Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation

Abstract

Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and tumor microenvironment (TME) remodeling; therefore, it will be interesting to investigate the relationship between chemotherapy-induced TME changes and TNBC immunomodulation. In this review, we focus on the immunosuppressive and immunoreactive role of TME in TNBC immunomodulation and the contribution of TME constituents to TNBC subtype classification. Further, we also discuss the role of chemotherapy-induced TME remodeling in modulating TNBC immune response and tumor progression with emphasis on DAMPs-associated molecules including high mobility group box1 (HMGB1), exosomes, and sphingosine-1-phosphate receptor 1 (S1PR1), which may provide us with new clues to explore effective combined treatment options for TNBC.

Keywords: immunomodulation; triple negative breast cancer; tumor microenvironment.

Figure 1

Immunosuppressive and immunoreactive TME. Immunosuppressive tumor microenvironment (TME) is mainly constituted of M2 macrophages, forkhead box P3⁺ (Foxp3⁺) regulatory T lymphocytes (Tregs), myeloid-derived suppressor cells (MDSCs), and PD-1/PD-L1 axis. Immunoreactive TME is mainly constituted of CD8⁺ T cells, natural killer (NK) cells, and M1 macrophages. PD-1/PD-L1 axis becomes immunoreactive in response to anti-PD1 or anti-PD-L1 monoclonal antibody (aPD-1/PD-L1 mAb) owing to the activation of CD8⁺ T cells. (Foxp3, forkhead box P3; Tregs, regulatory T lymphocytes; MDSC, myeloid-derived suppressor cell; NK, natural killer; PD-1, programmed cell death protein-1; PD-L1, programmed death-ligand 1; aPD-1 mAb, anti-PD-1 monoclonal antibody; ECM, extra cellular matrix; TME, tumor microenvironment).

Figure 2

Chemotherapy-induced immunogenic cell death and immunomodulation in TNBC. Chemotherapy induces immunogenic cell death (ICD), and then promotes the release of damage-associated molecular patterns (DAMPs) including high mobility group box1 (HMGB1), exosomes and sphingosine-1-phosphate receptor 1 (S1PR1) by damaged or activated cells. Chemotherapy combined with targeted therapy could enhance anti-tumor immunity through promoting function of immunoreactive lymphocytes and blocking or reversing function of immunosuppressive cells. (ICD, immunogenic cell death; DAMPs, damage-associated molecular patterns; HMGB1, high mobility group box1; S1P, sphingosine-1-phosphate; SPHK1, sphingosine kinase 1; S1PR1, sphingosine-1-phosphate receptor 1; TNBC, triple negative breast cancer; TME, tumor microenvironment).