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,...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 29; p. e2205378119
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 19.07.2022
Subjects:
Aging - immunology
Animals
CD4-Positive T-Lymphocytes - immunology
Chemokine CXCL13 - immunology
Immune Checkpoint Inhibitors - adverse effects
Immune Checkpoint Inhibitors - therapeutic use
Immune System Diseases - etiology
Immunotherapy - adverse effects
Lymphocyte Activation
Mice
Neoplasms - therapy
Programmed Cell Death 1 Receptor - antagonists & inhibitors
ISSN:1091-6490, 1091-6490
Online Access:Get more information
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Summary: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 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.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.2205378119