MUC4 is the principal mediator of TNF-induced trastuzumab resistance and fosters an immunosuppressive tumor microenvironment in HER2+ breast cancer

DE MARTINO, MARA; SANTA MARIA DE LA PARRA, LUCÍA; MAURO, FLORENCIA; ELIZALDE, PATRICIA V.; BRUNI, SOFÍA; MERCOGLIANO, MARÍA F.; SCHILLACI, ROXANA

Mar del Plata

Congreso; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2019

About 13-20% of breast cancer (BC) patients are HER2positive (HER2+) and receive trastuzumab (T), an anti-HER2 monoclonal antibody,but 30-50% of them relapse. We have demonstrated that tumor necrosis factoralpha (TNF) induces the expression of the transmembrane glycoprotein mucin 4(MUC4) that shields T epitope in HER2, impairing its antitumor effects, and thatthe soluble and transmembrane TNFα (sTNFα, tmTNFα) inhibitor Etanercept (E)downregulated MUC4 expression and sensitized de novo T-resistant BC xenografts to T. Here, we studied the invivo participation of MUC4 on T resistance and on antitumor innate immuneresponse.T-resistant JIMT-1 cell line was transduced with adoxycycline (Dox)-inducible MUC4 shRNA construct (JIMT-shMUC4). To block TNFα, we used E or the dominant negative-TNF protein INB03 (DN), able to neutralizesTNF. Nude mice bearing JIMT-1-shMUC4 tumors were assigned to the experimental(+Dox 2mg/ml in water) or control group (−Dox) and treated with IgG, T, E (5mg/kg), DN (10 mg/kg), T+E or T+DN i.p. twice a week. Tumor volume wasmonitored routinely. Tumor-infiltrating immune cells were evaluated by immunofluorescence and flow cytometry. In control groups, only T+E and T+DN inhibited tumorgrowth (72% and 75%, respectively, P