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Background Statins have been a cornerstone in cardiovascular care, particularly for patients with hypercholesterolemia. Early onset of hyperlipidemia has contributed to a rise in statin use among young adults. Therefore, a substantial cohort of cancer patients now present with a history of prolonged statin pre-exposure. Emerging research implicates hypercholesterolemia and dyslipidemia are associated with high cancer mortality, 1 emphasising the potential of repurposing statins as anti-cancer therapeutics. Nonetheless, clinical and epidemiological studies re-purposing statins as onco-therapeutic agents have demonstrated inconsistent results. Contemporary cohort studies indicate statins may delay breast cancer recurrence and modulate intratumoral immune components.2 3 However, the effects of hypercholesterolemia and subsequent statin pre-exposure on intratumoral antigen presentation by dendritic cells (DCs) remain unexplored. Our study aims to determine whether prior statin exposure modulates intra-tumoral immunosuppressive effects of hypercholesterolemia in Triple Negative Breast Cancer (TNBC) with emphasis on DC-mediated antigen presentation and T-cell priming.Methods Retrospective analysis of TNBC patient data, with/without atorvastatin use, was conducted to assess its impact on cancer recurrence. Intratumoral DCs (CD1c +CD141+) from TNBC patients with/without atorvastatin pre-exposure were analysed for antigen-processing/presentation and co-stimulation/co-inhibition molecules using RT-PCR, immunofluorescence and flow cytometry. 4T1 cells were inoculated in BALB/C mice following three months of atorvastatin pre-exposure; tumour growth was monitored, and the CD11c+CD8+ DC profile was analysed. Intratumoural cholesterol metabolism markers were examined in hypercholesterolemic tumour-bearing mice with/without atorvastatin. Tumour-conditioned, bone marrow-derived murine DCs were co-cultured with MACS-sorted CD3+CD8+ T-cells, with/without statin in hypercholesterolemic media, and cytokine profile was analysed by ELISA.Results Atorvastatin pre-exposure was associated with improved recurrence-free survival in TNBC patients, particularly with Stage II and III tumours (n=180). DCs from such patients showed upregulation of antigen presenting/processing and co-stimulatory molecules. Preclinical mice model studies reinforced that hypercholesterolemia promoted tumour growth, with significant tumour restriction on atorvastatin pre-exposure. CCR7 low, CD40low, CD80 low, CD86 lowPDL1high FASLhigh intratumoral DCs from hypercholesterolemic mice showed a noticeable increase in co-stimulation markers on atorvastatin treatment. Antigen-presenting molecules (TAP1, TAP2, Calnexin, Calreticulin) were upregulated intratumorally on atorvastatin pre-exposure in hypercholesterolemic cohort. Atorvastatin-remediated DCs were observed to efficiently activate tumour-specific (Perforinhigh, Granzyme Bhigh, IFNγhigh) CD8+ T-cells with augmented cytolytic activity and reduced PD1 expression. Atorvastatin pre-exposure rescued hypercholesterolemia-associated altered Notch1-DLL1 signalling in DC maturation to support optimum DC-T cell priming in TNBC.Conclusions Cumulatively, the results suggest that atorvastatin revitalises anti-tumour immunity in hypercholesterolemia by promoting DC maturation and functionality, thereby facilitating effective T-cell priming and anti-tumour responses as exhibited in ( figure 1).Acknowledgements We thank the Director, Chittaranjan National Cancer Institute, Kolkata, India, and the Director, National Institute of Pharmaceutical Education and Research, SAS Nagar, India, for providing institutional facilities. We thank the Animal Facility of CNCI, Kolkata. We also thank all members of our respective laboratories for their technical support for this work.References Baek AE, Yu YR, He S, Wardell SE, Chang CY, Kwon S, Pillai RV, McDowell HB, Thompson JW, Dubois LG, Sullivan PM. The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells . Nat Commun. 2017;8(1):864.Marti JL, Beckwitt CH, Clark AM, Wells A. Atorvastatin facilitates chemotherapy effects in metastatic triple-negative breast cancer. Br J Cancer. 2021;125(9):1285–98.Ma X, Bi E, Lu Y, Su P, Huang C, Liu L, Wang Q, Yang M, Kalady MF, Qian J, Zhang A. Cholesterol induces CD8+ T cell exhaustion in the tumor microenvironment. Cell Metab. 2019;30(1):143–56.Ethics Approval All human experiments were approved by Institutional Human Ethical Committee of Apollo Medical Hospitals, Kolkata, India on approval from Institutional Ethical Committee (IEC) (Approval No: IEC/BRI2024/06/09). All patients included gave informed consent before taking part in the study.Abstract 873 Figure 1Model proposing Atorvastatin mediated improvement of intratumoral DC function in hypercholesterolemia. Hypercholesterolemic tumour-microenvironment dampens DC functionality and maturation preventing anti-tumour cytotoxic activity of T-cells that remediates on statin pre-exposure