Impact of tumour microenvironment and Fc receptors on the activity of immunomodulatory antibodies

Trends Immunol. 2014 Jul;35(7):290-8. doi: 10.1016/ Epub 2014 Jun 18.


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.

Keywords: Fc gamma receptors; anti-CTLA-4; cancer; immunomodulatory therapy; tumour microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antibodies / immunology*
  • Antibody-Dependent Cell Cytotoxicity
  • Antigens, Differentiation / immunology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • CTLA-4 Antigen / immunology
  • Drug Discovery
  • Drug Synergism
  • Glucocorticoid-Induced TNFR-Related Protein / immunology
  • Humans
  • Immunomodulation
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Receptors, Fc / immunology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Microenvironment


  • Antibodies
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • Glucocorticoid-Induced TNFR-Related Protein
  • OX40Ig
  • Receptors, Fc
  • TNFRSF18 protein, human