Antigen presentation requirements for effective cDC1-based cancer immunotherapy

Abstract Type 1 conventional dendritic cells (cDC1s) are important for generating and sustaining antitumor immunity. Accordingly, the abundance of cDC1s in human tumors correlates with improved outcomes in cancer. Capitalizing on this role, we previously demonstrated that vaccination with in vitro-derived murine cDC1s elicits durable tumor control in multiple preclinical models; however, the immunological mechanisms underlying the efficacy of cDC1 vaccination remain unclear. Here, we examined whether in vitro-derived cDC1s resemble tumor-infiltrating DC populations and whether MHC-I and MHC-II antigen presentation contribute to cDC1-mediated tumor control following vaccination in melanoma. As expected, MHC-I- or MHC-II-deficiency had minimal impact on the transcriptional state of cDC1s in homeostasis or following stimulation with the adjuvant poly dI:dC. Moreover, in vitro-derived cDC1s cultured under steady-state conditions closely resembled tumor-infiltrating cDC1s, whereas their poly dI:dC-stimulated counterparts resembled CCR7+ tumor-infiltrating DC populations, also referred to as mregDCs or LAMP3+ DCs. Our data further show that both MHC-I and MHC-II contribute to tumor control upon cDC1 vaccination, and coexpression of MHC-I and MHC-II on the same cDC1 is necessary for a robust vaccine response. We also identified an important function for host cDC1s in supporting the efficacy of vaccination with in vitro-derived cDC1s, as judged by impaired tumor control in Irf8+32-/- mice, which lack endogenous cDC1s. Overall, these results indicate that effective antitumor responses depend on MHC-I and MHC-II antigen presentation by vaccine-delivered cDC1s, with additional contributions from host cDC1s. Key points In vitro-generated cDC1s resemble intratumoral DC populations found in mice and humans. MHC-I and MHC-II antigen presentation by vaccine-delivered cDC1s contribute to antitumor efficacy. Coexpression of MHC-I and MHC-II on the same cDC1 enhances vaccine responses. Antitumor responses reflect the activity of vaccine and endogenous cDC1s. Competing Interest Statement J.E.P. received educational support through the Janssen Scholars of Immunology Diversity Engagement Program funded by Janssen Research & Development, LLC. M.M.G. reports a personal honorarium from Springer Nature Ltd (as a Deputy Editor for Nature Precision Oncology) and serves as a paid consultant for Merck.