Soluble TNFα blockade inhibits cell migration, tumor growth, and induces innate immune response in lapatinib-resistant HER2+ breast cancer

ROLDAN DEAMICIS, AGUSTINA; ELIZALDE, PATRICIA V.; MAURO, FLORENCIA L.; MERCOGLIANO, MARÍA F.; BRUNI, SOFÍA; DE MARTINO, MARA; SCHILLACI, ROXANA

Congreso; Frontiers in Cancer Immunotherapy 2020; 2020

Lapatinib (L) isa dual EGFR/HER2 tyrosine kinase inhibitor used in HER2+ metastatic breastcancer (BC), but its clinical benefit is <30%. We showed that soluble TNF(sTNF) induces trastuzumab (T) resistance by upregulating mucin 4 (MUC4), atransmembrane glycoprotein that shields the T epitope on HER2 molecule, andthat  women with HER2+/MUC4+ BC haveworse survival. Here we studied the role of sTNF blockade in cell migration,tumor growth and innate immune response in JIMT-1, a T and L-resistant HER2+ BCmodel. To block sTNF we used INB03, a TNF dominant negative protein (DN).JIMT-1 cell migration was not prevented by L or DN treatment, but combinationof L+DN inhibited migration by 50% (p<0.001vs control).  When MUC4 was knocked down,L alone reduced cell migration and sTNF blockade did not further enhance thiseffect. In vivo L+DN treatmentinhibited JIMT-1 tumor growth by 54 % vs IgG, L or DN (p<0.001) in nude mice. Tumor immune cell infiltration analysisin the L+DN group showed a higher activation and degranulation of NK cells anda decrease in myeloid-derived suppressor cells vs control groups. We show thatsTNF blockade is able to overcome L resistance, inhibiting cell migration andtumor growth. sTNF neutralization along with L treatment triggers an anti-tumorinnate immune response. These findings highlight the potential use of L+DN inHER2+/MUC4+ BC, especially in patients with brain metastasis since L andDN both cross the blood brain barrier.