TY - JOUR
T1 - The critical role of CD41 T cells in PD-1 blockade against MHC-II–expressing tumors such as classic Hodgkin lymphoma
AU - Nagasaki, Joji
AU - Togashi, Yosuke
AU - Sugawara, Takeaki
AU - Itami, Makiko
AU - Yamauchi, Nobuhiko
AU - Yuda, Junichiro
AU - Sugano, Masato
AU - Ohara, Yuuki
AU - Minami, Yosuke
AU - Nakamae, Hirohisa
AU - Hino, Masayuki
AU - Takeuchi, Masahiro
AU - Nishikawa, Hiroyoshi
N1 - Funding Information:
Female C57BL/6J and BALB/cA mice (6-8 weeks old) were purchased from CLEA Japan (Tokyo, Japan). C57BL/6J-Prkdc,scid./Rbrc mice (B6 SCID; RBRC01346) were provided by RIKEN BRC (Tsukuba, Japan) through the National BioResource Project of the Ministry of Education, Culture, Sports, Science and Technology/Japan Agency for Medical Research and Development (MEXT/AMED). A20/OVA cells (5 ⨯ 106), E.G7 cells (5 ⨯ 106), or MC-38 cells (1 ⨯ 106) were inoculated subcutaneously, and tumor volume was monitored every 3 days. The means of the long and short diameters were used to generate tumor growth curves. Mice were grouped when the tumor volume reached ;100 mm3, and anti-PD-1 mAb (200 mg/mouse), anti-LAG-3 mAb (300 mg/ mouse), or control mAb was administered intraperitoneally 3 times every 3 days thereafter. For CD4+ and CD8+ T-cell deletion, anti-CD4 mAb (100 mg/mouse) and anti-CD8b mAb (100 mg/mouse), respectively, were administered intraperitoneally 1 day before tumor cell inoculation and then injected every 7 days. Tumors were harvested 14 days after tumor cell inoculation to collect TILs for evaluation by flow cytometry. All in vivo experiments were performed at least twice (n 5 6 per group). All mice were maintained under specific-pathogen–free conditions in the animal facility of the Institute of Biophysics. Mouse experiments were approved by the Animal Committee for Animal Experimentation of the National Cancer Center and Chiba Cancer Center. All experiments met the standards set forth in the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, Bethesda, MD).
Funding Information:
This study was supported by Grants-in-Aid for Scientific Research S grant 17H06162 (H. Nishikawa); Young Scientists grant 17J09900, Challenging Exploratory Research grant 19K22574, and B grant 20H03694 from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Y.T.); the Project for Cancer Research and Therapeutic Evolution (P-CREATE) grants 16cm0106301h0002 (H. Nishikawa) and 18cm0106340h0001 (Y.T.); Practical Research for Innovative Cancer Control grant 19ck0106521h0001 (Y.T.); the Development of Technology for Patient Stratification Biomarker Discovery grant 19ae0101074s0401 (H. Nishikawa) from the Japan Agency for Medical Research and Development (AMED); National Cancer Center Research and Development Fund grants 28-A-7 and 31-A-7 (H. Nishikawa); the Naito Foundation (Y.T. and H. Nishikawa); and a Chiba Prefecture research grant, the Takeda Science Foundation, the Mitsubishi Foundation, the Tokyo Biochemical Research Foundation, the Daiichi Sankyo Foundation, and the Foundation for Promotion of Cancer Research in Japan (Y.T.).
Funding Information:
Conflict-of-interest disclosure: Y.T. received a research grant from KOTAI Biotechnologies, Inc, and honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, Chugai Pharmaceutical, and MSD outside of this study. M.S. received a research grant from Sysmex outside of this study. Y.M. received a research grant from Ono Pharmaceutical and honoraria from Bristol-Myers Squibb, Novartis, and Pfizer outside of this study. H. Nakamae received research grants and honoraria from Bristol-Myers Squibb, Novartis, and Otsuka Pharmaceutical; research grants from MSD, Janssen Pharmaceutical, and Astellas Pharmaceutical; and honoraria from Pfizer, Kyowa-Kirin, and Takeda outside of this study. M.H. received a research grant and honoraria from Pfizer; research grants from Kyowa-Kirin, Chugai Pharmaceutical, Otsuka Pharmaceutical, Astellas Pharmaceutical, Takeda, MSD, Sumitomo Dainippon Pharmaceutical, Taiho Pharmaceutical, Tei-jin, Eisai, and Japan Blood Products Organization; and honoraria from Novartis and Bristol-Myers Squibb outside of this study. H. Nishikawa received research grants and honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, and Bristol-Myers Squibb; honoraria from MSD; and research grants from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Oncolys BioPharma, Debiopharma, Asahi-Kasei, Astellas Pharmaceutical, Sumitomo Dainippon Pharma, Fuji Film, SRL, Sysmex, and BD Japan outside of this study. The remaining authors declare no competing financial interests.
