Nam, Gi-Hoon Kwon, Minsu Jung, Hanul Ko, Eunbyeol Kim, Seong A. Choi, Yoonjeong Song, Su Jeong Kim, Seohyun Lee, Yeji Kim, Gi Beom Han, Jihoon Woo, Jiwan Cho, Yakdol Jeong, Cherlhyun Park, Seung-Yoon Roberts, Thomas M. Cho, Yong Beom Kim, In-San 2024-01-19T14:04:19Z 2024-01-19T14:04:19Z 2022-01-10 2021-07 2051-1426 https://pubs.kist.re.kr/handle/201004/116716 Background Statins 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 (KRAS(mut)) tumors. Methods The 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 KRAS(mut) 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. Results Statin-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 KRAS(mut) cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRAS(mut) tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRAS(mut) tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRAS(mut) tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRAS(mut) tumor models. Conclusions Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity. English BMJ PUBLISHING GROUP Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer Article 10.1136/jitc-2021-002474 1 JOURNAL FOR IMMUNOTHERAPY OF CANCER, v.9, no.7 JOURNAL FOR IMMUNOTHERAPY OF CANCER 9 7 N scie scopus 000691857000004 2-s2.0-85111776343 Oncology Immunology Oncology Immunology Article CALRETICULIN EXPOSURE CELLS LOVASTATIN APOPTOSIS PATHWAY GROWTH TUMORS DEATH immunotherapy dendritic cells antigen presentation CD8-positive T-lymphocytes drug therapy combination