MUC4 enables immune tumor evasion in HER2+ breast cancer

BRUNI S; MAURO F; MERCOGLIANO MF; PROIETTI CJ; ADAMI C; DUPONT A; INURRIGARRO G; CORDO RUSSO, ROSALÍA I.; ELIZALDE P V; SCHILLACI R

New Orleans

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

AACR

HER2+ is a breast cancer (BC) subtype characterized by the overexpression/amplification of HER2. Patients receivetrastuzumab (Tz) but many (27-42%) do not achieve an objective response. We demonstrated that theoverexpression of TNFɑ induces Tz resistance in tumors by upregulating the membrane glycoprotein MUC4, whichmasks Tz epitope on HER2, impairing its binding and reducing its therapeutic effects. We have also proved thatblocking the soluble TNFɑ isoform with INB03 (DN) reduces MUC4 expression, overcomes Tz resistance andunleashes an antitumor innate immune response characterized by an increase in NK cell-activation anddegranulation and a macrophage (Mφ) polarization to the M1 subtype.This study aims to determine the impact of MUC4 expression on Mφ and NK cells antitumor activity in thepresence of Tz or Tz+DN, and on human T-lymphocyte recruitment and differentiation. Tz-resistant HER2+ BChuman cell lines, JIMT-1 and KPL-4, were genetically modified to stably express a doxycycline-inducible (Dox) MUC4shRNA (shMUC4) or a scramble one (shControl), and injected s.c. into female nude mice. After tumorestablishment, the animals were randomly divided into a control group (-Dox) or an induced group (+Dox), andtreated 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). Chlodronate or anti-asialo GM1 was used to deplete Mφ or NK cells, respectively. Tumor volume wasmeasured routinely and, at the end point, tumors were processed and infiltrating immune cells were analyzed byflow cytometry.In -Dox tumors, both Mφ and NK cells are needed to achieve Tz+DN antitumor effect (p