Crosstalk between Immune Checkpoint Modulators, Metabolic Reprogramming and Cellular Plasticity in Triple-Negative Breast Cancer

Abstract

Breast cancer is one of the major causes of mortality in women worldwide. Accounting for 15–20% of all breast cancer diagnoses, the triple-negative breast cancer (TNBC) subtype presents with an aggressive clinical course, heightened metastatic potential and the poorest short-term prognosis. TNBC does not respond to hormonal therapy, only partially responds to radio- and chemotherapy, and has limited targeted therapy options, thus underlining the critical need for better therapeutic treatments. Although immunotherapy based on immune checkpoint inhibition is emerging as a promising treatment option for TNBC patients, activation of cellular plasticity programs such as metabolic reprogramming (MR) and epithelial-to-mesenchymal transition (EMT) causes immunotherapy to fail. In this report, we review the role of MR and EMT in immune checkpoint dysregulation in TNBCs and specifically shed light on development of novel combination treatment modalities for this challenging disease. We highlight the clinical relevance of crosstalk between MR, EMT, and immune checkpoints in TNBCs.

Receptor-Mediated Redox Imbalance: An Emerging Clinical Avenue against Aggressive Cancers

“…The pro-invasive and pro-metastatic roles of TGFβR are evident in a broad panel of cancers including colorectal cancer cells [ 26 ], triple negative breast cancer cells [ 27 ], prostate cancer cells [ 28 ], gastric cancer cells [ 29 ], pancreatic cancer cells [ 30 ], nasopharyngeal cancer cells [ 31 ], lung adenocarcinoma cells [ 32 ], and osteosarcoma cells [ 33 ]. The fundamental roles of TGFβ signaling in cancer metastasis has been attributed to its ability to foster cancer stemness, as exemplified by the elevated SOX4 expression in gastric cancers sustained by TGFβ over-activation [ 34 ].…”

Therapeutic Potential of Tumor Metabolic Reprogramming in Triple-Negative Breast Cancer

“…The conceptualization of the cancer hallmarks (sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, evading immune destruction, deregulating cellular energetics and genome instability and mutation) offers an opportunity to find an effective point of attack against this aggressive type [ 4 ]. Among these, a growing body of evidence suggests that dysregulated metabolism is a key characteristic of TNBC, contributing to its metastatic behavior and resistance to therapies [ 5 , 6 , 7 ].…”

Interferon-gamma is Quintessential for NOS2 and COX2 Expression in ER-Breast Tumors that Lead to Poor Outcome

“…Estrogen receptor alpha-negative (ER-) and triple negative breast cancer (TNBC) account for a smaller proportion of breast cancer types but are among the most aggressive malignancies with limited treatment strategies when compared to less aggressive ER+ tumors (1). During the past decade, a significant proportion of cancers have demonstrated elevated NOS2 expression (2), where cancers ranging from melanoma to glioma overexpress NOS2 (3)(4)(5)(6). In breast cancer, increased NOS2 has been reported in >70% of patients (7).…”