Immunotherapeutic approaches in triple-negative breast cancer: latest research and clinical prospects

Abstract

Triple-negative breast cancer (TNBC), as defined by the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression, is a challenging disease with the poorest prognosis of all breast cancer subtypes. Importantly, there are currently no known molecular targets for this subgroup of patients. Recent advances in genomics and gene expression profiling have shed new light on the molecule heterogeneity of TNBC. We present an overview of the scientific evidence suggesting that clinical outcome in TNBC is affected by tumor-infiltrating immune cells. We also describe tumor-associated antigens recently identified in TNBC. Finally, we review the current literature on promising immunotherapies for TNBC, including tumor vaccine approaches, immune-checkpoint inhibitors, antagonists of immunosuppressive molecules and adoptive cell therapies. It is our contention that selected patients with TNBC with lymphocytic tumor infiltrates at diagnosis may benefit from immune-based therapies and that these immunotherapies will be most beneficial in combination with cytotoxic drugs that potentiate adaptive anti-tumor immunity.

Keywords: T cell; basal like; breast cancer; immunotherapy.

Figure 1.

Immunotherapeutic opportunities for triple negative breast cancer (TNBC). Compared with other subtypes, the outcome of TNBC has been shown to be particularly influenced by tumor-infiltrating lymphocytes. Therefore, different immunotherapeutic strategies, aiming at blocking or activating specific targets, are currently envisaged. One of the most promising approaches consists of the use of antagonists against inhibitory receptors that become upregulated on antitumor T cells, such as programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), cytotoxic T-lymphocyte antigen 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3). Antitumor T cells also express the adenosine receptor A2A (ADORA2a), and antagonists of ADORA2a have been shown to enhance antitumor immunity. PD-L1 and IDO (indoleamine 2,3-dioxygenase), expressed on dendritic cells and tumor cells, as well as immunosuppressive cytokines [such as interleukin (IL)-10, IL-23, transforming growth factor β (TGFβ), adenosine, prostaglandin E2 (PGE2), vascular endothelial growth factor A (VEGF-A)] or immunosuppressive enzymes (such as CD73 and arginase I), could also be targeted to stimulate antitumor immune responses. Alternatively, some approaches aim to activate specific immune targets, such as the coreceptors CD137 (41BB) and OX40, expressed on T cells. Finally, recent evidence suggests that specific tumor antigens, such as MUC-1 and NY-ESO-1, may constitute targetable vaccine antigens. The adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells specific for these tumor antigens is also envisaged.