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Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors

INTRODUCTION: Increased T cell infiltration and interferon gamma (IFNγ) pathway activation are seen in tumors of melanoma patients who respond to ICI (immune checkpoint inhibitor) or MAPK pathway inhibitor (MAPKi) therapies. Yet, the rate of durable tumor control after ICI is almost twice that of MA...

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Autores principales: Ding, Lizhong, Sun, Lu, Bu, Melissa T., Zhang, Yanjun, Scott, Lauren N., Prins, Robert M., Su, Maureen A., Lechner, Melissa G., Hugo, Willy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10330698/
https://www.ncbi.nlm.nih.gov/pubmed/37435085
http://dx.doi.org/10.3389/fimmu.2023.1176994
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author Ding, Lizhong
Sun, Lu
Bu, Melissa T.
Zhang, Yanjun
Scott, Lauren N.
Prins, Robert M.
Su, Maureen A.
Lechner, Melissa G.
Hugo, Willy
author_facet Ding, Lizhong
Sun, Lu
Bu, Melissa T.
Zhang, Yanjun
Scott, Lauren N.
Prins, Robert M.
Su, Maureen A.
Lechner, Melissa G.
Hugo, Willy
author_sort Ding, Lizhong
collection PubMed
description INTRODUCTION: Increased T cell infiltration and interferon gamma (IFNγ) pathway activation are seen in tumors of melanoma patients who respond to ICI (immune checkpoint inhibitor) or MAPK pathway inhibitor (MAPKi) therapies. Yet, the rate of durable tumor control after ICI is almost twice that of MAPKi, suggesting that additional mechanisms may be present in patients responding to ICI therapy that are beneficial for anti-tumor immunity. METHODS: We used transcriptional analysis and clinical outcomes from patients treated with ICI or MAPKi therapies to delineate immune mechanisms driving tumor response. RESULTS: We discovered response to ICI is associated with CXCL13-driven recruitment of CXCR5+ B cells with significantly higher clonal diversity than MAPKi. Our in vitro data indicate that CXCL13 production was increased in human peripheral blood mononuclear cells by anti-PD1, but not MAPKi, treatment. Higher B cell infiltration and B cell receptor (BCR) diversity allows presentation of diverse tumor antigens by B cells, resulting in activation of follicular helper CD4 T cells (Tfh) and tumor reactive CD8 T cells after ICI therapy. Higher BCR diversity and IFNγ pathway score post-ICI are associated with significantly longer patient survival compared to those with either one or none. CONCLUSIONS: Response to ICI, but not to MAPKi, depends on the recruitment of CXCR5+ B cells into the tumor microenvironment and their productive tumor antigen presentation to follicular helper and cytotoxic, tumor reactive T cells. Our study highlights the potential of CXCL13 and B cell based strategies to enhance the rate of durable response in melanoma patients treated with ICI.
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spelling pubmed-103306982023-07-11 Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors Ding, Lizhong Sun, Lu Bu, Melissa T. Zhang, Yanjun Scott, Lauren N. Prins, Robert M. Su, Maureen A. Lechner, Melissa G. Hugo, Willy Front Immunol Immunology INTRODUCTION: Increased T cell infiltration and interferon gamma (IFNγ) pathway activation are seen in tumors of melanoma patients who respond to ICI (immune checkpoint inhibitor) or MAPK pathway inhibitor (MAPKi) therapies. Yet, the rate of durable tumor control after ICI is almost twice that of MAPKi, suggesting that additional mechanisms may be present in patients responding to ICI therapy that are beneficial for anti-tumor immunity. METHODS: We used transcriptional analysis and clinical outcomes from patients treated with ICI or MAPKi therapies to delineate immune mechanisms driving tumor response. RESULTS: We discovered response to ICI is associated with CXCL13-driven recruitment of CXCR5+ B cells with significantly higher clonal diversity than MAPKi. Our in vitro data indicate that CXCL13 production was increased in human peripheral blood mononuclear cells by anti-PD1, but not MAPKi, treatment. Higher B cell infiltration and B cell receptor (BCR) diversity allows presentation of diverse tumor antigens by B cells, resulting in activation of follicular helper CD4 T cells (Tfh) and tumor reactive CD8 T cells after ICI therapy. Higher BCR diversity and IFNγ pathway score post-ICI are associated with significantly longer patient survival compared to those with either one or none. CONCLUSIONS: Response to ICI, but not to MAPKi, depends on the recruitment of CXCR5+ B cells into the tumor microenvironment and their productive tumor antigen presentation to follicular helper and cytotoxic, tumor reactive T cells. Our study highlights the potential of CXCL13 and B cell based strategies to enhance the rate of durable response in melanoma patients treated with ICI. Frontiers Media S.A. 2023-06-26 /pmc/articles/PMC10330698/ /pubmed/37435085 http://dx.doi.org/10.3389/fimmu.2023.1176994 Text en Copyright © 2023 Ding, Sun, Bu, Zhang, Scott, Prins, Su, Lechner and Hugo 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
Ding, Lizhong
Sun, Lu
Bu, Melissa T.
Zhang, Yanjun
Scott, Lauren N.
Prins, Robert M.
Su, Maureen A.
Lechner, Melissa G.
Hugo, Willy
Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors
title Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors
title_full Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors
title_fullStr Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors
title_full_unstemmed Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors
title_short Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors
title_sort antigen presentation by clonally diverse cxcr5+ b cells to cd4 and cd8 t cells is associated with durable response to immune checkpoint inhibitors
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10330698/
https://www.ncbi.nlm.nih.gov/pubmed/37435085
http://dx.doi.org/10.3389/fimmu.2023.1176994
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