Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer
| Autor: | Seong A. Kim, Minsu Kwon, Cherlhyun Jeong, In San Kim, Hanul Jung, Ji-Hoon Han, Thomas M. Roberts, Seohyun Kim, Eunbyeol Ko, Gi Beom Kim, Yeji Lee, Gi-Hoon Nam, Su Jeong Song, Yong Beom Cho, Yakdol Cho, Yoonjeong Choi, Jiwan Woo, Seung-Yoon Park |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Cancer Research Statin Colorectal cancer medicine.drug_class medicine.medical_treatment Immunology medicine.disease_cause Transfection Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Mice 0302 clinical medicine Immunology and Allergy Medicine Animals Humans dendritic cells RC254-282 Pharmacology combination business.industry Immunogenicity Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cancer Basic Tumor Immunology Immunotherapy medicine.disease Endoplasmic Reticulum Stress drug therapy antigen presentation 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer cell Mutation Cancer research Molecular Medicine Immunogenic cell death CD8-positive T-lymphocytes KRAS immunotherapy Hydroxymethylglutaryl-CoA Reductase Inhibitors business |
| Zdroj: | Journal for Immunotherapy of Cancer Journal for ImmunoTherapy of Cancer, Vol 9, Iss 7 (2021) |
| ISSN: | 2051-1426 |
| Popis: | BackgroundStatins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.MethodsThe immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.ResultsStatin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.ConclusionsOur findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity. |
| Databáze: | OpenAIRE |
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