Good news! Cancer is history (soon)!
"Dendritic cells ... By using their long projections to display fragments of protein, they summon other immune cells to attack invaders and destroy diseased cells. But when dendritic cells find themselves inside a tumor, they tend to run out of steam. According to new research, these cells stop working because their mitochondria ... become degraded.
When scientists examined mice with melanoma, they found that some dendritic cells within the animals’ tumors had perfectly healthy mitochondria, while others were debilitated.
As the tumors grew, the number of cells with active mitochondria dwindled. Although it’s unclear exactly why these organelles go on the fritz, the team did determine that a protein called OPA1 appears to be essential to their functioning. Dendritic cells that possessed this protein were much better at rallying other immune cells, while those engineered to lack it were far less effective—leading to more tumor growth.
When the researchers injected the rodents’ dendritic cells with lots of additional mitochondria, the animals were able to mount a strong antitumor response and fared better when treated with a type of immunotherapy. ..."
From the Perspective abstract:
"Dendritic cells are innate immune cells that regulate the quality, magnitude, and duration of antitumor responses. Conventional type 1 dendritic cells (cDC1s) are crucial in this capacity but are paradoxically rare and functionally impaired in most solid tumors. This is a major barrier to effective immunotherapy. The molecular underpinnings of cDC1 dysfunction within the tumor microenvironment are poorly understood. On page 55 of this issue, You et al. (1) report that mitochondrial fitness is important for cDC1 function. They also demonstrate the therapeutic rescue of cDC1 function within the tumor microenvironment in mice, which provides a framework for metabolically reprogramming dendritic cells to restore antitumor immunity."
From the editor's summary and abstract:
"Editor’s summary
Type 1 conventional dendritic cells (cDC1s) promote CD8+ T cell–mediated antitumor responses. However, cDC1s can become dysfunctional in the tumor microenvironment, and the mechanisms governing cDC1 function versus dysfunction in cancer remain unclear. You et al. report that mitochondrial metabolic states and signaling direct cDC1 function in antitumor immunity (see the Perspective by Molina and Haldar). Loss of the mitochondrial protein OPA1 disrupted nuclear respiratory factor 1 (NRF1) activity and electron transport chain integrity, leading to defects in mitochondrial bioenergetics and redox balance in cDC1s, accompanied by reduced tumor control. OPA1-NRF1 signaling progressively declined during tumor progression, and tumor-bearing mice receiving cDC1s with high mitochondrial fitness had improved antitumor responses, especially in combination with immunotherapy. Therefore, “metabolic engineering” of cDC1s may provide a mechanism for cancer immunotherapy. —Priscilla N. Kelly
Structured Abstract
INTRODUCTION
Conventional type 1 dendritic cells (cDC1s) are essential for cytotoxic CD8+ T cell responses in cancer immunity and immunotherapy. Although previous studies have suggested that mitochondrial oxidative phosphorylation (OXPHOS) is dispensable for DC maturation in vitro and represents a hallmark of tolerance in human monocyte–derived DCs, whether and how mitochondrial metabolism regulates cDC1-CD8+ T cell interactions in antitumor immunity remain largely unknown. In this study, we reveal that intratumoral cDC1s have discrete mitochondrial states and that mitochondrial fusion protein OPA1 dictates cDC1 antitumor immunity by facilitating mitochondrial energy and redox metabolism.
RATIONALE
Despite the success of immunotherapy in cancer treatment, therapeutic resistance or relapse occurs in a large subset of patients. cDC1s determine antitumor effects and therapeutic benefits upon immune checkpoint blockade (ICB) by orchestrating CD8+ T cell activation and function. However, cDC1s often experience metabolic stress and exhibit decreased functional fitness within the tumor microenvironment. ...
RESULTS
We established, from both mouse and human tumors, that cDC1s exhibit discrete mitochondrial states.
One subpopulation, referred to as [TMRM/MG]hi cells, contained polarized mitochondria, as demonstrated by the ratio of mitochondrial membrane potential [measured with tetramethylrhodamine methyl ester perchlorate (TMRM)] compared with mitochondrial mass [measured with MitoTracker Green (MG)]; whereas the
other subpopulation, [TMRM/MG]lo cells, had depolarized mitochondria. Intratumoral cDC1s with polarized mitochondria more effectively primed CD8+ T cell responses than those with depolarized mitochondria.
Using unbiased profiling approaches and experimental validations, we uncovered that OPA1 orchestrates the mitochondrial states and morphology in intratumoral cDC1s.
Notably, OPA1 deletion in cDC1s led to increased tumor growth and impaired antitumor CD8+ T cell responses, corresponding to defective antigen presentation by cDC1s. Mechanistically, we established that OPA1 supports nuclear respiratory factor 1 (NRF1) activity and expression to sustain mitochondrial OXPHOS in cDC1s. OPA1-NRF1 axis–mediated OXPHOS inhibited autophagy and lysosome–dependent degradation of major histocompatibility complex I (MHC-I) and antigen. In addition, OPA1-mediated electron transport chain (ETC) flow contributed to cDC1 immunogenicity by facilitating NADH-to-NAD+ conversion (i.e., conversion from the reduced to the oxidized form of nicotinamide adenine dinucleotide). These OPA1-dependent effects were antagonized by mitochondrial fission protein DRP1.
During tumor progression, intratumoral cDC1s experienced a progressive mitochondrial dysfunction, as revealed by reduction of the [TMRM/MG]hi subpopulation as well as decreased mitochondrial volume and OPA1-NRF1 signaling.
Intratumoral administration of tumor antigen–pulsed cDC1s with polarized mitochondria into tumor-bearing mice resulted in superior tumor control compared with cDC1s with depolarized mitochondria, particularly when combined with ICB therapies. Indeed, a substantial proportion of mice receiving cotreatment of tumor antigen–pulsed cDC1s with polarized mitochondria plus ICB completely rejected tumors and developed durable immune memory responses upon tumor rechallenge.
CONCLUSION
We uncovered discrete mitochondrial states and the underlying mitochondrial metabolic signaling programs in cDC1s that support their functional fitness in antitumor immunity and the establishment of durable ICB responses. These discoveries provide opportunities to reinvigorate cDC1s for improved cancer immunotherapy."
ScienceAdviser
Mitochondrial metabolism and signaling orchestrate cDC1 antitumor responses.
