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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 29; pp. 1 - 11
• 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: Washington National Academy of Sciences 19.07.2022
• Subjects: Adverse events; Aging; Autoantibodies; Biological Sciences; Cancer immunotherapy; CD4 antigen; Cell activation; Chemokines; CXCL13 protein; Damage accumulation; Depletion; IgG antibody; Immune checkpoint; Immunoglobulin G; Immunotherapy; Interleukin 21; Lymphocytes; Lymphocytes B; Lymphocytes T; Organs; Pathogenicity; Pathogens; PD-1 protein; Therapy; Toxicity; Tumors
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2205378119

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.