Patritumab augments anti-tumor immune response of adoptive transfer of autologous T cells for breast cancer PDX models

Abstract

Abstract Background Signal transduction upon HER3/EGFR dimerization to PI3K/AKT/mTOR pathways are thought to be involved in cancer survival, proliferation and up-regulation of PD-L1 expression. It is therefore hypothesized that inhibition of HER3 signal could enhance anti-tumor immunity by regulating the expression of PD-L1. Methods Two patient-derived xenograft (PDX) models of breast cancer were evaluated with patritumab (anti-HER3 antibody), polyclonal activated autologous T cells (PATCs) or a combination of patritumab and PATCs (P-PATCs). Tumor size was measured for anti-tumor effects of each treatment. To test the immunological modulation by patritumab, tumors and liver tissue were immunohistochemically stained with anti-CD3, CD4, CD8, CD137 and PD-L1 antibody. Furthermore, quantitative real-time PCR and RNA-sequencing was performed on the tumor samples from the PDX models. Results Although treatment of PATCs or patritumab alone showed limited anti-tumor effects, P-PATCs treatment demonstrated a significantly greater anti-tumor response in both 2 PDX models. Interestingly, the proportion of CD137 expressing T cell infiltration was much higher in the P-PATCs group compared to the patritumab or PATCs group while the proportion of CD4+ T cell infiltration was also higher in P-PATCs group. There was an equal proportion of T cells without CD137 expression present in liver tissue in both PATCs and P-PATCs groups. Conclusions These data suggest that patritumab could help augmentation of antigen-specific T cell activation leading to additional anti-tumor effects on patritumab treatment alone by means of immunological mechanisms. Thus, patritumab treatment might become a novel treatment strategy for HER3/neuregulin (ligand for HER3)-expressing breast cancer patients in the future.