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Monitoring PD-1-Blocking Antibodies Bound to T Cells Derived from a Drop of Peripheral Blood
Published on: February 5, 2020
Aging-associated and CD4 T-cell-dependent ectopic CXCL13 activation predisposes to anti-PD-1 therapy-induced adverse
Hirotake Tsukamoto1,2, Yoshihiro Komohara3, Yusuke Tomita4
1Division of Clinical Immunology and Cancer Immunotherapy, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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.
Insights
Immune-related adverse events (irAEs) in cancer immunotherapy are linked to age. Aged mice treated with anti-PD-1 therapy developed irAEs mediated by an IL-21 and CXCL13 axis, suggesting new therapeutic targets for managing these toxicities.
Area of Science:
- Immunology
- Oncology
- Aging Research
Background:
- Immune-checkpoint blockade (ICB) therapy improves cancer treatment but can cause immune-related adverse events (irAEs).
- The precise mechanisms driving irAE development, particularly in aging populations, require further investigation.
Purpose of the Study:
- To elucidate the immunological mechanisms underlying irAEs in aged mice treated with anti-programmed death receptor (PD)-1 therapy.
- To identify potential therapeutic targets for mitigating ICB-induced toxicities.
Main Methods:
- Utilized a preclinical model of tumor-bearing aged mice receiving anti-PD-1 therapy.
- Investigated immune cell accumulation, immunoglobulin G (IgG) deposition, and cytokine/chemokine profiles (IL-21, CXCL13) in affected organs.
- Assessed the impact of B-cell depletion and blockade of IL-21 or CXCL13 on irAE development.
- Correlated findings with human patient data on CXCL13 and IL-21 expression in CD4 T cells.
Main Results:
- Aged mice treated with anti-PD-1 therapy exhibited irAE-like multiorgan dysfunction and ectopic immune cell accumulation.
- Organ toxicities were mediated by IgG deposition and linked to an IL-21-CXCL13 axis involving CD4 T cells and B cells.
- Therapeutic interventions targeting B cells, IL-21, or CXCL13 alleviated ICB-induced pathogenicity.
- Increased systemic CXCL13 and IL-21 expression in CD4 T cells correlated with irAE incidence in patients.
Conclusions:
- Age-associated immune dysregulation contributes to ICB-induced irAEs via an IL-21-CXCL13-autoantibody axis.
- The findings highlight the potential of targeting the IL-21-CXCL13 pathway for managing irAEs.
- CXCL13 may serve as a therapeutic target for irAE management in cancer immunotherapy.
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