MUC4 enables immune tumor evasion in HER2+breast cancer.

BRUNI S; MAURO F; MERCOGLIANO MF; ROLDAN DE-AMICIS, A; DE MARTINO M; PROIETTI CJ; CORDO RUSSO R; ELIZALDE PV; SCHILLACI R

Congreso; Reunión Conjunta de Sociedades de Biociencias del 17-20 de noviembre de 2021.; 2021

SAIC, SAI, AAFE, NANOMED

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 the overexpression of TNFɑ induces Tz resistance in cells and tumors by upregulating the membrane glycoprotein mucin 4 (MUC4), which hides Tz epitope on HER2 impairing its binding and pharmacological effects. Blocking the soluble TNFɑ isoform with INB03 (DN) reduces MUC4 expression, overcomes Tz resistance and unleashes an antitumor innate immune response (IIR) with a decrease in myeloid-derived suppressor 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 recruitment and 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 or Tz (5 mg/kg), DN (10 mg/kg) or 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 are needed to achieve Tz+DN antitumor effect. However, upon MUC4 silencing, only Mφ are required to mediate Tz antitumor effect. Secretome from JIMT-1 and KPL-4 cells with MUC4 silencing promoted differentiation of activated T-cells to effector cells. Finally, in our HER2+ BC patient cohort, we found a negative correlation between tumor infiltrating lymphocytes presence and MUC4 expression (p=0,005). We conclude that Mφ are key players in the Tz-mediated antitumor IIR and that MUC4 promotes cold HER2+ tumors with poor therapy response. Women with HER2+MUC4+ BC could benefit from the combined treatment of Tz+DN.