Interplay between Natural Killer Cells and Anti-HER2 Antibodies: Perspectives for Breast Cancer Immunotherapy

Abstract

Overexpression of the human epidermal growth factor receptor 2 (HER2) defines a subgroup of breast tumors with aggressive behavior. The addition of HER2-targeted antibodies (i.e., trastuzumab, pertuzumab) to chemotherapy significantly improves relapse-free and overall survival in patients with early-stage and advanced disease. Nonetheless, considerable proportions of patients develop resistance to treatment, highlighting the need for additional and co-adjuvant therapeutic strategies. HER2-specific antibodies can trigger natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity and indirectly enhance the development of tumor-specific T cell immunity; both mechanisms contributing to their antitumor efficacy in preclinical models. Antibody-dependent NK cell activation results in the release of cytotoxic granules as well as the secretion of pro-inflammatory cytokines (i.e., IFNγ and TNFα) and chemokines. Hence, NK cell tumor suppressive functions include direct cytolytic killing of tumor cells as well as the regulation of subsequent antitumor adaptive immunity. Albeit tumors with gene expression signatures associated to the presence of cytotoxic lymphocyte infiltrates benefit from trastuzumab-based treatment, NK cell-related biomarkers of response/resistance to HER2-specific therapeutic antibodies in breast cancer patients remain elusive. Several variables, including (i) the configuration of the patient NK cell repertoire; (ii) tumor molecular features (i.e., estrogen receptor expression); (iii) concomitant therapeutic regimens (i.e., chemotherapeutic agents, tyrosine kinase inhibitors); and (iv) evasion mechanisms developed by progressive breast tumors, have been shown to quantitatively and qualitatively influence antibody-triggered NK cell responses. In this review, we discuss possible interventions for restoring/enhancing the therapeutic activity of HER2 therapeutic antibodies by harnessing NK cell antitumor potential through combinatorial approaches, including immune checkpoint blocking/stimulatory antibodies, cytokines and toll-like receptor agonists.

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…Enhancing the activation and proliferation of NK cells may thus benefit anti-HER2 targeting approaches. Indeed, aside from cytokine administration (IL-2/15/12) and glyco-optimization, additional approaches, which include anti-PD-1/TIGIT blockade, and CD137/Tolllike receptor agonists have been shown to potentially augment Trastuzumab efficacy in combinatorial studies (213). Another effective strategy to improve NK cell ADCC is incorporation of Trastuzumab in the bispecific antibody format (discussed below).…”

Effect of Estrogen Receptor Status on Circulatory Immune and Metabolomics Profiles of HER2-Positive Breast Cancer Patients Enrolled for Neoadjuvant Targeted Chemotherapy

“…In this context, the ER status was found associated with a differential expression of tumor infiltrating lymphocytes (TILs), raising the possibility of different immune-tumor interactions based on ER status [26][27][28]. Moreover, peripheral blood immune cells involved in antibody-dependent cell cytotoxicity (ADCC) and serum cytokines have been also associated to the trastuzumab response [29][30][31][32]. However, the association of response to NATC, as well as of disease relapse, with the ER status appears very elusive, requiring new stratification models to better identify the patients that can receive the best pharmacological benefit.…”

Predictive impact of absolute lymphocyte counts for progression-free survival in human epidermal growth factor receptor 2-positive advanced breast cancer treated with pertuzumab and trastuzumab plus eribulin or nab-paclitaxel

“…Pertuzumab and trastuzumab are humanized monoclonal anti-HER2 antibodies with complementary proposed mechanisms of action. Both antibodies work through the disruption of HER2 dimerization with HER3 and other epidermal growth factor receptors (EGFRs), leading to the inhibition of HER2 signaling [ 4 ]. Anti-HER2 antibodies are thought to mediate tumor regression not only by interrupting oncogenic signaling, but also by inducing antibody-dependent cell-mediated cytotoxicity (ADCC) [ 4 ].…”