Breast cancer has been identified as one of the leading causes of cancer-related deaths worldwide. Abnormalities in proteins result in malignant transformation of cells that results in 25–40% of recurrence and metastasis of cancer (1). Breast cancer is a common malignant tumor and its rate of incidence was the highest among tumors detected in women in 2019 (2).

Approximately 627,000 people are expected to succumb to breast cancer in 2019. Due to the lack of specific therapeutic targets available for triple-negative breast cancer (TNBC), the prognosis of TNBC remains unsatisfactory. The emergence of anti-PD-L1/PD-1 therapeutics has shown promise for the treatment of TNBC (3). In the present study, the advancements in the efficacy of PD-L1 against TNBC are described. Programmed death ligand 1 (PD-L1) is a ligand of programmed cell death-1 (PD-1) and is expressed on various tumors and immune cells. Once PD-L1 binds to PD-1, it inhibits T-cell migration and proliferation and the secretion of cytotoxic mediators, thereby limiting its killing effect on tumor cells (3). PD-L1 has been revealed to be highly expressed in a variety of tumors and enhance antitumor immunity by inhibiting PD-L1 (4). The development and clinical application of targeted drugs against signaling pathways associated with the occurrence and development of breast cancer have become a hot spot in research on breast cancer treatment (5). Targeted therapy has better clinical efficacy and safety than cytotoxic drugs (6). The present study reviewed the current molecular targeted therapeutics in treating breast cancer.

Tumor immunotherapy is a method of treatment that has been developed in recent years. It stimulates and regulates immune function, enhances antitumor ability, and controls and kills tumor cells (7). Immunotherapy has attracted attention owing to the importance of antitumor immunity, diverse mechanisms in escape of tumors from immune surveillance, continuous discovery of novel therapeutic targets and immunotherapies (8,9). Tumor immunotherapy can be divided into active and passive immunotherapy. Active immunotherapy employs tumor vaccines to mimic tumor antigens to activate immune effects on tumors, thereby directly or indirectly promoting specific antitumor immune responses in humans (10). Passive immunotherapy includes the use of monoclonal antibodies, adoptive immune cells, and cytokines. Monoclonal antibody therapy involves the administration of specific antibodies to stimulate host immune response against tumor antigens (11,12). Adoptive immune cell therapy separates and expands immune cells to induce the production of cytokines before introducing the cells into patients to increase the abundance of immune cells and enhance their anticancer function (13). Cytokine therapy involves the direct injection of cytokines into the human body, which enhances antitumor function in immune cells (14,15). Compared to traditional methods of treatment, tumor immunotherapy has specific advantages: Tumor immune-related monoclonal antibodies and tumor vaccines exhibit fewer adverse reactions, strong specificity, and promising clinical application (13).

An increase in research on immune checkpoints has been observed in recent years. Immune checkpoints are inhibitory signaling pathways present in the immune system that regulate the persistence and intensity of immune response, maintain autoimmune tolerance, and avoid tissue damage (16,17). Dysfunction of key negative regulatory molecules during T-cell activation is important for the tolerance and escape of tumor immunity. Inhibition of the immune checkpoint can reverse the immunosuppressive state of the tumor microenvironment and enhance the clearance of tumor cells (18). Immunological checkpoints include cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), PD-1, B and T lymphocyte attenuator (BTLA), and lymphocyte activation gene 3 (LAG3). The FDA-approved immunological checkpoint inhibitor, ipilimumab, that targets CTLA-4 is used to treat melanoma (19,20). Researchers are further identifying novel therapeutic targets to regulate immune checkpoints. The most important monoclonal antibody currently in use targets the immune checkpoint PD-1 and its ligand PD-L1 (21). PD-L1/PD-1-related immunotherapy has become a hotspot for research on tumor immunotherapy.

