HER2-targeted antibody-drug conjugate induces host immunity against cancer stem cells

Abstract

We previously tested HER2-targeted antibody-drug conjugates (ADCs) in immunocompromised (SCID) mice, precluding evaluation of host immunity, impact on cancer stem cells (CSCs), and potential benefit when combined with PD-L1 blockade. In this study, we tested HER2-targeted ADC in two immunocompetent mouse tumor models. HER2-targeted ADC specifically inhibited the growth of HER2-expressing tumors, prolonged animal survival, and reduced HER2⁺ and PD-L1⁺ cells. ADC + anti-PD-L1 antibody augmented therapeutic efficacy, modulated immune gene signatures, increased the number and function of CD3⁺ and CD19⁺ tumor-infiltrating lymphocytes (TILs), induced tumor antigen-specific immunological memory, stimulated B cell activation, differentiation, and IgG1 production both systemically and in the tumor microenvironment. In addition, ADC therapy modulated T cell subsets and their activation in TILs. Furthermore, HER2-targeted ADC reduced the number and tumorigenicity of ALDH^hi CSCs. This study demonstrates that HER2-targeted ADC effectively targets ALDH^hi CSCs and this effect is augmented by co-administration of anti-PD-L1 antibody.

Keywords: CSCs; HER2; TILs; anti-PD-L1; antibody-drug conjugate (ADC).