You and Kim et al. identified discrete mitochondrial states in intratumoral cDC1s, wherein cDC1s with polarized mitochondria more effectively primed CD8+ T cells than depolarized cDC1s. OPA1 regulated mitochondrial fusion and membrane potential, sustaining NRF1 expression, OXPHOS, and NAD+/NADH balance to support cDC1 functional fitness. The OPA1-NRF1 axis suppressed autophagy- and lysosome-mediated degradation of MHC-I and antigens to support cDC1 immunogenic function. OPA1 loss impaired antigen presentation and promoted tumor growth, while whole-tumor-cell-pulsed polarized cDC1 administration synergized with ICB in solid tumor models.
Contributed by Shishir Pant
ABSTRACT: Antitumor immunity requires conventional type 1 dendritic cells (cDC1s). How cDC1s maintain functional fitness in the tumor microenvironment remains unclear. In this study, we established that intratumoral cDC1s exhibited discrete mitochondrial states and that OPA1-mediated mitochondrial energy and redox metabolism dictated cDC1 antitumor responses. Mechanistically, OPA1 orchestrated antigen presentation and the CD8(+) T cell priming function of cDC1s by promoting nuclear respiratory factor 1 (NRF1) expression and electron transport chain integrity, thereby supporting bioenergetics and NAD(+)/NADH balance. During tumor progression, mitochondrial membrane potential and volume, as well as OPA1-NRF1 signaling, declined in intratumoral cDC1s. Furthermore, intratumoral administration of cDC1s with polarized mitochondria showed immunotherapeutic benefits in mice, particularly in combination with immune checkpoint blockade. Collectively, our findings reveal mitochondrial metabolism and signaling as putative targets to reinvigorate cDC1 function for cancer immunotherapy.
Author Info: (1) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (2) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (3) De
Author Info: (1) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (2) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (3) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (4) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (5) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (6) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (7) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (8) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (9) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (10) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (11) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (12) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (13) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (14) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (15) Cell and Tissue Imaging Center, St. Jude Children's Research Hospital, Memphis, TN, USA. (16) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
