The Crosstalk Between Tumor Cells and the Immune Microenvironment in Breast Cancer: Implications for Immunotherapy

Abstract

Breast cancer progression is a complex process controlled by genetic and epigenetic factors that coordinate the crosstalk between tumor cells and the components of tumor microenvironment (TME). Among those, the immune cells play a dual role during cancer onset and progression, as they can protect from tumor progression by killing immunogenic neoplastic cells, but in the meanwhile can also shape tumor immunogenicity, contributing to tumor escape. The complex interplay between cancer and the immune TME influences the outcome of immunotherapy and of many other anti-cancer therapies. Herein, we present an updated view of the pro- and anti-tumor activities of the main immune cell populations present in breast TME, such as T and NK cells, myeloid cells, innate lymphoid cells, mast cells and eosinophils, and of the underlying cytokine-, cell-cell contact- and microvesicle-based mechanisms. Moreover, current and novel therapeutic options that can revert the immunosuppressive activity of breast TME will be discussed. To this end, clinical trials assessing the efficacy of CAR-T and CAR-NK cells, cancer vaccination, immunogenic cell death-inducing chemotherapy, DNA methyl transferase and histone deacetylase inhibitors, cytokines or their inhibitors and other immunotherapies in breast cancer patients will be reviewed. The knowledge of the complex interplay that elapses between tumor and immune cells, and of the experimental therapies targeting it, would help to develop new combination treatments able to overcome tumor immune evasion mechanisms and optimize clinical benefit of current immunotherapies.

Keywords: breast cancer; cancer immunotherapy; immune checkpoint inhibitors (ICI); immunosuppression; tumor microenvironment (TME).

Figure 1

Major players in immune breast TME. Among all cell populations present in breast TME, polymorphonuclear (PMN) and monocytic (Mo) Myeloid-Derived Suppressor Cells (MDSCs), Mast Cells (MCs), Innate Lymphoid Cells Type 2 and 3 (ILC2/3), M2-like Tumor Associated Macrophages (TAMs) and FoxP3⁺ regulatory T cells (Treg) are considered to exert an immunosuppressive action, while Tumor Infiltrating CD4⁺ and CD8⁺ Lymphocytes (TILs), Natural killer (NK) cells/Innate Lymphoid Cells Type 1 (ILC1), Dendritic cells (DCs) and Eosinophils are associated with an anti-tumor activity. Created with BioRender.com.

Figure 2

Mechanisms of immunosuppression in breast TME. Breast cancer cells developed several mechanisms to promote immunosuppression. (A) Cytokines and soluble factors are the main players in cell communication and signaling and they are able to mediate immune cell recruitment, mobilization and/or tumor infiltration. Moreover, they promote inflammation and contribute in changing TME composition, making it more immune suppressive. (B) Another strategy adopted by breast cancer cells is to overexpress on their surface immune checkpoint receptors such as PD-L1 or CTLA4, inducing cell–cell contact mediated death or anergy in T cells and suppressing immune response against tumor. (C) Finally, tumor derived exosomes could induce a reprograming in both immune suppressive and immune cells promoting tumor progression and survival by a wild range of molecules through different mechanisms. Created with BioRender.com.

Figure 3

Strategies to revert immune suppression and improve cancer immunotherapy. Actually, several methods used in breast cancer treatment take advantage of immunomodulation mechanisms and are promising tools for tumor immunotherapy. One strategy is to improve immune cell activity against the tumor by innovative therapies such as CAR-T/CAR-NK administration, which employs patient’s T/NK cells engineered with chimeric receptors targeting antigens characteristics of cancer cells, or as anti-cancer vaccination, which stimulates the activation of the patient’s tumor-specific T cells. An additional method ongoing in clinical studies is the use of monoclonal antibodies against immune checkpoints or immune checkpoints inhibitors (ICIs) to block T-cell suppression, and the use of BiKE and TriKE reagents to induce antitumor NK cell activation. Moreover, an antitumor immune response may be activated by chemotherapy drugs inducing immunogenic cell death. A second strategy to improve tumor immunotherapy is to revert the immunosuppressive activity of TME often displayed in several breast cancers. In this sense, cytokine pharmacological modulation or inhibition of specific immunosuppressive pathways can be performed. The effects of single or combined therapies are actually studied. Created with BioRender.com.