Cargando…

Aging-associated and CD4 T-cell–dependent ectopic CXCL13 activation predisposes to anti–PD-1 therapy-induced adverse events

Clinical success of immune-checkpoint blockade (ICB) cancer immunotherapy is compromised by increased risk of immune-related adverse events (irAEs). However, mechanistic action(s) of immune responses underlying development of irAE remain not fully explored. Here, we found that in tumor-bearing aged,...

Descripción completa

Detalles Bibliográficos
Autores principales: Tsukamoto, Hirotake, Komohara, Yoshihiro, Tomita, Yusuke, Miura, Yuji, Motoshima, Takanobu, Imamura, Kosuke, Kimura, Toshiki, Ikeda, Tokunori, Fujiwara, Yukio, Yano, Hiromu, Kamba, Tomomi, Sakagami, Takuro, Oshiumi, Hiroyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303859/
https://www.ncbi.nlm.nih.gov/pubmed/35858347
http://dx.doi.org/10.1073/pnas.2205378119
_version_ 1784751969028538368
author Tsukamoto, Hirotake
Komohara, Yoshihiro
Tomita, Yusuke
Miura, Yuji
Motoshima, Takanobu
Imamura, Kosuke
Kimura, Toshiki
Ikeda, Tokunori
Fujiwara, Yukio
Yano, Hiromu
Kamba, Tomomi
Sakagami, Takuro
Oshiumi, Hiroyuki
author_facet Tsukamoto, Hirotake
Komohara, Yoshihiro
Tomita, Yusuke
Miura, Yuji
Motoshima, Takanobu
Imamura, Kosuke
Kimura, Toshiki
Ikeda, Tokunori
Fujiwara, Yukio
Yano, Hiromu
Kamba, Tomomi
Sakagami, Takuro
Oshiumi, Hiroyuki
author_sort Tsukamoto, Hirotake
collection PubMed
description Clinical success of immune-checkpoint blockade (ICB) cancer immunotherapy is compromised by increased risk of immune-related adverse events (irAEs). However, mechanistic action(s) of immune responses underlying development of irAE remain not fully explored. Here, we found that in tumor-bearing aged, but not young, mice, antiprogrammed death receptor (PD)-1 therapy elicited irAE-like multiorgan dysfunctions with ectopic accumulation of T and B cells in damaged organs. In this preclinical model, the organ toxicities were mediated by immunoglobulin G (IgG) deposition because administration of IG from ICB-treated aged mice induced the pathogenicity specifically in naïve aged hosts. Mechanistically, CD4 T-cell–derived interleukin (IL)-21 upregulated B-cell–homing chemokine, CXCL13, preferentially in irAE organs from aged mice treated with anti–PD-1 therapy. The ICB-induced pathogenicity was alleviated by B-cell depletion or by blockade of IL-21 or CXCL13 activity. These results suggest that age-associated immune regulatory milieu contributes to the formation of tertiary lymphoid structure-like lymphocytic aggregates in irAE organs and irAE-related toxicity employing IL-21-CXCL13-auto-antibody axis. Supporting this, a systemic increase in CXCL13 and Il21 expression in CD4 T cells correlated with irAE incidence in ICB-treated patients. These findings provide rationale for therapeutic usefulness of CXCL13 in irAE management.
format Online
Article
Text
id pubmed-9303859
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher National Academy of Sciences
record_format MEDLINE/PubMed
spelling pubmed-93038592022-07-23 Aging-associated and CD4 T-cell–dependent ectopic CXCL13 activation predisposes to anti–PD-1 therapy-induced adverse events Tsukamoto, Hirotake Komohara, Yoshihiro Tomita, Yusuke Miura, Yuji Motoshima, Takanobu Imamura, Kosuke Kimura, Toshiki Ikeda, Tokunori Fujiwara, Yukio Yano, Hiromu Kamba, Tomomi Sakagami, Takuro Oshiumi, Hiroyuki Proc Natl Acad Sci U S A Biological Sciences Clinical success of immune-checkpoint blockade (ICB) cancer immunotherapy is compromised by increased risk of immune-related adverse events (irAEs). However, mechanistic action(s) of immune responses underlying development of irAE remain not fully explored. Here, we found that in tumor-bearing aged, but not young, mice, antiprogrammed death receptor (PD)-1 therapy elicited irAE-like multiorgan dysfunctions with ectopic accumulation of T and B cells in damaged organs. In this preclinical model, the organ toxicities were mediated by immunoglobulin G (IgG) deposition because administration of IG from ICB-treated aged mice induced the pathogenicity specifically in naïve aged hosts. Mechanistically, CD4 T-cell–derived interleukin (IL)-21 upregulated B-cell–homing chemokine, CXCL13, preferentially in irAE organs from aged mice treated with anti–PD-1 therapy. The ICB-induced pathogenicity was alleviated by B-cell depletion or by blockade of IL-21 or CXCL13 activity. These results suggest that age-associated immune regulatory milieu contributes to the formation of tertiary lymphoid structure-like lymphocytic aggregates in irAE organs and irAE-related toxicity employing IL-21-CXCL13-auto-antibody axis. Supporting this, a systemic increase in CXCL13 and Il21 expression in CD4 T cells correlated with irAE incidence in ICB-treated patients. These findings provide rationale for therapeutic usefulness of CXCL13 in irAE management. National Academy of Sciences 2022-07-11 2022-07-19 /pmc/articles/PMC9303859/ /pubmed/35858347 http://dx.doi.org/10.1073/pnas.2205378119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Tsukamoto, Hirotake
Komohara, Yoshihiro
Tomita, Yusuke
Miura, Yuji
Motoshima, Takanobu
Imamura, Kosuke
Kimura, Toshiki
Ikeda, Tokunori
Fujiwara, Yukio
Yano, Hiromu
Kamba, Tomomi
Sakagami, Takuro
Oshiumi, Hiroyuki
Aging-associated and CD4 T-cell–dependent ectopic CXCL13 activation predisposes to anti–PD-1 therapy-induced adverse events
title Aging-associated and CD4 T-cell–dependent ectopic CXCL13 activation predisposes to anti–PD-1 therapy-induced adverse events
title_full Aging-associated and CD4 T-cell–dependent ectopic CXCL13 activation predisposes to anti–PD-1 therapy-induced adverse events
title_fullStr Aging-associated and CD4 T-cell–dependent ectopic CXCL13 activation predisposes to anti–PD-1 therapy-induced adverse events
title_full_unstemmed Aging-associated and CD4 T-cell–dependent ectopic CXCL13 activation predisposes to anti–PD-1 therapy-induced adverse events
title_short Aging-associated and CD4 T-cell–dependent ectopic CXCL13 activation predisposes to anti–PD-1 therapy-induced adverse events
title_sort aging-associated and cd4 t-cell–dependent ectopic cxcl13 activation predisposes to anti–pd-1 therapy-induced adverse events
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303859/
https://www.ncbi.nlm.nih.gov/pubmed/35858347
http://dx.doi.org/10.1073/pnas.2205378119
work_keys_str_mv AT tsukamotohirotake agingassociatedandcd4tcelldependentectopiccxcl13activationpredisposestoantipd1therapyinducedadverseevents
AT komoharayoshihiro agingassociatedandcd4tcelldependentectopiccxcl13activationpredisposestoantipd1therapyinducedadverseevents
AT tomitayusuke agingassociatedandcd4tcelldependentectopiccxcl13activationpredisposestoantipd1therapyinducedadverseevents
AT miurayuji agingassociatedandcd4tcelldependentectopiccxcl13activationpredisposestoantipd1therapyinducedadverseevents
AT motoshimatakanobu agingassociatedandcd4tcelldependentectopiccxcl13activationpredisposestoantipd1therapyinducedadverseevents
AT imamurakosuke agingassociatedandcd4tcelldependentectopiccxcl13activationpredisposestoantipd1therapyinducedadverseevents
AT kimuratoshiki agingassociatedandcd4tcelldependentectopiccxcl13activationpredisposestoantipd1therapyinducedadverseevents
AT ikedatokunori agingassociatedandcd4tcelldependentectopiccxcl13activationpredisposestoantipd1therapyinducedadverseevents
AT fujiwarayukio agingassociatedandcd4tcelldependentectopiccxcl13activationpredisposestoantipd1therapyinducedadverseevents
AT yanohiromu agingassociatedandcd4tcelldependentectopiccxcl13activationpredisposestoantipd1therapyinducedadverseevents
AT kambatomomi agingassociatedandcd4tcelldependentectopiccxcl13activationpredisposestoantipd1therapyinducedadverseevents
AT sakagamitakuro agingassociatedandcd4tcelldependentectopiccxcl13activationpredisposestoantipd1therapyinducedadverseevents
AT oshiumihiroyuki agingassociatedandcd4tcelldependentectopiccxcl13activationpredisposestoantipd1therapyinducedadverseevents