Anti-CTLA-4 immunotherapy does not deplete FOXP3+ regulatory T cells (Tregs) in human cancers

Abstract Purpose: CTLA-4 was the first inhibitory immune checkpoint to be identified. Two monoclonal antibodies, ipilimumab (IgG1) and tremelimumab (IgG2), which block the function of CTLA-4, have demonstrated durable clinical activity in a subset of patients with advanced solid malignancies by augmenting effector T cell-mediated immune responses. Studies in mice suggest that anti-CTLA-4 monoclonal antibodies may also selectively deplete intratumoral FOXP3+ regulatory T cells via an Fc-dependent mechanism. However, it is unclear whether the depletion of FOXP3+ cells occurs in cancer patients treated with anti-CTLA-4 therapies. Experimental Design: Quantitative immunohistochemistry was used to evaluate the densities of intratumoral CD4+, CD8+ and FOXP3+ cells in stage-matched melanoma (N=19), prostate cancer (N=17) and bladder cancer (N=9) samples treated with ipilimumab and in paired melanoma tumors (N=18) treated with tremelimumab. These findings were corroborated with multiparametric mass cytometry analysis of tumor infiltrating cells from paired fresh melanoma tumors (N=5) treated with ipilimumab. Results: Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment. Conclusions: Anti-CTLA-4 immunotherapy does not deplete FOXP3+ cells in human tumors, which suggests that their efficacy could be enhanced by modifying the Fc portions of the monoclonal antibodies to enhance Fc-mediated depletion of intratumoral regulatory T cells.

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