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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Vydané v:	Proceedings of the National Academy of Sciences - PNAS Ročník 119; číslo 29; s. e2205378119
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 19.07.2022
Predmet:	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
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Abstract	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.
AbstractList	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. 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.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.
Author	Komohara, Yoshihiro Tsukamoto, Hirotake Miura, Yuji Kimura, Toshiki Fujiwara, Yukio Tomita, Yusuke Motoshima, Takanobu Ikeda, Tokunori Imamura, Kosuke Oshiumi, Hiroyuki Sakagami, Takuro Yano, Hiromu Kamba, Tomomi
Author_xml	– sequence: 1 givenname: Hirotake orcidid: 0000-0003-3214-1652 surname: Tsukamoto fullname: Tsukamoto, Hirotake organization: Department of Immunology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan – sequence: 2 givenname: Yoshihiro surname: Komohara fullname: Komohara, Yoshihiro organization: Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan – sequence: 3 givenname: Yusuke surname: Tomita fullname: Tomita, Yusuke organization: Department of Respiratory Medicine, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan – sequence: 4 givenname: Yuji surname: Miura fullname: Miura, Yuji organization: Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan – sequence: 5 givenname: Takanobu surname: Motoshima fullname: Motoshima, Takanobu organization: Department of Urology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan – sequence: 6 givenname: Kosuke surname: Imamura fullname: Imamura, Kosuke organization: Department of Respiratory Medicine, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan – sequence: 7 givenname: Toshiki surname: Kimura fullname: Kimura, Toshiki organization: Department of Respiratory Medicine, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan – sequence: 8 givenname: Tokunori surname: Ikeda fullname: Ikeda, Tokunori organization: Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Sojo University; Kumamoto, Japan – sequence: 9 givenname: Yukio surname: Fujiwara fullname: Fujiwara, Yukio organization: Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan – sequence: 10 givenname: Hiromu surname: Yano fullname: Yano, Hiromu organization: Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan – sequence: 11 givenname: Tomomi surname: Kamba fullname: Kamba, Tomomi organization: Department of Urology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan – sequence: 12 givenname: Takuro surname: Sakagami fullname: Sakagami, Takuro organization: Department of Respiratory Medicine, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan – sequence: 13 givenname: Hiroyuki surname: Oshiumi fullname: Oshiumi, Hiroyuki organization: Department of Immunology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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SubjectTerms	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
Title	Aging-associated and CD4 T-cell-dependent ectopic CXCL13 activation predisposes to anti-PD-1 therapy-induced adverse events
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