Kidani et al. performed single-cell analysis of tumor CD25+CD4+ Tregs to determine their T cell receptor clonotypes and gene expression profiles. In various cancers, human and mouse expanded tumor Tregs were found to be stable, highly differentiated, and CCR8+, compared to Tregs in other tissues and conventional T cells (Tconvs), which were mostly CCR8-. In mouse tumor models, a cell-depleting anti-CCR8 mAb depleted tumor Tregs and cured established tumors with long-lasting memory and minimal autoimmune side effects. Anti-CCR8 treatment synergized with PD-1 inhibitors and expanded activated Agn-specific CD8+ effector Tconvs that were less exhausted.
Contributed by Katherine Turner
ABSTRACT: Foxp3-expressing CD25(+)CD4(+) regulatory T cells (Tregs) are abundant in tumor tissues. Here, hypothesizing that tumor Tregs would clonally expand after they are activated by tumor-associated antigens to suppress antitumor immune responses, we performed single-cell analysis on tumor Tregs to characterize them by T cell receptor clonotype and gene-expression profiles. We found that multiclonal Tregs present in tumor tissues predominantly expressed the chemokine receptor CCR8. In mice and humans, CCR8(+) Tregs constituted 30 to 80% of tumor Tregs in various cancers and less than 10% of Tregs in other tissues, whereas most tumor-infiltrating conventional T cells (Tconvs) were CCR8(-) CCR8(+) tumor Tregs were highly differentiated and functionally stable. Administration of cell-depleting anti-CCR8 monoclonal antibodies (mAbs) indeed selectively eliminated multiclonal tumor Tregs, leading to cure of established tumors in mice. The treatment resulted in the expansion of CD8(+) effector Tconvs, including tumor antigen-specific ones, that were more activated and less exhausted than those induced by PD-1 immune checkpoint blockade. Anti-CCR8 mAb treatment also evoked strong secondary immune responses against the same tumor cell line inoculated several months after tumor eradication, indicating that elimination of tumor-reactive multiclonal Tregs was sufficient to induce memory-type tumor-specific effector Tconvs. Despite induction of such potent tumor immunity, anti-CCR8 mAb treatment elicited minimal autoimmunity in mice, contrasting with systemic Treg depletion, which eradicated tumors but induced severe autoimmune disease. Thus, specific removal of clonally expanding Tregs in tumor tissues for a limited period by cell-depleting anti-CCR8 mAb treatment can generate potent tumor immunity with long-lasting memory and without deleterious autoimmunity.
Author Info: (1) Department of Basic Research in Tumor Immunology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. Department of Experimental Immunology, Immunology Fronti
Author Info: (1) Department of Basic Research in Tumor Immunology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan. Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. (2) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. (3) Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan. (4) Department of Urology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (5) Department of Basic Research in Tumor Immunology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan. (6) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. (7) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. (8) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. (9) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. (10) Department of Basic Research in Tumor Immunology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan. Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. (11) Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan. (12) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. (13) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (14) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (15) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. (16) Department of Basic Research in Tumor Immunology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. (17) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (18) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. (19) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. (20) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. (21) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (22) Pharmaceutical Research Division, Shionogi & Co., Ltd., 561-0825 Osaka, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (23) Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan. (24) Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, 565-0871 Osaka, Japan. (25) Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, 565-0871 Osaka, Japan. (26) Department of Neurology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (27) Department of Neurology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (28) Department of Neurology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (29) Department of Urology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (30) Department of Urology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (31) Department of Urology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (32) Department of Urology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (33) Department of Dermatology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (34) Department of Dermatology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (35) Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (36) Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (37) Department of Urology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (38) Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (39) Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (40) Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. (41) Department of Basic Research in Tumor Immunology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan; nohkura@ifrec.osaka-u.ac.jp shimon@ifrec.osaka-u.ac.jp. Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan. (42) Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan; nohkura@ifrec.osaka-u.ac.jp shimon@ifrec.osaka-u.ac.jp.
