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

MAURO, F; SCHILLACI R; BRUNI, S; SANTA MARIA DE LA PARRA, L; DE MARTINO, M; ELIZALDE, PV

Congreso; Reunión Anual de SAIC; 2019

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 them relapse. We have demonstrated that tumor necrosis factor alpha (TNF) induces the expression of the transmembrane glycoprotein mucin 4 (MUC4) that shields T epitope in HER2, impairing its antitumor effects, and that the 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 in vivo participation of MUC4 on T resistance and on antitumor innate immune response.T-resistant JIMT-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-shMUC4 tumors were assigned to the experimental (+Dox 2mg/ml in water) or control group (−Dox) and treated with IgG, T, E (5 mg/kg), DN (10 mg/kg), T+E or T+DN i.p. twice a week. Tumor volume was monitored routinely. Tumor-infiltrating immune cells were evaluated by immunofluorescence and flow cytometry. In control groups, only T+E and T+DN inhibited tumor growth (72% and 75%, respectively, P