Antigen presentation requirements for effective cDC1-based cancer immunotherapy
(1) Pineda JE (2) Minowa T (3) Shen L (4) Zhou Y (5) Dyevoich A (6) Patel B (7) Schneider SM (8) Keshari S (9) Saha A (10) Riba MN (11) Wang J (12) Watowich SS (13) Gubin MM
Ex vivo-differentiated cDC1s offer superior tumor protection compared to monocyte-derived DCs used in DC vaccine trials. Pinesa and Minowa et al. found that vaccine-delivered cDC1s closely resembled tumor-infiltrating endogenous cDC1s transcriptionally. Robust tumor control upon cDC1 vaccination required both MHC-I and MHC-II antigen presentation on the same cDC1, and transient CD40 stimulation was insufficient to compensate for MHC-II KO on cDC1s vaccines, suggesting direct in cis coordination of CD4+ and CD8+ T cell responses. Lack of host cDC1s in Irf8+32-/- mice with poorly immunogenic B16 tumors reduced the efficacy of cDC1 vaccination.
Contributed by Ute Burkhardt
(1) Pineda JE (2) Minowa T (3) Shen L (4) Zhou Y (5) Dyevoich A (6) Patel B (7) Schneider SM (8) Keshari S (9) Saha A (10) Riba MN (11) Wang J (12) Watowich SS (13) Gubin MM
Ex vivo-differentiated cDC1s offer superior tumor protection compared to monocyte-derived DCs used in DC vaccine trials. Pinesa and Minowa et al. found that vaccine-delivered cDC1s closely resembled tumor-infiltrating endogenous cDC1s transcriptionally. Robust tumor control upon cDC1 vaccination required both MHC-I and MHC-II antigen presentation on the same cDC1, and transient CD40 stimulation was insufficient to compensate for MHC-II KO on cDC1s vaccines, suggesting direct in cis coordination of CD4+ and CD8+ T cell responses. Lack of host cDC1s in Irf8+32-/- mice with poorly immunogenic B16 tumors reduced the efficacy of cDC1 vaccination.
Contributed by Ute Burkhardt
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 murine cDC1s, generated in culture from bone marrow cells (termed here "in vitro-derived 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 that 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.
Author Info:
(1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The Univer
sity of Texas MD Anderson Cancer Center, Houston, TX, United States. (2) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (3) Department of Bioinformatics and Computational Biology, Division of Discovery Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (4) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (5) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (6) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (7) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (8) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (9) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (10) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (11) Department of Bioinformatics and Computational Biology, Division of Discovery Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (12) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (13) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
