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Modulation of lactate-lysosome axis in dendritic cells by clotrimazole potentiates antitumor immunity
- Source :
- Journal for Immunotherapy of Cancer, Journal for ImmunoTherapy of Cancer, Vol 9, Iss 5 (2021)
- Publication Year :
- 2021
-
Abstract
- BackgroundDendritic cells (DCs) play a critical role in antitumor immunity, but the therapeutic efficacy of DC-mediated cancer vaccine remains low, partly due to unsustainable DC function in tumor antigen presentation. Thus, identifying drugs that could enhance DC-based antitumor immunity and uncovering the underlying mechanism may provide new therapeutic options for cancer immunotherapy.MethodsIn vitro antigen presentation assay was used for DC-modulating drug screening. The function of DC and T cells was measured by flow cytometry, ELISA, or qPCR. B16, MC38, CT26 tumor models and C57BL/6, Balb/c, nude, and Batf3−/− mice were used to analyze the in vivo therapy efficacy and impact on tumor immune microenvironment by clotrimazole treatment.ResultsBy screening a group of small molecule inhibitors and the US Food and Drug Administration (FDA)-approved drugs, we identified that clotrimazole, an antifungal drug, could promote DC-mediated antigen presentation and enhance T cell response. Mechanistically, clotrimazole acted on hexokinase 2 to regulate lactate metabolic production and enhanced the lysosome pathway and Chop expression in DCs subsequently induced DC maturation and T cell activation. Importantly, in vivo clotrimazole administration induced intratumor immune infiltration and inhibited tumor growth depending on both DCs and CD8+ T cells and potentiated the antitumor efficacy of anti-PD1 antibody.ConclusionsOur findings showed that clotrimazole could trigger DC activation via the lactate-lysosome axis to promote antigen cross-presentation and could be used as a potential combination therapy approach to improving the therapeutic efficacy of anti-PD1 immunotherapy.
- Subjects :
- 0301 basic medicine
Cancer Research
Skin Neoplasms
medicine.medical_treatment
T-Lymphocytes
Programmed Cell Death 1 Receptor
Antifungal drug
Melanoma, Experimental
Lymphocyte Activation
Immunomodulating Agents
0302 clinical medicine
Cancer immunotherapy
Hexokinase
Tumor Microenvironment
Immunology and Allergy
Medicine
Clotrimazole
Immune Checkpoint Inhibitors
RC254-282
Mice, Knockout
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Tumor antigen
Tumor Burden
medicine.anatomical_structure
Basic-Leucine Zipper Transcription Factors
Oncology
030220 oncology & carcinogenesis
Colonic Neoplasms
Molecular Medicine
Female
immunotherapy
T cell
Immunology
Antigen presentation
Mice, Nude
Antineoplastic Agents
03 medical and health sciences
Lymphocytes, Tumor-Infiltrating
Antigen
Cell Line, Tumor
Animals
Lactic Acid
dendritic cells
Pharmacology
business.industry
Basic Tumor Immunology
Immunotherapy
Mice, Inbred C57BL
Repressor Proteins
030104 developmental biology
Cancer research
Cancer vaccine
business
Lysosomes
Transcription Factor CHOP
Subjects
Details
- ISSN :
- 20511426
- Volume :
- 9
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Journal for immunotherapy of cancer
- Accession number :
- edsair.doi.dedup.....e377d8cb3d1e7bb51c41d1668e7b527e