Statin drugs enhance responses to immune checkpoint blockade in head and neck cancer models

Abstract

BackgroundAnti-PD-1 immune checkpoint blockade is approved for first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but few patients respond. Statin drugs (HMG-CoA reductase inhibitors) are associated with superior survival in several cancer types, including HNSCC. Emerging data suggest that manipulation of cholesterol may enhance some aspects of antitumor immunity.MethodsWe used syngeneic murine models (mouse oral cancer, MOC1 and TC-1) to investigate our hypothesis that a subset of statin drugs would enhance antitumor immunity and delay tumor growth.ResultsUsing an ex vivo coculture assay of murine cancer cells and tumor infiltrating lymphocytes, we discovered that all seven statin drugs inhibited tumor cell proliferation. Simvastatin and lovastatin also enhanced T-cell killing of tumor cells. In mice, daily oral simvastatin or lovastatin enhanced tumor control and extended survival when combined with PD-1 blockade, with rejection of MOC1 tumors in 30% of mice treated with lovastatin plus anti-PD-1. Results from flow cytometry of tumors and tumor-draining lymph nodes suggested T cell activation and shifts from M2 to M1 macrophage predominance as potential mechanisms of combination therapy.ConclusionsThese results suggest that statins deserve further study as well-tolerated, inexpensive drugs that may enhance responses to PD-1 checkpoint blockade and other immunotherapies for HNSCC.

Characterization of the tumor microenvironment in the mouse oral cancer (MOC1) model after orthotopic implantation in the buccal mucosa

“…Fluorescent‐conjugated flow cytometry antibodies for mouse tumor experiments were obtained from BD Biosciences, Biolegend, Miltenyi, or Abcam (see previously published flow cytometry panels) 9 …”

“…Samples were analyzed on a BD Symphony A3 cytometer, then further analyzed using FlowJo (v10.8.1) software. Gating was performed as previously described 6,9 . “Fluorescence minus one” controls were tested for each multicolor flow panel.…”

“…Gating was performed as previously described. 6,9 "Fluorescence minus one" controls were tested for each multicolor flow panel.…”

Natural killer cell‐based signature: Prognostic analysis in head and neck squamous cell carcinoma

“…Regrettably, a majority of patients inevitably develop resistance to these targeted interventions, thereby perpetuating a bleak prognosis 2–5 . The utilization of immune checkpoint inhibitors (ICIs) has emerged as a novel therapeutic approach in the management of HNSCs 6–9 . Regrettably, the overall response rates and efficacy remain suboptimal, primarily because of the inherent “cold” nature of HNSCs characterized by an immunosuppressive tumor microenvironment (TME).…”

“…[2][3][4][5] The utilization of immune checkpoint inhibitors (ICIs) has emerged as a novel therapeutic approach in the management of HNSCs. [6][7][8][9] Regrettably, the overall response rates and efficacy remain suboptimal, primarily because of the inherent "cold" nature of HNSCs characterized by an immunosuppressive tumor microenvironment (TME). This immunosuppression hampers the favorable outcomes of ICI treatment, limiting its benefits to a subset of patients.…”