The critical role of CD4+ T cells in PD-1 blockade against MHC-II–expressing tumors such as classic Hodgkin lymphoma

Abstract

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 MHC-II–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.

Systemic CD4 Immunity as a Key Contributor to PD-L1/PD-1 Blockade Immunotherapy Efficacy

“…In addition, it is not clear yet whether CD4 memory T cells could also play a role within the tumor microenvironment under PD-L1/PD-1 blockade therapy. A recent study in Classic Hodgkin lymphoma (CHL) murine models demonstrated that PD-1 blockade therapy has strong anti-tumor effects on MHC-II expressing tumors mediated by cytotoxic CD4+ T cells (77). Moreover, they observed that CHL patients responding to PD-1 blockade therapy exhibited high CD4+ T cell infiltration compared to non-responders (77).…”

“…A recent study in Classic Hodgkin lymphoma (CHL) murine models demonstrated that PD-1 blockade therapy has strong anti-tumor effects on MHC-II expressing tumors mediated by cytotoxic CD4+ T cells (77). Moreover, they observed that CHL patients responding to PD-1 blockade therapy exhibited high CD4+ T cell infiltration compared to non-responders (77). Another study using murine models demonstrated that the expansion of tumor infiltrating follicular CD4+ PD1+ T cells after PD-1 blockade therapy correlated with enhanced CD8 CTL anti-tumor responses and tumor growth control (78).…”

The Evolving Knowledge on T and NK Cells in Classic Hodgkin Lymphoma: Insights into Novel Subsets Populating the Immune Microenvironment

“…Indeed, studies on murine solid tumor models revealed that PD-1 blockade exerted anticancer effects against MHC-I − MHC-II + but not MHC-I − MHC-II − tumors. In addition, the anticancer activity of anti-PD-1 antibodies was abolished in mice depleted of CD4 + T-cells, but not CD8 + T-cells [ 86 ]. Independent studies have also shown that Th lymphocytes may mount a cytolytic response in appropriate contexts [ 86 , 87 ].…”

“…In addition, the anticancer activity of anti-PD-1 antibodies was abolished in mice depleted of CD4 + T-cells, but not CD8 + T-cells [ 86 ]. Independent studies have also shown that Th lymphocytes may mount a cytolytic response in appropriate contexts [ 86 , 87 ]. Mice bearing MHC-II + tumors had larger amounts of intratumoral CD4 + T-cells that stained positive for GrB, and this subset further increased following PD-1 blockade [ 86 ].…”

“…Independent studies have also shown that Th lymphocytes may mount a cytolytic response in appropriate contexts [ 86 , 87 ]. Mice bearing MHC-II + tumors had larger amounts of intratumoral CD4 + T-cells that stained positive for GrB, and this subset further increased following PD-1 blockade [ 86 ]. Similarly, a candidate circulating CD4 + “cytotoxic” T-cell subset (GrB + PD-1 + with EM phenotype) has been identified in cHL patients, particularly in the R/R setting.…”