Breast cancer represents the world’s most prevalent cancer and has now surpassed lung cancer as the leading cause of death globally (Miller et al., 2020). Escaping tumor cells from destruction induced by the immune system represents an important hallmark of cancer (Hanahan and Weinberg, 2011). One of the mechanisms of immune escape is by inducing an exhausted phenotype in effector lymphocytes and further preventing effective antitumor effects (Barber et al., 2006). It has been well established that complex interactions of the receptor and ligand are involved in regulating T-cell activation and inducing checkpoint control of T-cell effector functions (Chauvin and Zarour, 2020). More recently, cancer immunotherapy has been emerging as a novel promising therapy option for cancer patients. Owing to the evident prognosis benefits of cancer immunotherapy, antibodies targeting the negative immune checkpoint molecules programmed cell death protein 1 (PD-1) or PD-1 ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (Hodi et al., 2010) has been approved by the FDA in the treatment of several cancer entities. However, only part of the patients responded to the treatment by blocking the immune checkpoint axis (Brahmer et al., 2012; Topalian et al., 2012; Bersanelli and Buti, 2017). This phenomenon has raised our interest in investigating other potential molecules involved in these immune response regulations.

CD80 is a member of the B7 family and the immunoglobulin superfamily, which is composed of molecules present in antigen-presenting cells (APCs) and their receptors present on the T cells (Mir, 2015). Previous studies have showed that CD80 is the ligand for the proteins CD28 involved in autoregulation and intercellular association and CTLA-4 (an important immune checkpoint molecule) expressed on the surface of T cells (Peach et al., 1995; van der Merwe et al., 1997; Mir, 2015; Chen et al., 2020). Interactions of CD80, CD28, and CTLA-4 played a complicated role in the immunological synapse in T- and B-cell activation, proliferation, and differentiation (Bhatia et al., 2005). The interaction between CD80 and CD28, together with TCR and MHC interaction, induces the activation of nuclear factor‐κB (NF-κB), mitogen‐activated protein kinase (MAPK), and the calcium–calcineurin pathway, thereby playing a diverse role in manipulating both the innate and the adaptive immune system (van der Merwe et al., 1997; Zheng et al., 2004; Chen et al., 2020). Given the role of CD80 in regulating the immune system is complicated, providing the opportunity for CD80 interactions to be involved in various diseases including multiple autoimmune diseases (Windhagen et al., 1995; Wong et al., 2005; Nolan et al., 2008), and various cancers (Yang et al., 2006; Imade et al., 2013). Among cancers, previous studies have reported that low surface expression of CD80 was associated with the immune escape mechanism of colon cancer, and upregulating CD80 on tumor cell surface successfully enhances antitumor immune responses (Bhatia et al., 2006). Despite multiple studies supporting that CD80 plays a critical role in regulating adaptive and innate immunity during tumor progression, the role of CD80 and its association with the tumor immune microenvironment in breast cancer remains largely unknown.

Taking advantage of the TCGA database, a comprehensive analysis of a large-scale CD80-related transcriptome profile was carried out, which revealed the potential role of CD80 in immune response and inflammatory activities. Furthermore, our findings were well-validated in another RNA-seq dataset of 1994 samples obtained from the METABRIC database. To the best of our knowledge, this is the first and largest study investigating the landscape of CD80 expression in breast cancer both molecularly and clinically.

Breast cancer is the leading cause of deaths and affects human health severely, reinforcing the urgent need for new therapeutic options. Most recently, cancer immunotherapy has been an emerging promising treatment option for patients with TNBC. In the past few years, most studies regarding the field of cancer immunotherapy have been focusing on a few checkpoint molecules including, PD-1/PD-L1 and CTLA-4. Owing to the complex interactions and roles of tumor immune modulators, previous strategies might be insufficient to inhibit tumor progression.

In the past few decades, most of the studies have been focused on the role of PD1/PDL1 and CTLA-4 in breast cancer (Hodi et al., 2010), while few studies paid attention to the potential role of CD80. A previous study reported that the CD80 expression was higher in MDA-MB-468, MCF-7, and MDA-MB-231 breast cancer cells than in normal MCF10A cells (Li et al., 2020). Evidence supported that pharmacological activation of TP53 can promote the CD80 expression in human cancer cells originating from the epithelium (Scarpa et al., 2021). Previous studies have showed that the CD80 expression is lower in several cancer cells, and the loss of CD80 alone promotes their ability to escape the attack from the immune system and imparts energy and apoptosis in tumor-infiltrating T cells (Tirapu et al., 2006). CD80 has also been reported to promote the memory response in cytotoxic T lymphocytes (CTLs) (Wang et al., 2013), which suggests that the CD80 expression on the tumor is involved in antitumor CTL effector function. In the present study, we analyzed the CD80 expression pattern in breast cancer via a total of 2994 breast cancer samples. We found the CD80 expression was associated with the higher malignant pathological type of breast cancer. Interestingly, our results showed that CD80 was significantly downregulated in several cancer types including LUAD (lung adenocarcinoma), LUSC (lung squamous cell carcinoma), and THCA (thyroid cancer); these results suggest that the role of CD80 might be varied by cancer types. Moreover, we observed that the association between the CD80 expression and immune and inflammatory responses is similar to the pattern of PD1 in breast cancer (Liu et al., 2020). In summary, our results suggest that CD80 and PD1 might play a synergistic role in regulating immune and inflammatory responses to promote tumor progression.

Taken together, the CD80 expression was closely correlated with tumor malignancy in breast cancer. Notably, CD80 might play important roles in regulating not only T-cell immune functions but also other immune cells, thereby regulating antitumor immune effects, Moreover, the strong correlation between CD80 and other immune genes suggests the possibility of co-regulating the immune microenvironment in breast cancer, which provides novel insights for targeting the combination of immune checkpoint members and CD80. To the best of our knowledge, this is the first integrative study characterizing the molecular and clinical features of CD80 in breast cancer via large-scale molecular data. Our findings further suggest that CD80 might be a promising target for immunotherapy in breast cancer; future studies are warranted to elaborate on the potential co-regulatory role of CD80 and other immune checkpoint members.