title: Impact of tumour microenvironment and Fc receptors on the activity of immunomodulatory antibodies.
abstract: Immunomodulatory antibodies influence the direction and magnitude of immune responses against cancer. Significant efficacy has been demonstrated across multiple solid tumour types within clinical trials. Recent preclinical studies indicate that successful outcome relies upon mechanistic activity extending beyond simple receptor stimulation or blockade. In addition to blocking co-inhibitory signals in secondary lymphoid organs, cytotoxic T-lymphocyte antigen (CTLA)-4 antibodies mediate depletion of tumour-infiltrating regulatory T cells by antibody-dependent cellular cytotoxicity (ADCC). This mechanism appears to be common to other immunomodulatory antibodies including those targeting OX40 and glucocorticoid-induced TNFR-related protein (GITR). If verified in the human setting, these findings have significant implications for antibody design, biomarker discovery, and the development of synergistic combinatorial therapies.
authors: Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK; The Royal Marsden Hospital, London, UK.
authors: Andrew J S
authors: AJ
authors: Furness
authors: Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK.
authors: Frederick Arce
authors: FA
authors: Vargas
authors: Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. Electronic address: k.peggs@ucl.ac.uk.
authors: Karl S
authors: KS
authors: Peggs
authors: Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. Electronic address: s.quezada@ucl.ac.uk.
authors: Sergio A
authors: SA
authors: Quezada
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D000943:Antigens, Differentiation / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000276:immunology; D055808:Drug Discovery; D004357:Drug Synergism; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000276:immunology; D006801:Humans; D056747:Immunomodulation; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011961:Receptors, Fc / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D059016:Tumor Microenvironment
chemical_list: D000906:Antibodies; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; D053450:Glucocorticoid-Induced TNFR-Related Protein; C406562:OX40Ig; D011961:Receptors, Fc; C491405:TNFRSF18 protein, human
keywords: Fc gamma receptors; anti-CTLA-4; cancer; immunomodulatory therapy; tumour microenvironment