Soluble TNFα blockade improves effectiveness of trastuzumab deruxtecan and boosts antitumor potential of macrophages in a HER2+ tumor model

SOFIA BRUNI ; FLORENCIA L. MAURO; SOFIA NAVEIRO; MARIA F. MERCOGLIANO; ROXANA SCHILLACI

Orlando

Congreso; American Association for Cancer Research Annual Meeting 2023; 2023

American Association for Cancer Research

HER2 positive (HER2+) is a subtype that affects 13-20% of breast cancer (BC) patients. They receive trastuzumab (T), an anti-HER2 monoclonal antibody, but 40-60% of them relapse. Therefore, new strategies to overcome trastuzumab resistance are needed. We recently demonstrated a novel tumor immune evasion strategy where TNFα induces upregulation of the expression of the transmembrane glycoprotein mucin 4 (MUC4) to impair trastuzumab binding, preventing antibody mediated killing of BC cells. Etanercept (E), an inhibitor of TNFα, downregulated MUC4 expression and sensitized de novo trastuzumab-resistant BC xenografts to trastuzumab. The aim of this work was to study whether etanercept improved antitumor innate immune response (IIR) mediated by trastuzumab.We used the de novo trastuzumab-resistant and TNFα-producing cell line JIMT-1 to establish s.c. tumors in female nude mice. Animals were treated with IgG, T, E or T+E (5 mg/kg each) i.p. twice a week. Treatment with T+E significantly reduced tumor growth in 72,4% (p˂0.01) vs. the control group, IgG. Spleen NK cells from T+E group showed an increase in the degranulation marker CD107a by flow cytometry (p˂0.05) vs. IgG. Moreover, spleen NK cells from T and T+E groups showed an enhanced trastuzumab-dependent degranulation in an ex vivo assay (p˂0.01) vs. IgG. In addition, T+E treatment also reduced total myeloid cells (CD11b+) infiltration in tumor microenvironment (TME) (p˂0.01) vs IgG, but granulocytic and monocytic subtypes distribution remained unchanged. MUC4 and cyclinD1 expression determined by Western blot were downregulated in 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 MUC4 expression reduces tumor burden and improves the IIR, increasing NK degranulation and generating a less suppressive TME. Patients with HER2+ MUC4+ BC could be eligible for the combined therapy T+E to overcome/avoid resistance.