TNFα blockade improves antitumor innate immune response and overcomes trastuzumab- resistance in her2+ breast cancer medicina

DE MARTINO M; FRAHM I; BRUNI S; PROIETTI CJ; SCHILLACI R; MERCOGLIANO MF; ELIZALDE PV,

Mar del Plata

Congreso; Reunion Anual SAIC; 2018

SAIC

HER2 positive (HER2+) is a subtype that affects 13-20% of breastcancer (BC) patients. They receive trastuzumab (T), an anti-HER2monoclonal antibody, but 40-60% of them relapse. Therefore, newstrategies to overcome trastuzumab resistance are needed. We recentlydemonstrated a novel tumor immune evasion strategy whereTNFα induces upregulation of the expression of the transmembraneglycoprotein mucin 4 (MUC4) to impair trastuzumab binding, preventingantibody mediated killing of BC cells. Etanercept (E), an inhibitorof TNFα, downregulated MUC4 expression and sensitized denovo trastuzumab-resistant BC xenografts to trastuzumab. The aimof this work was to study whether etanercept improved antitumorinnate immune response (IIR) mediated by trastuzumab.We used the de novo trastuzumab-resistant and TNFα-producingcell line JIMT-1 to establish s.c. tumors in female nude mice. Animalswere treated with IgG, T, E or T+E (5 mg/kg each) i.p. twicea week. Treatment with T+E significantly reduced tumor growth in72,4% (p˂0.01) vs. the control group, IgG. Spleen NK cells from T+Egroup showed an increase in the degranulation marker CD107a byflow cytometry (p˂0.05) vs. IgG. Moreover, spleen NK cells from Tand T+E groups showed an enhanced trastuzumab-dependent degranulationin an ex vivo assay (p˂0.01) vs. IgG. In addition, T+Etreatment also reduced total myeloid cells (CD11b+) infiltration intumor microenvironment (TME) (p˂0.01) vs IgG, but granulocytic andmonocytic subtypes distribution remained unchanged. MUC4 andcyclinD1 expression determined by Western blot were downregulatedin tumors treated with T+E (p˂0.01 and p˂0.05, respectively)and AKT phosphorylation was inhibited (p˂0.01) with respect to IgG,T and E.These results suggest that TNFα blockade downregulates MUC4expression reduces tumor burden and improves the IIR, increasingNK degranulation and generating a less suppressive TME. Patientswith HER2+ MUC4+ BC could be eligible for the combined therapyT+E to overcome/avoid resistance.