MedComm, Год журнала: 2024, Номер 5(6)

Опубликована: Июнь 1, 2024

Writing recently in Science, Lo and coworkers characterized a critical role of the gut microbiota CTLA-4 blockade-induced colitis, revealing that an Fc domain deficient anti-CTLA-4 antibody can elicit antitumor responses effectively while avoiding induction colitis-like disease.1 This research opens up novel avenues for employing therapy to circumvent onset which is often considered Achilles' heel what arguably most efficacious treatment certain blood cancers and/or solid tumors. domain-deficient Immune-checkpoint inhibitors (ICIs), involving anti-PD-1 antibodies, have emerged as effective cancer treatments over past decade. The such ipilimumab tremelimumab, are widely applied therapeutic agents clinical trials different cancers. These therapeutics enhance immune by blocking negative signals trigger T-cell activation, thus restoring tumor surveillance destroying cells. However, these immunotherapies also induce inflammatory toxicities known immune-related adverse events (irAEs), off-target effects resulting from excessively activated responses. Immune checkpoint blockade (ICB)-induced colitis represents one frequent severe irAEs among patients treated with either alone or combination antibodies. condition cuts short reduces quality life, ultimately causing fatality. Limited mechanistic understanding ICB-induced impedes continuous application finding approaches alleviate tissue damage associated therapy. inhibition may intestinal inflammation affects entire colon rather than segment it, leading severely compromised mucosa diffuse ulceration edema, observed endoscopic examination.2 Additionally, increased presence CD4+ effector Tregs cells, along enrichment CD8+ resident memory T (TRM) cells.3 Furthermore, lead loss self-tolerance mucosal flora autoantigens. Depletion cells appears play this process, though not all studies capitulate depletion following treatment.4 Consequently, it necessary carry out science, develop alternative without compromising benefits immunity (Figure 1). Built on observations free-living mice harboring wild microbiota, et al. performed functional comparison antibodies directed against PD-1 ICB-driven inflammation.1 In cecal accumulation IFNγ+ IL-17+ helper (TH) dual-positive IFNγ+IL-17+CD4+ TH was noted Day 9 after blockade. strong Tbet but comparatively moderate RORγt expression underscores TH1-skewed response during inflammation. proportion Foxp3+ decreases, selective RORγt+ throughout ICB period, indicating preferentially induces TH1 biased pTregs gut. Findings use IFNγ-neutralizing indicated T-cell-mediated IFNγ primarily responsible caused Moreover, data single-cell RNA sequencing (scRNA-seq) affirmed maintaining nonthymic closely linked homeostasis treatment. Considering above discovery via IFNγ, authors further explored pathogenic roles Following antibody, significant increase Tbet+ decrease were noted. suggests under homeostatic conditions, colitic generally restricted, be specifically when accompanied mouse microbiome-reconstituted (WildR) mice. Numerous preclinical FcRγ-dependent contributes efficacy induced ICB.4 minimal fecal LCN-2 induction, absence immunopathology tissues, low/no cytokine production FcRγ-deficient colonized WildR microbiota. Therefore, domain-dependent functions essential inflammation, evidenced humanized model To investigate necessity Fc-FcγR interactions developed extended half-life H11 (H11-HLE) comprised solely heavy chain fragments (VHHs) targeting CTLA-4. They used inoculated simultaneously monitor ICB-mediated rejection colitis. When administered monotherapeutic blockade, tumor-inoculated H11-HLE exhibited comparable activity those yet A decreased percentage animals compared isotype control, albeit lesser extent. suggest nanobodies still irAEs. alongside anti-PD-L1 did Their work provides evidence utility domain-lacking combined stimulated responses, presenting potential suffering settings Several early could restrain activation independently both autoimmunity responses.5 Hence, researches required thoroughly examine cumulative underlying mechanisms Notably, ICIs including across broad range organ systems, manifesting diverse frequencies severities. Thus, investigating other types irAEs, cutaneous pulmonary cardiac neurological so forth,2 equally important. utilizing domain-removed conjunction merits exploration. divergence between human models, humans entirely replicated animal models. researchers must prudent interpreting results studies, there crucial need their validation primates before translating into bench-side. Setting stepping stone encouraging study, scientists related field better prepared next-generation reduced toxicities, thereby improved potency. Jingjing Chen wrote initial draft manuscript drew figure. Dexuan Wang Hu Zhang supervised revised manuscript. All reviewed approved article. We thank members our laboratory helpful discussion. supported Wenzhou Traditional Chinese Medicine Hospital Zhejiang Medical University, Natural Science Foundation Province (LY17H050006), Public Welfare Technology Plan Project City (Y2020925), Sichuan International (grant number 2022NSFSC1363). Figure 1 created BioRender.com. declare they no conflicts interest. Not applicable.

Язык: Английский