%0 Journal Article %A Gi-Hoon Nam %A Minsu Kwon %A Hanul Jung %A Eunbyeol Ko %A Seong A Kim %A Yoonjeong Choi %A Su Jeong Song %A Seohyun Kim %A Yeji Lee %A Gi Beom Kim %A Jihoon Han %A Jiwan Woo %A Yakdol Cho %A Cherlhyun Jeong %A Seung-Yoon Park %A Thomas M. Roberts %A Yong Beom Cho %A In-San Kim %T Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer %D 2021 %R 10.1136/jitc-2021-002474 %J Journal for ImmunoTherapy of Cancer %P e002474 %V 9 %N 7 %X 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 (KRASmut) 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 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.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 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.Conclusions Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity.All data relevant to the study are included in the article or uploaded as supplementary information. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. %U https://jitc.bmj.com/content/jitc/9/7/e002474.full.pdf