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Anti-CTLA-4 antibodies drive myeloid activation and reprogram the tumor microenvironment through FcγR engagement and type I interferon signaling.
Yofe, Ido; Landsberger, Tomer; Yalin, Adam; Solomon, Isabelle; Costoya, Cristobal; Demane, Dafne Franz; Shah, Mansi; David, Eyal; Borenstein, Chamutal; Barboy, Oren; Matos, Ignacio; Peggs, Karl S; Quezada, Sergio A; Amit, Ido.
Afiliación
  • Yofe I; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
  • Landsberger T; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
  • Yalin A; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
  • Solomon I; Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK.
  • Costoya C; Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK.
  • Demane DF; Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK.
  • Shah M; Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK.
  • David E; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
  • Borenstein C; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
  • Barboy O; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
  • Matos I; Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK.
  • Peggs KS; Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK.
  • Quezada SA; Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. s.quezada@ucl.ac.uk.
  • Amit I; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. ido.amit@weizmann.ac.il.
Nat Cancer ; 3(11): 1336-1350, 2022 11.
Article en En | MEDLINE | ID: mdl-36302895
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 (Treg) is critical for antitumor activity. Here, using single-cell RNA sequencing, we dissect the impact of anti-CTLA-4-blocking, Treg 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 Treg cell ablation models, we show that immune remodeling was not driven solely by Treg 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Interferón Tipo I / Microambiente Tumoral Tipo de estudio: Prognostic_studies Idioma: En Revista: Nat Cancer Año: 2022 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Interferón Tipo I / Microambiente Tumoral Tipo de estudio: Prognostic_studies Idioma: En Revista: Nat Cancer Año: 2022 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Reino Unido