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The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-κB pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo . Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

FOXP3+ regulatory T (Treg) cells are necessary to coordinate resolution of lung inflammation and a return to homeostasis after respiratory viral infections, but the specific molecular requirements for these functions and the cell types governed by Treg cells remain unclear. This question holds significance as clinical trials of Treg cell transfer therapy for respiratory viral infection are being planned and executed. Here, we report causal experiments in mice determining that Treg cells are necessary to control the numbers of activated CD8+ T cells during recovery from influenza infection. Using a genetic strategy paired with adoptive transfer techniques, we determined that Treg cells require the transcription factor TBET to regulate these potentially pro-inflammatory CD8+ T cells. Surprisingly, we found that Treg cells are dispensable for the generation of CD8+ lung tissue resident-memory T (Trm) cells yet similarly influence the transcriptional programming of CD8+ Trm and activated T cells. Our study highlights the role of Treg cells in regulating the CD8+ T cell response during recovery from influenza infection., Competing Interests: Competing Interest Statement: NM is currently an employee and owns stock in Vertex Pharmaceuticals. BDS holds United States Patent No. US 10,905,706 B2, Compositions and Methods to Accelerate Resolution of Acute Lung Inflammation, and serves on the Scientific Advisory Board of Zoe Biosciences. The other authors have no competing interests to declare.

CD4+FOXP3+ regulatory T (Treg) cells maintain self-tolerance, suppress the immune response to cancer, and protect against tissue injury in the lung and other organs. Treg cells require mitochondrial metabolism to exert their function, but how Treg cells adapt their metabolic programs to sustain and optimize their function during an immune response occurring in a metabolically stressed microenvironment remains unclear. Here, we tested whether Treg cells require the energy homeostasis-maintaining enzyme AMP-activated protein kinase (AMPK) to adapt to metabolically aberrant microenvironments caused by malignancy or lung injury, finding that AMPK is dispensable for Treg cell immune-homeostatic function but is necessary for full Treg cell function in B16 melanoma tumors and during acute lung injury caused by influenza virus pneumonia. AMPK-deficient Treg cells had lower mitochondrial mass and exhibited an impaired ability to maximize aerobic respiration. Mechanistically, we found that AMPK regulates DNA methyltransferase 1 to promote transcriptional programs associated with mitochondrial function in the tumor microenvironment. In the lung during viral pneumonia, we found that AMPK sustains metabolic homeostasis and mitochondrial activity. Induction of DNA hypomethylation was sufficient to rescue mitochondrial mass in AMPK-deficient Treg cells, linking DNA methylation with AMPK function and mitochondrial metabolism. These results define AMPK as a determinant of Treg cell adaptation to metabolic stress and offer potential therapeutic targets in cancer and tissue injury., Competing Interests: Competing Interest Statement: NM is currently an employee and owns stock in Vertex Pharmaceuticals. BDS holds United States Patent No. US 10,905,706 B2, Compositions and Methods to Accelerate Resolution of Acute Lung Inflammation, and serves on the Scientific Advisory Board of Zoe Biosciences. The other authors have no competing interests to declare.