Mevalonate Blockade in Cancer Cells Triggers CLEC9A+ Dendritic Cell-Mediated Antitumor Immunity.

Abstract

Hyperactive mevalonate (MVA) metabolic activity is often observed in cancer cells, and blockade of this pathway inhibits tumor cell lipid synthesis and cell growth and enhances tumor immunogenicity. How tumor cell MVA metabolic blockade promotes antitumor immune responses, however, remains unclear. Here we show that inhibition of the MVA metabolic pathway in tumor cells elicits type 1 classical dendritic cells (cDC1)-mediated tumor recognition and antigen cross-presentation for antitumor immunity. Mechanistically, MVA blockade disrupted prenylation of the small GTPase Rac1 and induced cancer cell actin filament exposure, which was recognized by CLEC9A, a C-lectin receptor specifically expressed on cDC1s, in turn activating antitumor T cells. MVA pathway blockade or Rac1 knockdown in tumor cells induced CD8+ T-cell-mediated antitumor immunity in immunocompetent mice but not in Batf3 -/- mice lacking CLEC9A+ dendritic cells. These findings demonstrate tumor MVA metabolic blockade stimulates a cDC1 response through CLEC9A-mediated immune recognition of tumor cell cytoskeleton, illustrating a new immune surveillance mechanism by which dendritic cells monitor tumor metabolic dysregulation and providing insight into how MVA pathway inhibition may potentiate anticancer immunity. SIGNIFICANCE: These findings suggest that mevalonate blockade in cancer cells disrupts Rac1 prenylation to increase recognition and cross-presentation by conventional dendritic cells, suggesting this axis as a potential target for cancer immunotherapy.

• Authors: Feifei Xu, Zining Wang, Hongxia Zhang, Jiemin Chen, Xiaojuan Wang, Lei Cui, Chunyuan Xie, Mengyun Li, Fang Wang, Penghui Zhou, Jinyun Liu, Peng Huang, Xiaodong Xia, Xiaojun Xia
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 17 Pg. 4514-4528 (09 01 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 34266895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Basic-Leucine Zipper Transcription Factors
• CLEC9a protein, human
• Lectins, C-Type
• Neuropeptides
• Polyisoprenyl Phosphates
• RAC1 protein, human
• Rac1 protein, mouse
• Receptors, Mitogen
• Repressor Proteins
• SNFT protein, mouse
• rac1 GTP-Binding Protein
• geranylgeranyl pyrophosphate
• Mevalonic Acid

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Basic-Leucine Zipper Transcription Factors (genetics)
• Cells, Cultured
• Cross-Priming
• Cytoskeleton (metabolism)
• Dendritic Cells (cytology)
• Female
• HEK293 Cells
• Humans
• Immunity, Cellular
• Immunotherapy
• Lectins, C-Type (genetics)
• Lymphocyte Activation
• Melanoma, Experimental
• Mevalonic Acid (pharmacology)
• Mice
• Neuropeptides (metabolism)
• Polyisoprenyl Phosphates
• Receptors, Mitogen (genetics)
• Repressor Proteins (genetics)
• T-Lymphocytes (cytology)
• rac1 GTP-Binding Protein (metabolism)