The role of MHC class I and MHC class II tumor antigen presentation by migratory Type 1 conventional dendritic cell vaccines 4571

Description Dendritic cell (DC) cancer vaccines have underperformed as cancer therapies, possibly due to the use of suboptimal DC populations and targeting non-mutant MHC class I (MHC-I) antigens rather than tumor-specific MHC-I and MHC-II neoantigens. CD103+ type 1 DCs (DC1s) can cross-present tumor antigens to CD8 T cells and receive a CD40-dependent licensing signal when presenting MHC-II antigens to CD4 T cells, which enhances their survival and expression of MHC and T cell costimulatory molecules. However, in a DC1 vaccine context, it is unknown whether or how MHC-I and MHC-II neoantigen presentation shapes T cell responses and vaccine efficacy. To investigate this, we used DC1 neoantigen vaccines and a melanoma model expressing MHC-I and MHC-II model neoantigens to evaluate the anti-tumor efficacy of WT, MHC-I-deficient, and MHC-II-deficient DC1 vaccines. Our results show DC1 vaccines require presentation of both MHC-I and MHC-II antigens on the same cell for full therapeutic efficacy. Additionally, in vitro stimulation of DC1s with polyI:C and αCD40 induced expression of CD70, 4-1BBL, and the anti-apoptotic transcript Bcl2l1, suggesting MHC-II neoantigen presentation to CD4 T cells by DC1 vaccines is critical for their CD40-dependent licensing, enhanced T cell costimulation, and survival. Overall, these data highlight the importance of both MHC-I and MHC-II antigen presentation and CD40 licensing by DC1 vaccines for optimal anti-tumor immunity. Funding Sources NCI R01CA282027, CPRIT RR190017, 2R56AI109294-06A1, Johnson & Johnson Scholars of Immunology Diversity and Engagement Program.