Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma
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Résumé
Treatment with monoclonal antibody specific for cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), an inhibitory receptor expressed by T lymphocytes, has emerged as an effective therapy for the treatment of metastatic melanoma. Although subject to debate, current models favor a mechanism of activity involving blockade of the inhibitory activity of CTLA-4 on both effector (T eff) and regulatory (T reg) T cells, resulting in enhanced antitumor effector T cell activity capable of inducing tumor regression. We demonstrate, however, that the activity of anti-CTLA-4 antibody on the T reg cell compartment is mediated via selective depletion of T reg cells within tumor lesions. Importantly, T reg cell depletion is dependent on the presence of Fcγ receptor-expressing macrophages within the tumor microenvironment, indicating that T reg cells are depleted in trans in a context-dependent manner. Our results reveal further mechanistic insight into the activity of anti-CTLA-4-based cancer immunotherapy, and illustrate the importance of specific features of the local tumor environment on the final outcome of antibody-based immunomodulatory therapies.
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La notice
- Revue
- The Journal of Experimental Medicine
- Thématique
- T-cell and B-cell Immunology
- Domaine
- Immunology and Microbiology
- Établissements canadiens
- —
- Organismes subventionnaires
- National Cancer InstituteCanadian Institutes of Health ResearchCancer Research UK
- Mots-clés
- Cytotoxic T cellCTLA-4Tumor microenvironmentCancer researchMelanomaImmunotherapyEffectorT cellImmunologyContext (archaeology)BiologyCancer immunotherapyAntigenMonoclonal antibodyTumor-infiltrating lymphocytesAntibodyImmune systemIn vitro
- Résumé présent dans OpenAlex
- oui