen H. Landeloos, Ewout Serneels, Jens Cafarello, Sarah Trusso Van Herck, Yannick Mastrantonio, Roberta Köhler, Arnaud Garg, Abhishek D. Flamand, Véronique Tamagnone, Luca Marine, Jean-Christophe Matteo, Mario Di Costa, Bruno M. Bechter, Oliver Mazzone, Massimiliano |
author_facet | Celus, Ward Oliveira, Ana I. Rivis, Silvia Van Acker, Heleen H. Landeloos, Ewout Serneels, Jens Cafarello, Sarah Trusso Van Herck, Yannick Mastrantonio, Roberta Köhler, Arnaud Garg, Abhishek D. Flamand, Véronique Tamagnone, Luca Marine, Jean-Christophe Matteo, Mario Di Costa, Bruno M. Bechter, Oliver Mazzone, Massimiliano |
author_sort | Celus, Ward |
collection | PubMed |
description | Cytotoxic T cell (CTL) infiltration of the tumor carries the potential to limit cancer progression, but their exclusion by the immunosuppressive tumor microenvironment hampers the efficiency of immunotherapy. Here, we show that expression of the axon guidance molecule Plexin-A4 (Plxna4) in CTLs, especially in effector/memory CD8(+) T cells, is induced upon T-cell activation, sustained in the circulation, but reduced when entering the tumor bed. Therefore, we deleted Plxna4 and observed that Plxna4-deficient CTLs acquired improved homing capacity to the lymph nodes and to the tumor, as well as increased proliferation, both achieved through enhanced Rac1 activation. Mice with stromal or hematopoietic Plxna4 deletion exhibited enhanced CTL infiltration and impaired tumor growth. In a melanoma model, adoptive transfer of CTLs lacking Plxna4 prolonged survival and improved therapeutic outcome, which was even stronger when combined with anti–programmed cell death protein 1 (PD-1) treatment. PLXNA4 abundance in circulating CTLs was augmented in melanoma patients versus healthy volunteers but decreased after the first cycle of anti–PD-1, alone or in combination with anti–cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4), in those patients showing complete or partial response to the treatment. Altogether, our data suggest that Plxna4 acts as a “checkpoint,” negatively regulating CTL migration and proliferation through cell-autonomous mechanisms independent of the interaction with host-derived Plxna4 ligands, semaphorins. These findings pave the way toward Plxna4-centric immunotherapies and propose Plxna4 detection in circulating CTLs as a potential way to monitor the response to immune checkpoint blockade in patients with metastatic melanoma. |
format | Online Article Text |
id | pubmed-7612191 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-76121912022-07-01 Plexin-A4 Mediates Cytotoxic T-cell Trafficking and Exclusion in Cancer Celus, Ward Oliveira, Ana I. Rivis, Silvia Van Acker, Heleen H. Landeloos, Ewout Serneels, Jens Cafarello, Sarah Trusso Van Herck, Yannick Mastrantonio, Roberta Köhler, Arnaud Garg, Abhishek D. Flamand, Véronique Tamagnone, Luca Marine, Jean-Christophe Matteo, Mario Di Costa, Bruno M. Bechter, Oliver Mazzone, Massimiliano Cancer Immunol Res Research Articles Cytotoxic T cell (CTL) infiltration of the tumor carries the potential to limit cancer progression, but their exclusion by the immunosuppressive tumor microenvironment hampers the efficiency of immunotherapy. Here, we show that expression of the axon guidance molecule Plexin-A4 (Plxna4) in CTLs, especially in effector/memory CD8(+) T cells, is induced upon T-cell activation, sustained in the circulation, but reduced when entering the tumor bed. Therefore, we deleted Plxna4 and observed that Plxna4-deficient CTLs acquired improved homing capacity to the lymph nodes and to the tumor, as well as increased proliferation, both achieved through enhanced Rac1 activation. Mice with stromal or hematopoietic Plxna4 deletion exhibited enhanced CTL infiltration and impaired tumor growth. In a melanoma model, adoptive transfer of CTLs lacking Plxna4 prolonged survival and improved therapeutic outcome, which was even stronger when combined with anti–programmed cell death protein 1 (PD-1) treatment. PLXNA4 abundance in circulating CTLs was augmented in melanoma patients versus healthy volunteers but decreased after the first cycle of anti–PD-1, alone or in combination with anti–cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4), in those patients showing complete or partial response to the treatment. Altogether, our data suggest that Plxna4 acts as a “checkpoint,” negatively regulating CTL migration and proliferation through cell-autonomous mechanisms independent of the interaction with host-derived Plxna4 ligands, semaphorins. These findings pave the way toward Plxna4-centric immunotherapies and propose Plxna4 detection in circulating CTLs as a potential way to monitor the response to immune checkpoint blockade in patients with metastatic melanoma. American Association for Cancer Research 2022-01-01 2021-11-23 /pmc/articles/PMC7612191/ /pubmed/34815265 http://dx.doi.org/10.1158/2326-6066.CIR-21-0061 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Research Articles Celus, Ward Oliveira, Ana I. Rivis, Silvia Van Acker, Heleen H. Landeloos, Ewout Serneels, Jens Cafarello, Sarah Trusso Van Herck, Yannick Mastrantonio, Roberta Köhler, Arnaud Garg, Abhishek D. Flamand, Véronique Tamagnone, Luca Marine, Jean-Christophe Matteo, Mario Di Costa, Bruno M. Bechter, Oliver Mazzone, Massimiliano Plexin-A4 Mediates Cytotoxic T-cell Trafficking and Exclusion in Cancer |
title | Plexin-A4 Mediates Cytotoxic T-cell Trafficking and Exclusion in Cancer |
title_full | Plexin-A4 Mediates Cytotoxic T-cell Trafficking and Exclusion in Cancer |
title_fullStr | Plexin-A4 Mediates Cytotoxic T-cell Trafficking and Exclusion in Cancer |
title_full_unstemmed | Plexin-A4 Mediates Cytotoxic T-cell Trafficking and Exclusion in Cancer |
title_short | Plexin-A4 Mediates Cytotoxic T-cell Trafficking and Exclusion in Cancer |
title_sort | plexin-a4 mediates cytotoxic t-cell trafficking and exclusion in cancer |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612191/ https://www.ncbi.nlm.nih.gov/pubmed/34815265 http://dx.doi.org/10.1158/2326-6066.CIR-21-0061 |
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