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

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.