Introduction: The clinical relevance of soluble forms of programmed cell death-1 (sPD-1) and programmed cell death-ligand 1 (sPD-L1) remains unclear. We here investigated the relation between the efficacy of PD-1 blockade and pretreatment plasma levels of sPD-1 and sPD-L1 across a broad range of cancer types., Methods: We retrospectively analyzed clinical data from 171 patients with advanced solid tumors who received nivolumab or pembrolizumab monotherapy regardless of treatment line. The concentrations of sPD-1 and sPD-L1 were measured with a fully automated immunoassay (HISCL system)., Results: The study subjects comprised patients with head and neck cancer ( n = 50), urothelial cancer ( n = 42), renal cell cancer ( n = 37), gastric cancer ( n = 20), esophageal cancer ( n = 10), malignant pleural mesothelioma ( n = 6), or microsatellite instability-high tumors ( n = 6). High or low levels of sPD-1 or sPD-L1 were not significantly associated with progression-free survival (PFS) or overall survival (OS) for PD-1 blockade in the entire study population. Comparison of treatment outcomes according to combinations of high or low sPD-1 and sPD-L1 levels, however, revealed that patients with low sPD-1 and high sPD-L1 concentrations had a significantly poorer PFS (HR of 1.79 [95% CI, 1.13-2.83], p = 0.01) and a tendency toward poorer OS (HR of 1.70 [95% CI, 0.99-2.91], p = 0.05) compared with all other patients., Conclusion: Our findings suggest that the combination of low sPD-1 and high sPD-L1 levels is a potential negative biomarker for PD-1 blockade therapy., Competing Interests: TKu: honoraria from AstraZeneca K.K. KC: grants or contracts from Meiji Seika Pharma Co., Ltd., Meiji Holdings Co., Ltd., Shimazu Corporation, and Menarini Biomarkers Singapore.; payment or honoraria from Cosmo Bio Co., Ltd., Bristol Myers Squibb Japan, Merck KGaA, AstraZeneca K.K., CHUGAI PHARMACEUTICAL CO., LTD., Novartis Pharma K.K, Hitachi, Ltd., Corning Incorporated., Agilent Technologies Japan, Ltd., and SBI Pharmaceuticals Co., Ltd.; patents to WO2017/099034, WO2018/084204, WO2017/115816, WO2020/149026, WO2019/188354, WO2021/095599, and PCT/JP2022/006843; program committee of Japanese Cancer Association.; board member of Japanese Society for Immunology, and Japanese Society of Cancer Immunology. SS: research funds from Nippon Boehringer Ingelheim Co., Ltd. HKan: lecture fees or honoraria from Chugai Pharmaceutical Co.,Ltd., and AstraZeneca K.K.; research funds from Chugai Pharmaceutical Co.,Ltd., and Takeda Pharmaceutical Co.,Ltd. SM: payment or honoraria from Taiho Pharmaceutical Co., and Ono Pharmaceutical Co. Ltd.: participation on a Data Safety Monitoring Board or Advisory Board to Chugai Pharmaceutical Co. Ltd. KT: payment or honoraria from AstraZeneca K.K., Merck Biopharma Co., Ltd., Eisai.Inc., Bristol Myers Squibb Company, ONO Pharmaceutical Co., MSD K.K., Chugai Pharmaceutical Co., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Novartis Pharma K.K. HKaw: Consulting or advisory fees from Astellas Pharma Inc. and Daiichi-Sankyo Co. Ltd.; honoraria from Bristol-Myers Squibb Co. Ltd., Ono Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., MSD K.K., Chugai Pharmaceutical Co. Ltd., Daiichi-Sankyo Co. Ltd., Merck Biopharma Co. Ltd., Takeda Pharmaceutical Co. Ltd., Yakult Pharmaceutical Industry, Taiho Pharmaceutical Co. Ltd., and Nippon Kayaku Co. Ltd.; and research funding from Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Kobayashi Pharmaceutical Co. Ltd., and Eisai Co. Ltd. YK: honoraria from Eisai Co., Ltd. TKo: lecture fees or honoraria from Janssen Pharmaceutical K.K., Astellas Pharma Inc., and Bayer Yakuhin, Ltd. KN: honoraria from Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Amgen Inc., Kyowa Kirin Co., Ltd., Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Co., Ltd., AstraZeneca K.K., 3H Clinical Trial Inc., Chugai Pharmaceutical