Science and Technology Production
Congress
Authorship
Sofia Bruni
;
Mauro, Florencia Luciana
;
MERCOGLIANO, MARIA FLORENCIA
;
Proietti, Cecilia Jazmín
;
Cordo-Russo, Rosalía
;
Elizalde, Patricia Virginia
;
Schillaci, Roxana
Date
2022
Publishing House and Editing Place
AACR scientific publications
Summary
Information provided by the agent in
SIGEVA
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 ...
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<0.01 and p<0.05, respectively). However, upon MUC4 silencing, only Mφ are required to mediate Tz antitumor effect (p<0.01). To address MUC4 role on T-lymphocyte differentiation, we isolated human T-cells from peripheral blood, activated them with CD3/CD28 beads and exposed them to conditioned mediums obtained from JIMT-1 and KPL-4 cells, with or without MUC4 silencing. We observed that the absence of MUC4 generated a secretome that promoted the differentiation of naïve T-cells to an effector subtype. Finally, we studied the tumor infiltrating lymphocytes (TILs) in a 90-patient HER2+ BC cohort, and found a negative correlation between the presence of TILs and MUC4 expression (p=0.01).We conclude that Mφ are key players in the Tz-mediated antitumor IIR. Moreover, MUC4 expression impairs T-cell effector function and promotes immunologically cold HER2+ tumors. We propose that women with HER2+MUC4+ BC could benefit from the combined treatment of Tz+DN to enhance innate and adaptive antitumor immune responses and prevent or overcome Tz resistance.
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Key Words
IMMUNE EVASIONMUCIN 4BREAST CANCERTRASTUZUMAB