MUC4 enables inmune tumor evasion in HER2+ breast cancer

BRUNI, SOFIA; MAURO, FLORENCIA L.; MERCOGLIANO, MARÍA FLORENCIA; ROLDAN DEAMICIS, AGUSTINA; DE MARTINO, MARA; PROIETTI, CECILIA JAZMÍN; CORDO RUSSO, ROSALÍA; ELIZALDE, PATRICIA VIRGINIA; SCHILLACI, ROXANA

Congreso; LXVI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2021

Sociedad Argentina de Investigación Clínica (SAIC)

HER2+ is a breast cancer (BC) subtype characterized by the overexpression/amplification of HER2. Patients receive trastuzumab(Tz), but 27-42% of them do not respond. We demonstrated that theoverexpression of TNFɑ induces Tz resistance in cells and tumorsby upregulating the membrane glycoprotein MUC4, which hides Tzepitope on HER2 impairing its binding and pharmacological effects.Blocking the soluble TNFɑ isoform with INB03 (DN) reduces MUC4expression, overcomes Tz resistance and unleashes an antitumorinnate immune response (IIR) with a decrease in myeloid-derivedsuppressor cells, an increase in NK cell-activation and degranulation and a macrophage (Mφ) polarization to the M1 subtype.We studied Mφ and NK cells contribution to the Tz-mediated antitumor IIR and MUC4 impact in human T-lymphocyte recruitmentand differentiation. We genetically modified the Tz-resistant HER2+BC cell lines JIMT-1 and KPL-4 to express a doxycycline-inducible(Dox) MUC4 shRNA (shMUC4) or a control one (shControl) and injected them into female nude mice, which were treated with IgG orTz (5 mg/kg), DN (10 mg/kg) or the combination of Tz+DN, with(+Dox) or without (-Dox) shRNA induction.After Mφ depletion with chlodronate or NK cell depletion with anti-asialo GM1, in -Dox tumors we found that both populations areneeded to achieve Tz+DN antitumor effect (p