Nanomedicine as a Promising Tool to Overcome Immune Escape in Breast Cancer

Abstract

Breast cancer is the most common type of malignancy and leading cause of cancer death among women worldwide. Despite the current revolutionary advances in the field of cancer immunotherapy, clinical response in breast cancer is frequently below expectations, in part due to various mechanisms of cancer immune escape that produce tumor variants that are resistant to treatment. Thus, a further understanding of the molecular events underlying immune evasion in breast cancer may guarantee a significant improvement in the clinical success of immunotherapy. Furthermore, nanomedicine provides a promising opportunity to enhance the efficacy of cancer immunotherapy by improving the delivery, retention and release of immunostimulatory agents in targeted cells and tumor tissues. Hence, it can be used to overcome tumor immune escape and increase tumor rejection in numerous malignancies, including breast cancer. In this review, we summarize the current status and emerging trends in nanomedicine-based strategies targeting cancer immune evasion and modulating the immunosuppressive tumor microenvironment, including the inhibition of immunosuppressive cells in the tumor area, the activation of dendritic cells and the stimulation of the specific antitumor T-cell response.

Keywords: breast cancer; cancer immunotherapy; cancer treatment; immune escape; nanomedicine.

Figure 1

Induction of immunogenic cell death (ICD) of cancer cells by nanomedicine-based photodynamic or photothermal therapy. Nanoparticles (NPs) carrying a photodynamic agent extravasate blood vessels, reach breast tumors and are internalized by cancer cells, where they release their loading. Upon laser irradiation, the dying cancer cells secrete tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs), such as ATP and high-mobility group box 1 protein (HMGB-1). Tumor cells also express DAMPs on the cell surface, including calreticulin (CRT) and heat-shock proteins (HSP). DAMPs can be recognized by different pattern recognition receptors expressed on dendritic cells (DCs), resulting in their maturation and activation. Mature DCs migrate to the draining lymph nodes and induce the activation of tumor-specific effector CD8+ and CD4+ T cells, which infiltrate the tumor and mediate the specific antitumor immune response.

Figure 2

Cancer immunity cycle and nanoparticle (NP)-based strategies to overcome mechanisms of immune escape. NP-based approaches can ameliorate various mechanisms of immune evasion in order to finally induce a strong antitumor T-cell response that inhibits tumor growth in breast cancer. (1) NPs loaded with an extensive repertoire of drugs have been demonstrated to induce the immunogenic cell death (ICD) of cancer cells in breast tumors. (2) NPs are able to enhance the presentation of the released tumor antigens by dendritic cells (DCs), as well as the maturation and activation of DCs, hampered in the tumor microenvironment (TME). (3) Upon the interaction between HLA-II-presenting tumor antigens on DCs and the T-cell receptor (TCR), T cells are activated. Thus, NPs increase T-cell priming. Furthermore, NPs can prevent T-cell inactivation by DCs through the blockade of PD-1/PD-L1 and CD86-CD80/CTLA-4 interactions. (4) Carcinoma-associated fibroblasts (CAFs) form a physical barrier in the TME and inhibit the function of T cells via the secretion of the vascular endothelial growth factor (VEGF). NPs deactivate CAFs and improve the tumor infiltration of specific effector T cells. (5) The infiltrated T cells specifically recognize cancer cells via TCR and tumor HLA-I/peptide interaction. Nevertheless, cancer cells often exhibit alterations in the expression of the HLA-I, which complicates their recognition. Despite that, there is not any NP-based strategy to overcome this mechanism of immune escape in breast cancer yet. (6) Tumor cells and immunosuppressive cells within the TME can hinder the activation of T cells or promote their inactivation. Several NP-based approaches consist in inactivating or reducing immunosuppressive myeloid dendritic stem cells (MDSC), regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) in the tumor area to improve the antitumor T-cell response. Similarly, the inhibition of the indoleamine 2,3-dioxygenase (IDO), IL-10 production and PD-1/PD-L1 interaction promotes the activity of the effector T cells.

Figure 3

Representative classes of nanoparticle designs and mechanisms of action to overcome mechanisms of cancer immune escape. CAFs: carcinoma-associated fibroblasts; TME: tumor microenvironment; MDSCS: myeloid-derived suppressor cells; ICD: immunogenic cell death; APCs: antigen-presenting cells; IDO-1: indoleamine 2,3-dioxygenase 1; TAMs: tumor-associated macrophages; Tregs: regulatory T cells; NK: natural killer; CTLs: cytotoxic T lymphocytes; PD-1: programmed cell death protein 1; PD-L1: programmed cell death ligand 1.