Bromodomain and extraterminal domain (BET) proteins have evolved as key multifunctional super-regulators that control gene expression. These proteins have been shown to upregulate transcriptional machinery leading to over expression of genes involved in cell proliferation and carcinogenesis. Based on favorable preclinical evidence of BET inhibitors in various cancer models; currently, 26 clinical trials are underway in various stages of study on various hematological and solid organ cancers. Unfortunately, preliminary evidence for these clinical studies does not support the application of BET inhibitors as monotherapy in cancer treatment. Furthermore, the combinatorial efficiency of BET inhibitors with other chemo-and immunotherapeutic agents remain elusive. In this review, we will provide a concise summary of the molecular basis and preliminary clinical outcomes of BET inhibitors in cancer therapy, with special focus on triple negative breast cancer.

Immune checkpoint inhibitor (ICI) therapy has revolutionized the breast cancer treatment landscape. However, ICI-induced systemic inflammatory immune-related adverse events (irAE) remain a major clinical challenge. Previous studies in our laboratory and others have demonstrated that a high-salt (HS) diet induces inflammatory activation of CD4+T cells leading to anti-tumor responses. In our current communication, we analyzed the impact of dietary salt modification on therapeutic and systemic outcomes in breast-tumor-bearing mice following anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibody (mAb) based ICI therapy. As HS diet and anti-CTLA4 mAb both exert pro-inflammatory activation of CD4+T cells, we hypothesized that a combination of these would lead to enhanced irAE response, while low-salt (LS) diet through blunting peripheral inflammatory action of CD4+T cells would reduce irAE response. We utilized an orthotopic murine breast tumor model by injecting Py230 murine breast cancer cells into syngeneic C57Bl/6 mice. In an LS diet cohort, anti-CTLA4 mAb treatment significantly reduced tumor progression (day 35, 339 ± 121 mm3), as compared to isotype mAb (639 ± 163 mm3, p < 0.05). In an HS diet cohort, treatment with anti-CTLA4 reduced the survival rate (day 80, 2/15) compared to respective normal/regular salt (NS) diet cohort (8/15, p < 0.05). Further, HS plus anti-CTLA4 mAb caused an increased expression of inflammatory cytokines (IFNγ and IL-1β) in lung infiltrating and peripheral circulating CD4+T cells. This inflammatory activation of CD4+T cells in the HS plus anti-CTLA4 cohort was associated with the upregulation of inflammasome complex activity. However, an LS diet did not induce any significant irAE response in breast-tumor-bearing mice upon treatment with anti-CTLA4 mAb, thus suggesting the role of high-salt diet in irAE response. Importantly, CD4-specific knock out of osmosensitive transcription factor NFAT5 using CD4cre/creNFAT5flox/flox transgenic mice caused a downregulation of high-salt-mediated inflammatory activation of CD4+T cells and irAE response. Taken together, our data suggest that LS diet inhibits the anti-CTLA4 mAb-induced irAE response while retaining its anti-tumor efficacy.

Tumor initiating stem cells (TISCs) are a subset of tumor cells, which are implicated in cancer relapse and resistance to chemotherapy. The metabolic programs that drive TISC functions are exquisitely unique and finely-tuned by various oncogene-driven transcription factors to facilitate pro-cancerous adaptive challenges. While this change in TISC metabolic machinery allows for the identification of associated molecular targets with diagnostic and prognostic value, these molecules also have a potential immunological application. Recent studies have shown that these TISC-associated molecules have strong antigenic properties enabling naïve CD8+T lymphocytes to differentiate into cytotoxic effector phenotype with anticancer potential. In spite of the current challenges, a detailed understanding in this direction offers an immense immunotherapeutic opportunity. In this review, we highlight the molecular targets that characterize TISCs, the metabolic landscape of TISCs, potential antitumor immune cell activation, and the opportunities and challenges they present in the development of new cancer therapeutics.

Recent phase I DNA vaccine clinical trials with Mammaglobin-A (Mam-A), a human breast tumor-associated antigen (TAA), have shown to be safe and efficient. However, the success of cancer vaccines is limited by the diminished expression of HLA class I molecules on cancer cells. In our current communication, we studied the impact of various selenocompounds towards the expression of HLA class I molecules on breast cancer cells and their impact on the cytotoxicity of MamA2.1 (HLA-A2 immunodominant epitope of Mam-A) activated human CD8+T lymphocytes (hCTLs). We noted an enhanced HLA-A2 expression along with upregulation of components involved in antigen presentation machinery in all four breast cancer cell lines, namely AU565, UACC-812, MCF-7, and MDA-MB-231, following treatment with methyselenol producing methylseninic acid (MSA) and dimethylselenide (DMDSe). Furthermore, we have demonstrated enhanced cytotoxicity of MamA2.1 activated CTLs on HLA-A2+/Mam-A+ AU565 and UACC-812 cell lines following pre-treatment with MSA and DMDSe, while no significant toxicity was noted under similar conditions on HLA-A2+/Mam-A− MCF-7 and MDA-MB-231 breast cancer cell lines. Taken together, our data demonstrated that MSA and DMDSe potentiate effector cytotoxic responses following TAA vaccine specific activation of CD8+T lymphocytes, and thus suggesting their futuristic role as vaccine adjuvants in cancer immunotherapy.