Present and Future of Immunotherapy for Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptors (ERs), human epidermal growth factor receptor 2 (HER2), and progesterone receptors (PRs). TNBC has the poorest prognosis among breast cancer subtypes and is more likely to respond to immunotherapy due to its higher expression of PD-L1 and a greater percentage of tumor-infiltrating lymphocytes. Immunotherapy has revolutionized TNBC treatment, especially with the FDA's approval of pembrolizumab (Keytruda) combined with chemotherapy for advanced cases, opening new avenues for treating this deadly disease. Although immunotherapy can significantly improve patient outcomes in a subset of patients, achieving the desired response rate for all remains an unmet clinical goal. Strategies that enhance responses to immune checkpoint blockade, including combining immunotherapy with chemotherapy, molecularly targeted therapy, or radiotherapy, may improve response rates and clinical outcomes. In this review, we provide a short background on TNBC and immunotherapy and explore the different types of immunotherapy strategies that are currently being evaluated in TNBC. Additionally, we review why combination strategies may be beneficial, provide an overview of the combination strategies, and discuss the novel immunotherapeutic opportunities that may be approved in the near future for TNBC.

Keywords: TNBC; chemotherapy; immune checkpoint inhibitors; immunotherapy; radiation therapy; triple-negative breast cancer.

Figure 1

Immunological components of TNBC tumor microenvironment. This illustration sets forth the immunological components of the TNBC tumor microenvironment, which includes tumor-infiltrating lymphocytes (TILs), regulatory T cells (Tregs), tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), tumor-associated neutrophils (TANs), dendritic cells (DCs), natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs), cancer-associated adipocytes (CAAs), and immune checkpoints.

Figure 2

Current clinical immunotherapy approaches in TNBC. Clinical immunotherapy approaches for TNBC have been diversified in recent years and this illustration summarizes those strategies which include cytokines, mAbs/ADCs, immune checkpoint inhibitors, vaccines, adoptive cell therapies, and oncolytic virus therapy.

Figure 3

Mechanism of action of ICIs targeting PD-L1, PD-1, and CTLA-4. T-cell inactivation and the prevention of tumor cell death are caused by their binding to the corresponding ligands on the surface of cancer cells. Immune checkpoint inhibition promotes anticancer activity and promotes T-cell activation.