Using quantitative immunohistochemistry to monitor the density of T cell subsets (with specificity verified by multiparametric CyTOF analysis), Sharma and Subudhi et al. demonstrate that in human cancers (melanoma, prostate cancer, and bladder cancer), treatment with anti-CTLA-4 (either IgG1 ipilimumab or IgG2 tremelimumab) increases the density of CD4+ and CD8+ T cells, but surprisingly does not deplete (and in some cases, increases) intratumoral Tregs. CD68+ macrophages were highly abundant and not impacted by anti-CTLA-4. Thus, in contrast to preclinical studies, depletion of Tregs may not be the operative mechanism of anti-CTLA-4.
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.
Author Info: (1) Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center. (2) Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Cent
Author Info: (1) Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center. (2) Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center. (3) Department of Immunology, MD Anderson Cancer Center. (4) Immunology, MD Anderson Cancer Center. (5) Immunology, University of Texas MD Anderson Cancer Center. (6) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center. (7) Department of Immunology, MD Anderson Cancer Center. (8) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (9) Department of Immunology, MD Anderson Cancer Center PadSharma@mdanderson.org.
