Focusing on NK cells and ADCC: A promising immunotherapy approach in targeted therapy for HER2-positive breast cancer

Abstract

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer has a high metastatic potential. Monoclonal antibodies (mAbs) that target HER2, such as trastuzumab and pertuzumab, are the cornerstone of adjuvant therapy for HER2-positive breast cancer. A growing body of preclinical and clinical evidence points to the importance of innate immunity mediated by antibody-dependent cellular cytotoxicity (ADCC) in the clinical effect of mAbs on the resulting anti-tumor response. In this review, we provide an overview of the role of natural killer (NK) cells and ADCC in targeted therapy of HER2-positive breast cancer, including the biological functions of NK cells and the role of NK cells and ADCC in anti-HER2 targeted drugs. We then discuss regulatory mechanisms and recent strategies to leverage our knowledge of NK cells and ADCC as an immunotherapy approach for HER2-positive breast cancer.

Keywords: ADCC; HER-2 positive breast cancer; NK cells; immunotherapy approach; monoclonal antibodies.

Figure 1

Regulatory mechanisms of NK cells and ADCC. The activating receptors of NK cells are NKG2D, CD94/NKG2C, NKp46, NKp44, NKp30, recombinant NK cell receptor 2B4 (NKR2B4, 2B4), NKp80, NTB-A, and CD59, and the inhibiting receptors are KIR, LIRs, and TIGIT. CISH normally inhibits IL-15/IL15R signaling in NK cells. The main cytokines secreted by NK cells are CX3CL1, chemokine (C motif) ligand 1 (XCL1), IL10, IFN-γ, TNF-α, and GM-CSF. HLA-G and HLA-E expressed by tumor cells bind to inhibitory receptors KIR2DL4 and CD94/NKG2A of NK cells respectively to exert immunosuppressive effects; CD137 counteracts the immunosuppression caused by the overexpression of TGF-β by tumor cells. The figure was drawn by Figdraw.

Figure 2

ADCC process including NK cells, mAb, and tumor cells. The mAbs include the Fab and Fc segments. The Fab segment is an endometrioid by heavy-chain constant region (C_H1) and heavy chain variable region (V_H), in which the amino acid sequence is constant. The amino acid sequences of light-chain constant region (C_L) and heavy-chain variable region (V_L) sites are variable. Complementary determining regions (CDRs) of the Fab segment bind on tumor cells by different amino acid sequences, such as trastuzumab binding to HER2 extracellular region IV. The Fc segment includes C_H2 and C_H3. NK cells bind to the Fc segment of mAb via CD16. CD16 interacts with C_H2 of mAb in a 1:1 manner, where the N-glycan chain at the N297 position on C_H2 also plays a key role in this interaction.