Journal
BLOOD ADVANCES
Volume 4, Issue 17, Pages 4069-4082Publisher
ELSEVIER
DOI: 10.1182/bloodadvances.2020002098
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [17H06162, 17J09900, 19K22574, 20H03694]
- Project for Cancer Research and Therapeutic Evolution (P-CREATE) [16cm0106301h0002, 18cm0106340h0001]
- Practical Research for Innovative Cancer Control grant [19ck0106521h0001]
- Development of Technology for Patient Stratification Biomarker Discovery grant from the Japan Agency for Medical Research and Development (AMED) [19ae0101074s0401]
- National Cancer Center Research and Development Fund [28-A-7, 31-A-7]
- Naito Foundation
- Chiba Prefecture research grant
- Takeda Science Foundation
- Mitsubishi Foundation
- Tokyo Biochemical Research Foundation
- Daiichi Sankyo Foundation
- Foundation for Promotion of Cancer Research in Japan
- Grants-in-Aid for Scientific Research [17J09900, 19K22574, 20H03694] Funding Source: KAKEN
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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)/CD8(+) T-cell axis plays a critical role. In this study, we investigated the role of the MHC-II/CD4(+) 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. CD4(+) T cells highly infiltrated the tumor microenvironment of MHC-II-expressing cHL, regardless of MHC-I expression status. Consequently, CD4(+) T-cell, but not CD8(+) T-cell, infiltration was a good prognostic factor in cHL, and PD-1 blockade showed antitumor efficacy against MHC-II-expressing cHL associated with CD4(+) T-cell infiltration. Murine lymphoma and solid tumor models revealed the critical role of antitumor effects mediated by CD4(+) T cells: an anti-PD-1 monoclonal antibody exerted antitumor effects on MHC-I+-MHC-II+ tumors but not on MHC-I+MHC-II+ tumors, in a cytotoxic CD4(+) T-cell-dependent manner. Furthermore, LAG-3, which reportedly binds to MHC-II, was highly expressed by tumor-infiltrating CD4(+) 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 MHCII-expressing tumors such as cHL that are mediated by cytotoxic CD4(+) T cells and that LAG-3 could be a candidate for combination therapy with PD-1 blockade.
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