Abstract: Cancer immunotherapy has evolved dramatically with improved understanding of immune microenvironment and immunosurveillance. The immunogenicity of breast cancer is rather heterogeneous. Specific subtypes of breast cancer such as estrogen receptor (ER)-negative, human EGF receptor 2 (HER2)-positive, and triple-negative breast cancer (TNBC) have shown evidence of immunogenicity based on tumor–immune interactions. Several preclinical and clinical studies have explored the potential for immunotherapy to improve the clinical outcomes for different subtypes of breast cancer. This review describes the immune microenvironment of HER2-positive breast cancer and summarizes recent clinical advances of immunotherapeutic treatments in this breast cancer subtype. The review provides rationale and ongoing clinical evidence to the use of immune checkpoint inhibitors, therapeutic vaccines, and adoptive T cell immunotherapy in breast cancer. In addition, the present paper describes the most relevant clinical progress of strategies for the combination of immunotherapy with standard treatment modalities in HER2-positive breast cancer including chemotherapy, targeted therapy, and radiotherapy.


Keywords: immunotherapy, breast cancer, HER2, checkpoint inhibitors, vaccines 


BACKGROUND

Role of immune microenvironment in cancer

Immune cells represent a major component of the tumor microenvironment.1 Immune elements infiltrating the tumor microenvironment include macrophages, natural killer (NK) cells, dendritic cells (DCs), and adaptive immune cells.1,2 The role of immune system in cancer development and progression is described through immunoediting.3 The concept of tumor immunoediting is represented by three phases designated as elimination, equilibrium, and escape.3 The elimination phase implies a process known as tumor immune surveillance, whereby immune system identifies cancerous cells and eliminates them preventing tumor growth.3 In the equilibrium phase, sporadic tumor cells that have escaped immune attack during elimination remain dormant and a temporary state of equilibrium develops between immune system and cancer cells. During this period, immune system will exert a selective pressure to eliminate susceptible tumor cells. However, cancer cells that acquire resistance to antitumor immune response enter the escape phase and continue to grow allowing tumors to develop aggressively.3 Host antitumor immune responses are predominantly mediated via cellular immunity in which CD8+ cytotoxic T lymphocytes (CTLs) are considered the cornerstone cellular element in anticancer immunity.4,5 Activated CTLs exert antitumor effects by secreting interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) along with other cytotoxins.4,6,7 In this regard, prevention of tumor growth and development is determined, in part, by the number of CTLs invading through the tumor microenvironment and the ability of CTLs to recognize tumor-associated antigens (TAAs).4 Other anti-oncogenic effects of immune system have been mediated through the activation of macrophages, NK cells, and CD4+ T helper (Th) 1 cells.2

A hallmark of cancers is the ability to evade the immune system through tumor-mediated immune escape mechanisms.2 Tumors avoid recognition by immune system through multiple mechanisms including the downregulation of components of antigen processing and presentation machinery leading to loss of major histocompatibility complex (MHC) class I protein expression, low human leukocyte antigen (HLA) class I expression, and defects in T cell receptor (TCR) signaling.6,8 In addition, growing tumors can avoid destruction by immune system through recruitment of immunosuppressive elements such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages.6,8,9 These immune cells can suppress the actions of CTLs promoting tumor growth.10Furthermore, growing cancer cells have been shown to enhance the production of immunosuppressive cytokines within the tumor microenvironment such as TGF-β and IL-10 to escape immune attack.8,9Advancements in immunotherapy research have revealed a key immune evasion mechanism through the utilization of immune checkpoints by tumor cells to suppress the cellular immune response and promote immune tolerance.2,8 Therefore, immunotherapeutic interventions are directed to enhance tumor recognition by immune system and augment CTL activity.

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Breast cancer is a heterogeneous disease with a high degree of diversity between and within tumors.11Comprehensive gene expression profiling classifies breast tumors into three major molecular subtypes: luminal, human EGF receptor 2 (HER2)-positive, and basal-like cancers.12,13 Recently, growing evidence is supporting the immunogenic potential of specific breast cancer subtypes.14,15 Immunogenic nature of breast cancer was illustrated by the identification of tumor-infiltrating lymphocytes (TILs) in breast tumors.15,16 Analysis of breast tumor samples had demonstrated higher level of TILs among patients harboring HER2-positive and triple-negative breast cancer (TNBC) than hormone-dependent subtypes.17–19 Analysis of TILs in a large cohort of breast cancer patients indicated that the presence of CD8+ T cells is associated with a lower risk of mortality in estrogen receptor (ER)-negative and ER-positive/HER2-positive tumors.14,20 However, the presence of CD8+ infiltrates was not associated with survival advantage for patients harboring ER-positive tumors. In the same study, Tregs that are characterized by FOXP3-positive expression were not associated with a prognostic impact among the different subsets of breast tumors evaluated.14,20 Intra-tumoral CD4+ T cell number has been found to positively correlate with advanced tumor stages, large tumor size, positive lymph node status, and HER2 expression in breast cancer patients.21 In addition, CD4+ TILs in breast cancer patients were positively correlated with FOXP3-positive Tregs. The CD4/CD8 ratios were negatively correlated with overall survival (OS) and relapse-free survival in breast cancer patients.21