PD-1 is a type I transmembrane protein expressed on the surface of activated T cells, B cells, monocytes and dendritic cells and is composed of extracellular, hydrophobic transmembrane, and cytoplasmic regions (22). Its extracellular domain consists of a single IgV-like domain with an immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based motif (23). ITIM can be commonly found in numerous immunosuppressive receptors (24). The immunosuppressive function of PD-1 is primarily exerted via ITIM. PD-L1 and PD-L2 are the ligands of PD-1 (25). PD-L1 is the primary ligand that is upregulated in various solid tumors. This reduces the infiltration of CD4⁺ and CD8⁺ T cells into tumors and concomitant cytokine production. PD-L1 is a member of the B7 superfamily and a type I transmembrane glycoprotein (26,27). PD-L1 is expressed in various tumors, such as urothelial, ovarian, breast, cervical, colorectal, pancreatic, gastric, melanoma, malignant glioma, and non-small cell lung cancers among others. This suggests the involvement of PD-1 signaling in tumors for immune evasion (7,28–30). PD-1/PD-Ls exerts a negative immunomodulatory effect. The surface of tumor cells in the tumor microenvironment exhibit increased expression of PD-L1 that binds to PD-1 on activated T cells, which leads to apoptosis or immunological inactivation of tumor antigen-specific T cells, thereby inhibiting immune response and promoting the evasion of tumor cells (31).

PD-L1 is expressed on the surface of various tumor and immune cells, such as T, B, and dendritic cells (13). Tumor cells bind to PD-1 on the surface of tumor infiltrating lymphocytes (TILs) via PD-L1. Activation of TILs enables immunosuppressive signaling, inhibits T-cell migration and proliferation, secretion of cytotoxic mediators, induces T-cell depletion, and limits its antitumor effects, thereby resulting in immune evasion (32,33). Decreased binding of PD-L1 to PD-1 reverses immune escape, enhances antitumor immunity, and inhibits tumor progression (34). However, PD-L1/PD-1-targeted immunotherapy has been revealed to be effective in clinical trials of various tumors, suggesting that the PD-L1/PD-1 pathway plays an important role in tumor progression (13). This targeted immunotherapy has the potential to improve the prognosis of cancer patients by inhibiting the PD-L1/PD-1 pathway (35–37). Thus, it is imperative to further identify and develop anti-PD-L1/PD-1 therapeutics for TNBC.

PD-L1 is overexpressed in most breast cancers, especially TNBC tissues, as compared to its expression in normal breast tissue (59,61–64). Previous research revealed that PD-L1 was expressed in 45% of breast cancers and 59% of TNBCs among 116 breast cancer tissues. Overexpression of PD-L1 has been revealed to be associated with poor prognosis (63), larger tumors, higher tumor grade, estrogen receptor (ER)-negative, progesterone receptor-negative, and HER-2-positive status, cell proliferation, and an increased abundance of TILs in patients with breast cancer (59,64,65). Using high-throughput analysis of 650 breast cancer tissue microarrays, it was revealed that patients with breast cancer and overexpression of PD-L1 had significantly shorter overall survival (OS) (66). Previous research has demonstrated that PD-L1 expression is associated with prolonged recurrence-free survival (62). In patients with TNBC, overexpression of PD-L1 was also associated with metastasis-free survival and specific OS. The higher the expression of PD-L1, the higher the reactivity to chemotherapy (65). The potential of PD-L1 as an independent prognostic factor is unclear. This could be attributed to a variety of factors, such as detection methods and sample heterogeneity; however, it is widely recognized that PD-L1 is associated with factors related to the poor prognosis of breast cancer (42). Tumors overexpressing PD-L1 are often accompanied by the infiltration of PD-1-positive TILs that are associated with shortened OS, indicating a poor prognosis of breast cancer (67,68). This further highlights the need for utilizing PD-L1/PD-1 signaling in developing efficacious therapeutics for the treatment of TNBC.

