| RRC ID |
83308
|
| 著者 |
Tsukamoto H, Komohara Y, Tomita Y, Miura Y, Motoshima T, Imamura K, Kimura T, Ikeda T, Fujiwara Y, Yano H, Kamba T, Sakagami T, Oshiumi H.
|
| タイトル |
Aging-associated and CD4 T-cell-dependent ectopic CXCL13 activation predisposes to anti-PD-1 therapy-induced adverse events.
|
| ジャーナル |
Proc Natl Acad Sci U S A
|
| 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 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.
|
| 巻・号 |
119(29)
|
| ページ |
e2205378119
|
| 公開日 |
2022-7-19
|
| DOI |
10.1073/pnas.2205378119
|
| PMID |
35858347
|
| PMC |
PMC9303859
|
| MeSH |
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
|
| IF |
9.412
|
| リソース情報 |
| ヒト・動物細胞 |
Colon-26(RCB2657) |
