期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：29
DOI：10.1073/pnas.2205378119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Immune-related adverse events (irAEs) induced by immune-checkpoint blockade including antiprogrammed death receptor (PD)-1 therapy are a major problematic issue in cancer immunotherapy. Preclinical models for more physiologically occurring irAEs are potentially useful for the clarification of fundamental causes and natural developmental course of irAEs. Here, we found that in tumor-bearing aged, but not young, mice, anti–PD-(L)1 therapy alone induces irAE-like multiorgan toxicities through CD4 T-cell–derived interleukin (IL)-21 and subsequent age-specific CXCL13 expression in tertiary lymphoid structure. Consistent with this animal model, a systemic increase in CXCL13 correlates with irAE incidence in cancer patients. These findings provide insight into the development of management strategies for irAE that balance both irAE-related immune response and antitumor immune surveillance.
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.