Publisher Copyright:
© 2020 by The American Society of Hematology.
PY - 2020/9/8
Y1 - 2020/9/8
N2 - Classic Hodgkin lymphoma (cHL) responds markedly to PD-1 blockade therapy, and the clinical responses are reportedly dependent on expression of major histocompatibility complex class II (MHC-II). This dependence is different from other solid tumors, in which the MHC class I (MHC-I)/CD81 T-cell axis plays a critical role. In this study, we investigated the role of the MHC-II/CD41 T-cell axis in the antitumor effect of PD-1 blockade on cHL. In cHL, MHC-I expression was frequently lost, but MHC-II expression was maintained. CD41 T cells highly infiltrated the tumor microenvironment of MHC-II–expressing cHL, regardless of MHC-I expression status. Consequently, CD41 T-cell, but not CD81 T-cell, infiltration was a good prognostic factor in cHL, and PD-1 blockade showed antitumor efficacy against MHC-II–expressing cHL associated with CD41 T-cell infiltration. Murine lymphoma and solid tumor models revealed the critical role of antitumor effects mediated by CD41 T cells: an anti-PD-1 monoclonal antibody exerted antitumor effects on MHC-I2MHC-II1 tumors but not on MHC-I2MHC-II2 tumors, in a cytotoxic CD41 T-cell–dependent manner. Furthermore, LAG-3, which reportedly binds to MHC-II, was highly expressed by tumor-infiltrating CD41 T cells in MHC-II–expressing tumors. Therefore, the combination of LAG-3 blockade with PD-1 blockade showed a far stronger antitumor immunity compared with either treatment alone. We propose that PD-1 blockade therapies have antitumor effects on MHC-II–expressing tumors such as cHL that are mediated by cytotoxic CD41 T cells and that LAG-3 could be a candidate for combination therapy with PD-1 blockade.
AB - Classic Hodgkin lymphoma (cHL) responds markedly to PD-1 blockade therapy, and the clinical responses are reportedly dependent on expression of major histocompatibility complex class II (MHC-II). This dependence is different from other solid tumors, in which the MHC class I (MHC-I)/CD81 T-cell axis plays a critical role. In this study, we investigated the role of the MHC-II/CD41 T-cell axis in the antitumor effect of PD-1 blockade on cHL. In cHL, MHC-I expression was frequently lost, but MHC-II expression was maintained. CD41 T cells highly infiltrated the tumor microenvironment of MHC-II–expressing cHL, regardless of MHC-I expression status. Consequently, CD41 T-cell, but not CD81 T-cell, infiltration was a good prognostic factor in cHL, and PD-1 blockade showed antitumor efficacy against MHC-II–expressing cHL associated with CD41 T-cell infiltration. Murine lymphoma and solid tumor models revealed the critical role of antitumor effects mediated by CD41 T cells: an anti-PD-1 monoclonal antibody exerted antitumor effects on MHC-I2MHC-II1 tumors but not on MHC-I2MHC-II2 tumors, in a cytotoxic CD41 T-cell–dependent manner. Furthermore, LAG-3, which reportedly binds to MHC-II, was highly expressed by tumor-infiltrating CD41 T cells in MHC-II–expressing tumors. Therefore, the combination of LAG-3 blockade with PD-1 blockade showed a far stronger antitumor immunity compared with either treatment alone. We propose that PD-1 blockade therapies have antitumor effects on MHC-II–expressing tumors such as cHL that are mediated by cytotoxic CD41 T cells and that LAG-3 could be a candidate for combination therapy with PD-1 blockade.
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U2 - 10.1182/bloodadvances.2020002098
DO - 10.1182/bloodadvances.2020002098
M3 - Article
C2 - 32870971
AN - SCOPUS:85097612122
VL - 4
SP - 4069
EP - 4082
JO - Blood advances
JF - Blood advances
SN - 2473-9529
IS - 17
ER -