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Published on: June 22, 2016
MerTK Induces Dysfunctional Dendritic Cells by Metabolic Reprogramming
Eden Y Zewdie1,2, George M Edwards1, Debra M Hunter1
1UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
Abstract:
Checkpoint inhibitors, specifically anti-programmed cell death protein 1 (PD1), have shown success in treating metastatic melanoma; however, some patients develop resistance. Dendritic cells (DC) 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-PD1 exhibited increased levels of MerTK+ DCs. Treating wild-type DCs with apoptotic 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-PD1 to slow tumor progression and induce antigen 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-PD1 therapy.
Insights
Targeting MerTK in dendritic cells (DCs) can overcome resistance to anti-programmed cell death protein 1 (PD1) therapy in melanoma. Inhibiting MerTK restores DC function, enhancing anti-PD1 efficacy and improving anti-tumor immune responses.
Area of Science:
- Immunology
- Cancer Biology
- Metabolism
Background:
- Checkpoint inhibitors like anti-PD1 are effective against metastatic melanoma but face resistance.
- Dendritic cells (DCs) are crucial for immune responses but can become dysfunctional in tumors.
- MerTK, a receptor tyrosine kinase, mediates clearance of dead cells by myeloid cells.
Purpose of the Study:
- To investigate the role of MerTK in regulating DC function and metabolism within the tumor microenvironment.
- To determine if MerTK contributes to anti-PD1 resistance in melanoma.
Main Methods:
- Assessed MerTK levels in DCs from anti-PD1 resistant tumors.
- Treated wild-type and MerTK-deficient DCs with apoptotic melanoma cells in vitro.
- Analyzed DC metabolism (mitochondrial respiration, fatty acid oxidation) and T-cell stimulatory capacity.
- Evaluated anti-PD1 efficacy in mice with selective MerTK ablation in DCs.
Main Results:
- Anti-PD1 resistant tumors showed increased MerTK+ DCs.
- Apoptotic melanoma cells induced MerTK expression, altered metabolism, and reduced T-cell stimulation in wild-type DCs.
- MerTK-deficient DCs maintained function and stimulatory capacity when exposed to dead cells.
- MerTK ablation in DCs significantly enhanced anti-PD1 therapy efficacy and T-cell infiltration.
Conclusions:
- MerTK signaling in DCs promotes metabolic dysfunction and impairs anti-tumor immunity.
- Targeting MerTK in DCs represents a potential strategy to overcome anti-PD1 resistance in melanoma.
- Modulating DC metabolism via MerTK inhibition could enhance current immunotherapies.
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