1. Differential control of human Treg and effector T cells in tumor immunity by Fc-engineered anti–CTLA-4 antibody
- Author
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Ichiro Katayama, Karen Wei Weng Teng, Evan W. Newell, Danbee Ha, James B. Wing, Tatsuya Kibayashi, Hiroyoshi Nishikawa, Dennis Adeegbe, Shimon Sakaguchi, Atsushi Tanemura, Atsushi Tanaka, Daisuke Sugiyama, and Ee Lyn Lim
- Subjects
0301 basic medicine ,T cell ,medicine.medical_treatment ,chemical and pharmacologic phenomena ,CD8-Positive T-Lymphocytes ,Cancer Vaccines ,T-Lymphocytes, Regulatory ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Antineoplastic Agents, Immunological ,Cancer immunotherapy ,Neoplasms ,medicine ,Animals ,Humans ,CTLA-4 Antigen ,Antibody-dependent cell-mediated cytotoxicity ,Mice, Inbred BALB C ,Multidisciplinary ,biology ,Chemistry ,Antibody-Dependent Cell Cytotoxicity ,FOXP3 ,hemic and immune systems ,030104 developmental biology ,medicine.anatomical_structure ,PNAS Plus ,CTLA-4 ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Antibody ,CD8 - Abstract
Anti–CTLA-4 mAb is efficacious in enhancing tumor immunity in humans. CTLA-4 is expressed by conventional T cells upon activation and by naturally occurring FOXP3(+)CD4(+) Treg cells constitutively, raising a question of how anti–CTLA-4 mAb can differentially control these functionally opposing T cell populations in tumor immunity. Here we show that FOXP3(high) potently suppressive effector Treg cells were abundant in melanoma tissues, expressing CTLA-4 at higher levels than tumor-infiltrating CD8(+) T cells. Upon in vitro tumor-antigen stimulation of peripheral blood mononuclear cells from healthy individuals or melanoma patients, Fc-region–modified anti–CTLA-4 mAb with high antibody-dependent cell-mediated cytotoxicity (ADCC) and cellular phagocytosis (ADCP) activity selectively depleted CTLA-4(+)FOXP3(+) Treg cells and consequently expanded tumor-antigen–specific CD8(+)T cells. Importantly, the expansion occurred only when antigen stimulation was delayed several days from the antibody treatment to spare CTLA-4(+) activated effector CD8(+)T cells from mAb-mediated killing. Similarly, in tumor-bearing mice, high-ADCC/ADCP anti–CTLA-4 mAb treatment with delayed tumor-antigen vaccination significantly prolonged their survival and markedly elevated cytokine production by tumor-infiltrating CD8(+) T cells, whereas antibody treatment concurrent with vaccination did not. Anti–CTLA-4 mAb modified to exhibit a lesser or no Fc-binding activity failed to show such timing-dependent in vitro and in vivo immune enhancement. Thus, high ADCC anti–CTLA-4 mAb is able to selectively deplete effector Treg cells and evoke tumor immunity depending on the CTLA-4–expressing status of effector CD8(+) T cells. These findings are instrumental in designing cancer immunotherapy with mAbs targeting the molecules commonly expressed by FOXP3(+) Treg cells and tumor-reactive effector T cells.
- Published
- 2018