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

BRUNI, SOFIA; DE MARTINO, MARA; MAURO, FLORENCIA L.; MERCOGLIANO, MARÍA FLORENCIA; SANTA MARÍA DE LA PARRA, MARÍA LUCÍA; ELIZALDE, PATRICIA; SCHILLACI, ROXANA

Mar del Plata

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

Sociedad Argentina de Investigación Clínica (SAIC)

About 13-20 % of breast cancer (BC)patients are HER2 positive (HER2+) and receive trastuzumab(T), an anti-HER2 monoclonal antibody, but 30-50 % of themrelapse. We have demonstrated that tumor necrosis factor alpha(TNF) induces the expression of the transmembrane glycoproteinmucin 4 (MUC4) that shields T epitope in HER2, impairing itsantitumor effects, and that the soluble and transmembrane TNFα(sTNFα, tmTNFα) inhibitor Etanercept (E) downregulated MUC4expression and sensitized de novo T-resistant BC xenografts toT. Here, we studied the in vivo participation of MUC4 on Tresistance and on antitumor innate immune response. T-resistantJIMT-1 cell line was transduced with a doxycycline (Dox)-inducible MUC4 shRNA construct (JIMT-shMUC4). To block TNFα,we used E or the dominant negative-TNF protein INB03 (DN),able to neutralize sTNF. Nude mice bearing JIMT-1-shMUC4tumors were assigned to the experimental (+Dox 2 mg/ml inwater) 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. Tumorvolume was monitored routinely. Tumor-infiltrating immune cellswere evaluated by immunofluorescence and flow cytometry. Incontrol groups, only T+E and T+DN inhibited tumor growth (72and 75 %, respectively, p