Binding of PD-1 to PD-L1 or PD-L2 activates PD-1 signaling (69). PD-L1 is key for the proliferation of tumor cells during antitumor immunity. Notably, tumor immunogenicity is weakened significantly and this promotes the escape of the tumor cells from immune surveillance and response. PD-L1/PD-1 plays a crucial positive stimulating role in tumor invasion and metastasis (70). Blocking the PD-L1/PD-1 interaction reduces the inhibition of innate immunity and promotes tumor-specific T-cell activation (28).

Overexpression of PD-L1 and PD-1 and abundance of TILs suggest that PD-L1/PD-1 are reliable candidates for PD-L1/PD-1 immunotherapy (35,38,72,87,88). The current treatment methods for breast cancer primarily include surgery, radiation therapy, chemotherapy, endocrine therapy, and targeted therapy. There are no specific and effective treatment options for TNBC patients owing to the lack specific targets, resulting in unsatisfactory disease prognosis. To that extent, the emergence of PD-L1 as a novel target is an exciting avenue in TNBC treatment (58,70).

A phase 1 clinical trial comprising patients with metastatic TNBC was reported in 2015; the monoclonal antibody, atezolizumab, targeting PD-L1 was demonstrated to be safe, tolerable, and consistently exhibited antitumor effects (89). In addition to the PD-L1/PD-1 antibody, clinical trials have used other immunological targets to enhance its antitumor effects, such as the CTLA-4 monoclonal antibody ipilimumab (90). CTLA-4 monoclonal antibodies block negative co-stimulatory signaling, promote the activation and proliferation of tumor-specific T cells, and prevent T-cell disability. PD-1 and PD-L1-targeting monoclonal antibodies reverse the immunosuppressive state of the tumor microenvironment by inhibiting the PD-L1/PD-1 axis. Compared with the CTL-4 monoclonal antibody, the PD-1 and PD-L1 monoclonal antibodies are associated with reduced adverse reactions, improved tolerance, and safety. Thus, PD-L1 antibodies are also used in combination with chemotherapeutics, such as atezolizumab in combination with white protein and abraxane or MEDI4736 (durvalumab) in combination with ibrutinib, in patients with TNBC (91). Several clinical trials are underway to evaluate the efficacy of PD-L1/PD-1 monoclonal antibodies in treating TNBC (Table I).

The past few decades have seen significant progress in the treatment of breast cancer. This has been associated with decreased rates of mortality rate in patients with breast cancer and improved quality of life. However, the prognosis for most patients with TNBC remains poor (92). Exploring TNBC-specific therapeutic targets is key to prolonging patient survival and further improving quality of life. PD-L1/PD-1 signaling is currently a research hotspot for tumor immunotherapy (84). Although PD-L1/PD-1 immunotargeting drugs have not been approved by the FDA for the treatment of TNBC, clinical trials have revealed encouraging results. Thus, PD-L1/PD-1 immunotargeting drugs are expected to be used in the treatment of patients with TNBC in the near future (92).

Despite this, several issues remain worthy of further discussion: i) PD-L1 detection methods, and outcome judgment criteria need to be further improved to accurately determine the expression of PD-L1 and select patients to avoid over- or ineffective treatment. ii) Recently, new members of the B7 family other than PD-L1/PD-1 have been discovered and may form novel targets for tumor immunotherapy. For example, PD-L2 is also expressed in TNBC; thus, anti-PD-1 antibody may be ineffective for PD-L1-negative patients. The reason why the expressed patient is effective; B7-H3 and B7-H4 have immunosuppressive roles and are expressed in tumor cells. Thus, they are excellent novel candidates to be used in tumor immunotherapy; however, their physiological functions remain to be studied (93). iii) The accuracy and adverse reactions of PD-L1/PD-1 immunotargeting therapy need to monitored. It is important to target PD-L1/PD-1-specific drugs to tumor cells during treatment and reduce the impact on autoimmune function. The growing research on these candidates will soon establish immunotherapy as an indispensable method for the comprehensive treatment of cancers.