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

Cell Chem Biol. 2021 May 20;28(5):610-624.e5. doi: 10.1016/j.chembiol.2021.02.013. Epub 2021 Mar 11.


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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Female
  • Humans
  • Immunoconjugates / chemistry
  • Immunoconjugates / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / immunology
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / immunology


  • Immunoconjugates
  • Erbb2 protein, mouse
  • Receptor, ErbB-2