論文 - 詳細
| 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 9 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Colon-26(RCB2657) |