MUC4 ENABLES IMMUNE TUMOR EVASION IN HER2+ BREAST CANCER

SOFIA BRUNI; MAURO, FLORENCIA LUCIANA; MERCOGLIANO, MARÍA FLORENCIA; PROIETTI, CECILIA JAZMÍN; CORDO-RUSSO, ROSALÍA; ELIZALDE, PATRICIA VIRGINIA; SCHILLACI, ROXANA

New Orleans

Congreso; American Association for Cancer Research Annual Meeting 2022; 2022

HER2+ is a breast cancer (BC) subtype characterized by the overexpression/amplification of HER2. Patients receive trastuzumab (Tz) but about 27-42% do not achieve an objective response. We demonstrated that the overexpression of TNFɑ induces Tz resistance in tumors by upregulating the membrane glycoprotein MUC4, which masks Tz epitope on HER2, impairing its binding and reducing its therapeutic effects. We have also proved that blocking the soluble TNFɑ isoform with INB03 (DN) reduces MUC4 expression, overcomes Tz resistance and unleashes an antitumor innate immune response (IIR) characterized by an increase in NK cell-activation and degranulation and a macrophage (Mφ) polarization to the M1 subtype.Our aim was to study the impact of MUC4 expression on the contribution of Mφ and NK cells to the Tz-mediated antitumor IIR and on human T-lymphocyte recruitment and differentiation. We genetically modified two de novo Tz-resistant HER2+ BC human cell lines, JIMT-1 and KPL-4, to stably express a doxycycline-inducible (Dox) MUC4 shRNA (shMUC4) or a control one (shControl), and injected them s.c. into female nude mice. After tumor establishment, the animals were randomly divided in a control group with no doxycycline induction (-Dox) or an induced group (+Dox), and treated twice a week i.p. with IgG (5 mg/kg) or Tz+DN (5 and 10 mg/kg each, respectively) (-Dox) and with IgG or Tz (+Dox). We used chlodronate to deplete Mφ and anti-asialo GM1 to deplete NK cells. Tumor volume was measured routinely and, at the end point, tumors were processed and infiltrating immune cells were analyzed by flow cytometry. In -Dox tumors, we found that both Mφ and NK cells are needed to achieve Tz+DN antitumor effect (p