Reconstituting Immune Surveillance in Breast Cancer: Molecular Pathophysiology and Current Immunotherapy Strategies

Abstract

Over the past 50 years, breast cancer immunotherapy has emerged as an active field of research, generating novel, targeted treatments for the disease. Immunotherapies carry enormous potential to improve survival in breast cancer, particularly for the subtypes carrying the poorest prognoses. Here, we review the mechanisms by which cancer evades immune destruction as well as the history of breast cancer immunotherapies and recent developments, including clinical trials that have shaped the treatment of the disease with a focus on cell therapies, vaccines, checkpoint inhibitors, and oncolytic viruses.

Keywords: breast cancer; immune tumour microenvironment; immunoediting; immunotherapy.

Figure 1

Breast cancer subtypes: prognosis and standard treatments. BC can be classified into four subtypes based on the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Targeted and endocrine therapies are administered based on the molecular markers. The triple-negative breast cancer types (i.e., ER⁻, PR⁻, HER2⁻), have the worst prognosis and do not respond to the endocrine therapies or HER2 targeting agents. Chemotherapy is the only therapeutic regimen used.

Figure 2

The three phases of cancer immunoediting in breast cancer. Elimination is the first phase of cancer immunoediting. Early in mammary tumorigenesis, acute inflammation induces the activation of innate immunity, including type 1- polarized macrophages (M1), natural killer (NK), and natural killer T cells (NKT), resulting in both tumour cell death and the maturation of dendritic cells (DC), which can prime tumour-specific T cells (CD4⁺ and CD8⁺). Inflammation-related soluble factors, including IL-2, IFNγ, perforin, and TNF, can be found in the TME. This stage is followed by either immune-mediated rejection of incipient tumours or the selection of tumour cell variants, which can induce chronic inflammation. Hence, the persistent cells enter the equilibrium phase. Ultimately, this leads to the escape phase, which results in a complex and immune-tolerant TME, consisting of suppressive immune cells, including regulatory T cells (Treg), type 2- polarized tumour-associated macrophages (M2), and myeloid-derived suppressor cells (MDSC), and inhibitory molecules such as IL-6, IDO, galectin, IL-10, and TGF-β, that allow overt immune escape and tumour progression to occur.

Figure 3

Major players in the immune microenvironment of breast cancer. Subtypes of immune cells can elicit both tumour-promoting and tumour-suppressing effects. The anti-tumour activity is mainly driven by immunostimulating immune cells, including M1 macrophages, CD8⁺ and CD4⁺ lymphocytes, NK and NKT1 cells, and DCs and N1 neutrophils. They secrete cytokines and soluble factors which help fighting the tumour development (including IFNγ, TNFα, IL-1β, IL-2, and IL-12). In contrast, immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), mast cells (MCs), regulatory T cells (Tregs), type 2- polarized tumour-associated macrophages (M2-TAMs), and N2 tumour-associated neutrophils (N2-TAN) can be recruited to the tumour site counteracting the anti-tumour activity and facilitating tumour growth. These cells release immuno-inhibitory pro-tumour cytokines (TGF-β, VEGF, IL-6, IL-8, and IL-10).

Figure 4

Immunotherapy approaches in breast cancer. The first cancer immunotherapy treatment entered the clinical practice for BC patients in September 1998 with the FDA approval of the humanized HER2 monoclonal antibody trastuzumab for the treatment of metastatic BC patients with HER2 overexpression and/or gene amplification. This represented a milestone in the treatment of BC and has been followed by other different anti-HER2 monoclonal antibodies including lapatinib, neratinib, gefitinib, or afatinib, delivered as monotherapy or in combination with conventional treatments [83]. After that, despite BC immune landscape being dynamic and heterogeneous among tumour stages, subtypes, and disease settings, an emerging body of preclinical and clinical data started to emerge, highlighting the effectiveness of immunotherapies in BC. Following the encouraging long-term success of checkpoint inhibitors in the treatment of different tumours, the FDA approved the first checkpoint inhibitor immunotherapy drug, the anti-PD-L1 antibody atezolizumab in combination with chemotherapy (Abraxane) for the treatment of triple-negative, metastatic BC patients with positive PD-L1 protein expression as a result of the findings from the Phase III double-blind IMpassion130 trial (NCT02425891). However, the limited complete response rates and the immune-mediated serious adverse events encouraged the search of new immunotherapeutic strategies, including adoptive cell transfer and oncolytic viruses, either as monotherapy or in combination with other treatments. A summary of the most recent and relevant immunotherapy approaches being currently under investigation in clinical trials for the treatment of BC is reported.