| RRC ID |
60965
|
| Author |
Nagasaki J, Togashi Y, Sugawara T, Itami M, Yamauchi N, Yuda J, Sugano M, Ohara Y, Minami Y, Nakamae H, Hino M, Takeuchi M, Nishikawa H.
|
| Title |
The critical role of CD4+ T cells in PD-1 blockade against MHC-II-expressing tumors such as classic Hodgkin lymphoma.
|
| Journal |
Blood Adv
|
| 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.
|
| Volume |
4(17)
|
| Pages |
4069-4082
|
| Published |
2020-9-8
|
| DOI |
10.1182/bloodadvances.2020002098
|
| PII |
S2473-9529(20)31169-1
|
| PMID |
32870971
|
| PMC |
PMC7479950
|
| MeSH |
Animals
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Histocompatibility Antigens Class II
Hodgkin Disease* / drug therapy
Mice
Programmed Cell Death 1 Receptor
Tumor Microenvironment
|
| IF |
4.91
|
| Resource |
| Mice |
RBRC01346 |
