The critical role of CD41 T cells in PD-1 blockade against MHC-II–expressing tumors such as classic Hodgkin lymphoma

Joji Nagasaki, Yosuke Togashi, Takeaki Sugawara, Makiko Itami, Nobuhiko Yamauchi, Junichiro Yuda, Masato Sugano, Yuuki Ohara, Yosuke Minami, Hirohisa Nakamae, Masayuki Hino, Masahiro Takeuchi, Hiroyoshi Nishikawa

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)4069-4082
Number of pages14
JournalBlood Advances
Issue number17
Publication statusPublished - Sept 8 2020
Externally publishedYes

ASJC Scopus subject areas

  • Hematology


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