Anti-CTLA4 antibodies induce an FcγR-dependent depletion of Tregs to promote tumor rejection.
Major finding: Anti-CTLA4 antibodies induce an FcγR-dependent depletion of Tregs to promote tumor rejection.
Clinical relevance: A high affinity FcγR polymorphism is linked to ipilimumab response in patients with melanoma.
Impact: Enhancing the Fc effector function of anti-CTLA4 antibodies may improve their antitumor activity.
Immune checkpoint blockade with anti-CTLA4 antibodies relieves inhibition of effector T cells to promote antitumor immune responses. In addition, recent preclinical data has suggested that anti-CTLA4 may also deplete regulatory T cells (Treg) via antibody-dependent cell-mediated cytotoxicity (ADCC), but the effects on Tregs are not well understood. Vargas, Furness, and colleagues investigated the role of Treg depletion in anti-CTLA4–mediated antitumor immunity in vivo using a mouse model expressing human Fc-gamma receptors (FcγR) treated with anti-CTLA4 monoclonal antibodies. CTLA4 was highly expressed by tumor-infiltrating Treg cells, and treatment with anti-CTLA4 antibodies induced FcγR-dependent cytotoxicity in vitro and depleted intratumoral Tregs in vivo. This resulted in an increase in the ratio of intratumoral T effector cells to Tregs, thereby enhancing antitumor immunity. In mouse models of fibrosarcoma or colon carcinoma, anti-CTLA4 alone was insufficient to produce a robust antitumor immune response, whereas CTLA4 blockade with an antibody with enhanced affinity for activating FcγRs produced durable tumor regression. However, this effect was not observed in a B16 melanoma model, suggesting that it may be relevant only to inflamed tumors with abundant expression of FcγR-expressing innate effector cells. In patients with advanced melanoma, a single nucleotide polymorphism in the FcγR-activating receptor CD16a (CD16a-V158F) that resulted in an increased affinity for IgG was associated with an increased response to treatment with the anti-CTLA4 antibody ipilimumab in inflamed tumors. Taken together, these findings suggest that enhancing the FcγR binding activity of anti-CTLA4 antibodies may result in superior efficacy, depleting intratumoral Tregs to improve the antitumor activity.
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