Co., Ltd., Care Net, Inc., Eli Lilly Japan K.K., Medical Review Co., Ltd., MSD K.K., Medical Mobile Communications co., Ltd, Pfizer Japan Inc., YODOSHA CO., LTD., Nippon Boehringer Ingelheim Co., Ltd., Nikkei Business Publications, Inc., Taiho Pharmaceutical Co.,Ltd., Japan Clinical Research Operations, Bayer Yakuhin, Ltd., CMIC Co., Ltd., CMIC ShiftZero K.K., Novartis Pharma K.K., Life Technologies Japan Ltd., TAIYO Pharma Co., Ltd., Neo Communication, Bristol Myers Squibb Company, Daiichi Sankyo Co., Ltd., Janssen Pharmaceutical K.K., and Incyte biosciences Japan; research funding from PAREXEL International Corp., Eisai Co., Ltd., PRA HEALTHSCIENCES, AstraZeneca K.K., EPS Corporation., Mochida Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Labcorp Development Japan K.K.(Covance Japan Inc.), EPS International Co.,Ltd., Japan Clinical Research Operations, Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co.,Ltd., Taiho Pharmaceutical Co.,Ltd., GlaxoSmithKline K.K., MSD K.K., Sanofi K.K., Ono Pharmaceutical Co.,Ltd., Chugai Pharmaceutical Co.,Ltd., PPD-SNBL K.K, Nippon Boehringer Ingelheim Co.,Ltd., SymBio Pharmaceuticals Limited., Sysmex Corporation, IQVIA Services JAPAN K.K., Medical Research Support, SYNEOS HEALTH CLINICAL K.K., Eli Lilly Japan K.K., Nippon Kayaku Co.,Ltd., Amgen Inc., EP-CRSU Co., Ltd., Novartis Pharma K.K., Mebix, Inc., Otsuka Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., SRL, Inc., Janssen Pharmaceutical K.K., Pfizer R&D Japan G.K., CMIC CO., Ltd., Bayer Yakuhin, Ltd, Shionogi & Co., Ltd., Pfizer Japan Inc, Astellas Pharma Inc., Ascent Development Services, Kobayashi Pharmaceutical Co., Ltd., and Eisai Inc.; Consulting or advisor role to Eli Lilly Japan K.K., and Ono Pharmaceutical Co.,Ltd.; patent royalties from Daiichi Sankyo Co., Ltd. TH: grants or contracts from Meiji Seika Pharma Co., Ltd., Meiji Holdings Co., Ltd., Shimazu Corporation, Menarini Biomarkers Singapore; Royalties or licenses from ONO PHARMACEUTICAL CO., LTD.; patents to WO2017/099034, WO2018/084204, WO2017/115816, WO2020/149026, WO2019/188354, WO2021/095599, and PCT/JP2022/006843; honorary member of Japanese Cancer Association, Japanese Society for Immunology, Japanese Biochemical Society. HH: Grants or contracts IQVIA Services JAPAN K.K., Eisai Co., Ltd., SYNEOS HEALTH CLINICAL K.K., EP-CRSU CO., LTD., EPS Corporation., Shionogi & Co., Ltd., Nippon Kayaku Co.,Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.,Ltd., GlaxoSmithKline K.K., MSD K.K., Sanofi K.K., Amgen Inc., Chugai Pharmaceutical Co.,Ltd., Taiho Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim Co.,Ltd., Bristol Myers Squibb Company, SRL Medisearch Inc., Janssen Pharmaceutical K.K., PRA Health Sciences Inc., CMIC CO., Ltd., Astellas Pharma Inc., Pfizer R&D Japan G.K., Ascent Development Services, Labcorp Development Japan K.K., Eisai Inc., Kobayashi Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd, Pfizer Japan Inc.; payment or honoraria from Ono Pharmaceutical Co.,Ltd., Merck Biopharma Co., Ltd., Daiichi Sankyo Co., Ltd., 3H Clinical Trial Inc., AstraZeneca K.K., Novartis Pharma K.K., Chugai Pharmaceutical Co.,Ltd., Bristol Myers Squibb Company, Eli Lilly Japan K.K., Amgen Inc., MSD K.K., Sysmex Corporation, Pfizer Japan Inc., Takeda Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim Co.,Ltd. TS, CS and MY are employees of and receive remuneration from Sysmex Corporation. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. This study received funding from Sysmex Corporation. The funder had the following involvement with the study: conception and design, acquisition of data, analysis and interpretation of data, and writing and review of the manuscript., (Copyright © 2023 Kurosaki, Chamoto, Suzuki, Kanemura, Mitani, Tanaka, Kawakami, Kishimoto, Haku, Ito, Sato, Suminaka, Yamaki, Chiba, Yaguchi, Omori, Kobayashi, Nakagawa, Honjo and Hayashi.)