Statin Drugs Plus Thl Cytokines Potentiate Apoptosis and Ras Derealization in Human Breast Cancer Lines and Combine with Dendritic Cell-Based Immunotherapy to Suppress Tumor Growth in a Mouse Model of HER-[2.sup.pos] Disease

• Published in: Vaccines (Basel) Vol. 8; no. 1; p. 1
• Main Authors: Oechsle, Crystal M, Showalter, Loral E, Novak, Colleen M, Czerniecki, Brain J, Koski, Gary K
• Format: Journal Article
• Language: English
• Published: MDPI AG 01.03.2020
• Subjects: Apoptosis; Breast cancer; Cytokines; Dosage and administration; Growth factor receptors; Health aspects; Immunotherapy; Methods; Prevention; Statins; United States
• ISSN: 2076-393X; 2076-393X
• DOI: 10.3390/vaccines8010072

A dendritic cell-based, Type 1 Helper T cell (Thl)-polarizing anti-Human Epidermal Growth Factor Receptor-2 (HER-2) vaccine supplied in the neoadjuvant setting eliminates disease in up to 30% of recipients with HER-2-positive (HER-[2.sup.Pos]) ductal carcinoma in situ (DCIS). We hypothesized that drugs with low toxicity profiles that target signaling pathways critical for oncogenesis may work in conjunction with vaccine-induced immune effector mechanisms to improve efficacy while minimizing side effects. In this study, a panel of four phenotypically diverse human breast cancer lines were exposed in vitro to the combination of Thl cytokines Interferon-gamma (IFN-[gamma]) and Tumor Necrosis Factor-alpha (TNF-[alpha]) and lipophilic statins. This combination was shown to potentiate multiple markers of apoptotic cell death. The combination of statin drugs and Thl cytokines minimized membrane K-Ras localization while maximizing levels in the cytoplasm, suggesting a possible means by which cytokines and statin drugs might cooperate to maximize cell death. A combined therapy was also tested in vivo through an orthotopic murine model using the neu-transgenic TUBO mammary carcinoma line. We showed that the combination of HER-2 peptide-pulsed dendritic cell (DC)-based immunotherapy and simvastatin, but not single agents, significantly suppressed tumor growth. Consistent with a Thl cytokine-dependent mechanism, parenterally administered recombinant IFN-[gamma] could substitute for DC-based immunotherapy, likewise inhibiting tumor growth when combined with simvastatin. These studies show that statin drugs can amplify a DC-induced effector mechanism to improve anti-tumor activity.