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.

Intra-Tumor Heterogeneity Revealed by Mass Spectrometry Imaging Is Associated with the Prognosis of Breast Cancer

“…Therefore, clusters of these heterotypic components of TME could be revealed by MALDI-MSI. The immune system plays an important role in cancer progression, either by eliminating cancer cells or by stimulating tumor growth [60,61]. It is noteworthy that tumor infiltration by lymphocytes indicated an antitumor response of breast cancer, and the level of tumor-infiltrating lymphocytes (TILs) was associated with a better outcome in HER2-positive cancers [62,63].…”

IDO Inhibition Facilitates Antitumor Immunity of Vγ9Vδ2 T Cells in Triple-Negative Breast Cancer

“…IDO expression was correlated with increased tumor-infiltrating T regulatory cells (T reg); studies had suggested that tumor cells or IDO-expressing APCs could mediate T reg cells to strongly dampen the antitumor responses of T cells ( 16 , 39 ). The intratumor ratio of infiltrating lymphocytes (TILs) to T reg cells was considered as a marker of favorable immunological responses, which was a possible key factor to control tumor progression ( 5 , 55 ). Previous work showed that intratumoral γδ T cell numbers were positively correlated with advanced tumor stages, HER2 expression status, FOXP3 + cells, and high lymph node metastasis, but inversely correlated with relapse-free survival and overall survival of breast cancer patients ( 6 ).…”

Epstein–Barr Virus—Associated Malignancies and Immune Escape: The Role of the Tumor Microenvironment and Tumor Cell Evasion Strategies

“…This is controlled by EBV-miR-BART7 and EBV-miR-BART2-5p [135,295] negatively interfering with NK cell responses. The enhanced recruitment and activation of Tregs, the subsequent anergy of CD8 + cytotoxic T cells, the crosstalk with tumor-growth-promoting M2 macrophages and the overexpression of the immune-suppressive enzyme indoleamine 2,3-deoxygenase (IDO) are also involved in immune evasion [296][297][298]. Innate immune cells play an important role in the host response against viral infections including EBV [294].…”