Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer

Abstract

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.

Resistance to immune checkpoint inhibitors in KRAS-mutant non-small cell lung cancer

“…In the KRAS-mutant lung cancer model, blockade of both PD-1 and helix-loop-helix transcription factor inhibitor of differentiation 1 knock out significantly enhances the amount of CD8 + T cells as well as the expression of PD-L1, which impairs the tumor growth and increases the survival [126] . In other studies of KRAS mut lung cancer, anti-PD-1 combined with inhibition of the AKT-mTOR pathway by mTOR inhibitor or the STAT3 pathway by natural compound luteolin can remarkably decreased the expression of PD-1 or PD-L1, respectively, which consequently surmounts the resistance to anti-PD-1 [127,128] .…”

How cancer cells remodel lipid metabolism: strategies targeting transcription factors

“…RAS signaling in human cancer cells has anti-endoplasmic reticulum stress effect. Inhibition of RAS prenylation enhances endoplasmic reticulum stress and leads to the CD8(+) T cell-mediated cell death of colon cancer cells [ 214 ]. Palmitoylation stabilizes the programmed-death ligand 1 (PD-L1) by blocking its lysosomal degradation.…”

Recent Advances of WEE1 Inhibitors and Statins in Cancers With p53 Mutations

“…This drug, along with others such as, as it was found that 10 patients who had statin treatment after immunotherapy had a much higher survival rate than those who did not receive statin treatment after immunotherapy. Statins was found to overcome resistance to PD-1 blockade therapies and improve the survival rate of KRAS mut tumor models of syngeneic colorectal cancer, genetically engineered lung and pancreatic tumors, indicating that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity ( 41 ). Statins can reduce inflammation by inhibiting isoprenoid synthesis of the mevalonate pathway ( 42 ).…”

“…Statins also block inflammatory responses of endothelial cells and T cells by activating Kruppel-like transcription factors KLF2 and KLF4 ( 42 ). However, statins were also found to promote the differentiation of Forkhead box P3 (Foxp3+) CD4+ regulatory T cells (Tregs) cells while blocking the differentiation of proinflammatory helper T (Th17) cells ( 41 – 43 ). It is important to mention, though, that this finding is only observational and requires further testing to ensure its significance and validity ( 41 – 43 ).…”