Zewdie et al. demonstrated the role of MerTK in regulating DC metabolism and function in the tumor microenvironment. In a melanoma model, resistance to anti-PD-1 therapy correlated with increased expression of MerTK in DCs. Wild-type DCs treated with apoptotic melanoma cells showed elevated MerTK expression, mitochondrial respiration, fatty acid oxidation, and reduced T cell stimulatory capacity, while MerTK-deficient DCs maintained an antigen-presenting stimulatory phenotype. DC-specific MerTK ablation increased T cell infiltration, reduced tumor growth, and enhanced anti-PD-1 efficacy, pointing to MerTK as a therapeutic target.
Contributed by Shishir Pant
ABSTRACT: Checkpoint inhibitors, specifically anti-PD-1, have shown success in treating metastatic melanoma; however, some patients develop resistance. Dendritic cells (DCs) play a key role in initiating an immune response but in certain circumstances they become ineffective. We investigated the role of MerTK, a receptor tyrosine kinase responsible for myeloid cell clearance of dead cells, in the regulation of DC function and metabolism in the tumor microenvironment. Tumors resistant to anti-PD-1 exhibited increased levels of MerTK+ DCs. Treating wild-type DCs with apoptotic dead melanoma cells in vitro resulted in increased MerTK expression, elevated mitochondrial respiration and fatty acid oxidation, and reduced T-cell stimulatory capacity, all characteristics of dysfunctional DCs. In contrast, dead cells had only limited effect on the metabolism of MerTK-deficient DCs, which instead maintained an antigen presenting, stimulatory phenotype. The efficacy of anti-PD-1 to slow tumor progression and induce specific T-cell infiltration was markedly increased in mice with selective ablation of MerTK in the DC compartment, suggesting the possibility of therapeutically targeting MerTK to modulate DC metabolism and function and enhance anti-PD-1 therapy.
Author Info: (1) University of North Carolina at Chapel Hill, United States. (2) East Carolina University, Greenville, NC, United States. (3) University of North Carolina at Chapel Hill, Chapel
Author Info: (1) University of North Carolina at Chapel Hill, United States. (2) East Carolina University, Greenville, NC, United States. (3) University of North Carolina at Chapel Hill, Chapel Hill,, North Carolina, United States. (4) University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. (5) University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
