Anti-CTLA-4 antibodies drive myeloid activation and reprogram the tumor microenvironment through FcγR engagement and type I interferon signaling

Ido Yofe, Tomer Landsberger, Adam Yalin, Isabelle Solomon, Cristobal Costoya, Dafne Franz Demane, Mansi Shah, Eyal David, Chamutal Borenstein, Oren Barboy, Ignacio Matos, Karl S. Peggs, Sergio A. Quezada, Ido Amit

نتاج البحث: نشر في مجلةمقالةمراجعة النظراء

ملخص

Despite the clinical success of checkpoint inhibitors, a substantial gap still exists in our understanding of their mechanism of action. While antibodies to cytotoxic T lymphocyte-associated protein-4 (CTLA-4) were developed to block inhibitory signals in T cells, several recent studies have demonstrated that Fcγ receptor (FcγR)-dependent depletion of regulatory T cells (T reg) is critical for antitumor activity. Here, using single-cell RNA sequencing, we dissect the impact of anti-CTLA-4-blocking, T reg cell-depleting and FcR-engaging activity on the immune response within tumors. We observed a rapid remodeling of the innate immune landscape as early as 24 h after treatment. Using genetic T reg cell ablation models, we show that immune remodeling was not driven solely by T reg cell depletion or CTLA-4 blockade but mainly through FcγR engagement, downstream activation of type I interferon signaling and reduction of suppressive macrophages. Our findings indicate that FcγR engagement and innate immune remodeling are involved in successful anti-CTLA-4 treatment, supporting the development of optimized immunotherapy agents bearing these features.

اللغة الأصليةالإنجليزيّة
الصفحات (من إلى)1336-1350
عدد الصفحات15
دوريةNature Cancer
مستوى الصوت3
رقم الإصدار11
تاريخ مبكر على الإنترنت27 أكتوبر 2022
المعرِّفات الرقمية للأشياء
حالة النشرنُشِر - نوفمبر 2022

All Science Journal Classification (ASJC) codes

  • !!Oncology
  • !!Cancer Research

بصمة

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