After 4 of 36 gastric cancer patients treated with anti-PD-1 developed hyperprogressive disease (HPD), Kamada, Togashi, and Tay et al. analyzed the pre-treatment and post-treatment tumor samples and discovered that the treatment increased the frequency of tumor-infiltrating, proliferating, activated PD-1+CD45RA-CD25highFoxP3high effector Tregs in HPD patients. The blockade or deficiency of PD-1 in Tregs increased their proliferation and immunosuppressive function in vitro and in vivo, and promoted tumor growth in mice with B16F0 melanoma. Thus, agents that deplete PD-1+ Tregs during anti-PD-1 treatment may prevent HPD.
PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in approximately 10% of anti-PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we explored how anti-PD-1 mAb caused HPD in these patients and how HPD could be treated and prevented. In the majority of GC patients, tumor-infiltrating FoxP3(high)CD45RA(-)CD4(+) T cells [effector Treg (eTreg) cells], which were abundant and highly suppressive in tumors, expressed PD-1 at equivalent levels as tumor-infiltrating CD4(+) or CD8(+) effector/memory T cells and at much higher levels than circulating eTreg cells. Comparison of GC tissue samples before and after anti-PD-1 mAb therapy revealed that the treatment markedly increased tumor-infiltrating proliferative (Ki67(+)) eTreg cells in HPD patients, contrasting with their reduction in non-HPD patients. Functionally, circulating and tumor-infiltrating PD-1(+) eTreg cells were highly activated, showing higher expression of CTLA-4 than PD-1(-) eTreg cells. PD-1 blockade significantly enhanced in vitro Treg cell suppressive activity. Similarly, in mice, genetic ablation or antibody-mediated blockade of PD-1 in Treg cells increased their proliferation and suppression of antitumor immune responses. Taken together, PD-1 blockade may facilitate the proliferation of highly suppressive PD-1(+) eTreg cells in HPDs, resulting in inhibition of antitumor immunity. The presence of actively proliferating PD-1(+) eTreg cells in tumors is therefore a reliable marker for HPD. Depletion of eTreg cells in tumor tissues would be effective in treating and preventing HPD in PD-1 blockade cancer immunotherapy.
Author Info: (1) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 104-0045 Tokyo, Japan. Department of Immunolo
Author Info: (1) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 104-0045 Tokyo, Japan. Department of Immunology, Nagoya University Graduate School of Medicine, 466-8550 Nagoya, Japan. (2) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 104-0045 Tokyo, Japan. (3) Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan. (4) Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan. (5) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 277-8577 Chiba, Japan. (6) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 277-8577 Chiba, Japan. (7) Department of Pathology, Institute of Medical Science, Tokyo Medical University, 160-0023 Tokyo, Japan. (8) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 104-0045 Tokyo, Japan. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 277-8577 Chiba, Japan. (9) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 104-0045 Tokyo, Japan. (10) Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan. (11) Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan. (12) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 104-0045 Tokyo, Japan. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 277-8577 Chiba, Japan. (13) Department of Surgical Oncology, National Cancer Center Hospital East, 277-8577 Chiba, Japan. (14) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 277-8577 Chiba, Japan. (15) Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan; shimon@ifrec.osaka-u.ac.jp hnishika@ncc.go.jp. (16) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 104-0045 Tokyo, Japan; shimon@ifrec.osaka-u.ac.jp hnishika@ncc.go.jp. Department of Immunology, Nagoya University Graduate School of Medicine, 466-8550 Nagoya, Japan.
