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

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 ALDHhi CSCs. This study demonstrates that HER2-targeted ADC effectively targets ALDHhi CSCs and this effect is augmented by co-administration of anti-PD-L1 antibody. [Display omitted] •HER2-targeted ADC shows anti-tumor activity in immune-competent mouse models•HER2-targeted ADC induces humoral and cellular immunity and immunological memory•The ADC inhibits tumor growth and prolongs survival by targeting ALDHhigh CSCs•HER2-targeted ADC augments the therapeutic efficacy of anti-PD-L1 antibody A major challenge for current cancer management is the relapse of the disease due to CSCs that are resistant to traditional therapies. Here, Xia and colleagues show that HER2-targeted ADC targets both bulk tumor cells and ALDHhigh CSCs via inducing anti-tumor cellular and humoral immune responses and immunological memory.