Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3⁺ Regulatory T Cells (Tregs) in Human Cancers.

Abstract

CTLA-4 was the first inhibitory immune checkpoint to be identified. Two mAbs, 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 mAbs 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 patients with cancer treated with anti-CTLA-4 therapies. Quantitative IHC was used to evaluate the densities of intratumoral CD4⁺, CD8⁺, and FOXP3⁺ cells in stage-matched melanoma (<i>n</i> = 19), prostate cancer (<i>n</i> = 17), and bladder cancer (<i>n</i> = 9) samples treated with ipilimumab and in paired melanoma tumors (<i>n</i> = 18) treated with tremelimumab. These findings were corroborated with multiparametric mass cytometry analysis of tumor-infiltrating cells from paired fresh melanoma tumors (<i>n</i> = 5) treated with ipilimumab. Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4⁺ and CD8⁺ cells without significantly changing or depleting FOXP3⁺ cells within the tumor microenvironment. 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 mAbs to enhance Fc-mediated depletion of intratumoral regulatory T cells.See related commentary by Quezada and Peggs, p. 1130.