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, 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.

R-CHOP Chemotherapy for Disseminated Mycobacterium avium Complex Disease due to Anti-Interferon-Gamma Autoantibodies: A Case Report.

A 77-year-old Japanese man with disseminated Mycobacterium avium complex (MAC) disease due to anti-interferon-gamma autoantibodies received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy because of non-Hodgkin lymphoma complication. The hepatobiliary nodules due to MAC resolved with R-CHOP and multidrug antimycobacterial treatment. R-CHOP could serve as an alternative adjunctive therapy for patients with anti-interferon-gamma autoantibodies.

Endobronchial Lesions from Disseminated Mycobacterium avium Infection in a Patient with Anti-interferon-gamma Autoantibodies.

A 78-year-old man was admitted to our hospital with a fever and left chest pain. Computed tomography showed multiple lung nodules, narrowing of the right bronchus intermedius with mediastinal lymphadenopathy, and an osteolytic lesion. Bronchoscopic findings showed rapid progression of multiple polypoid lesions and the bronchial stenosis. A biopsy of the endobronchial lesions revealed non-necrotizing granulomatous inflammation, and a tissue culture identified Mycobacterium avium. An anti-human immunodeficiency virus antibody was negative. Finally, anti-interferon-gamma (IFN-γ) autoantibodies were detected, and the patient was diagnosed with disseminated nontuberculous mycobacterium infection with anti-IFN-γ autoantibodies. Antimycobacterial therapy was effective, and radiographic findings, including the endobronchial lesions, were resolved.