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

A Sharma, SK Subudhi, J Blando, J Scutti, L Vence… - Clinical Cancer …, 2019 - AACR
A Sharma, SK Subudhi, J Blando, J Scutti, L Vence, J Wargo, JP Allison, A Ribas, P Sharma
Clinical Cancer Research, 2019AACR
Purpose: 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 …
Purpose
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.
Experimental Design
Quantitative IHC 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 mAbs to enhance Fc-mediated depletion of intratumoral regulatory T cells.
See related commentary by Quezada and Peggs, p. 1130
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