Abstract
Breast cancer is the most common neoplasm diagnosed in women around the world. Checkpoint inhibitors, targeting the programmed death receptor-1 or ligand-1 (PD-1/PD-L1) axis, have dramatically changed the outcome of cancer treatment. These therapies have been recently considered as alternatives for treatment of breast cancers, in particular those with the triple-negative phenotype (TNBC). A further understanding of the regulatory mechanisms of PD-L1 expression is required to increase the benefit of PD-L1/PD-1 checkpoint immunotherapy in breast cancer patients. In this review, we will compile the most recent studies evaluating PD-1/PD-L1 checkpoint inhibitors in breast cancer. We review factors that determine the therapeutic success of PD-1/PD-L1 immunotherapies in this pathology. In particular, we focus on pathways that interconnect the epithelial-mesenchymal transition (EMT) with regulation of PD-L1 expression. We also discuss the relationship between cellular metabolic pathways and PD-L1 expression that are involved in the promotion of resistance in TNBC.
Highlights
Breast cancer is the most frequent female-associated neoplasm that affects women worldwide [1]
Durvalumab is an anti-PD-L1 antibody that has demonstrated clinical efficacy in bladder and lung cancers [87, 88]. The effect of this therapy has not been sufficiently evaluated in patients with triple-negative breast cancer (TNBC), but the better clinical response is associated with increased stromal tumor-infiltrating lymphocytes (TILs) and intratumoral TILs, in addition to increased pretherapeutic PD-L1 expression on tumor cells
Transcription factors, as well as molecules that interconnect epithelial-mesenchymal transition (EMT) with PD-L1 expression, supporting treatment resistance in TNBC
Summary
Breast cancer is the most frequent female-associated neoplasm that affects women worldwide [1]. Several reasons are associated with the poor effectiveness of immunotherapies in breast cancer patients, such as the type and activation grade of immune infiltrating cells, the tumor cytokine pattern within the microenvironment, tumor cell mutations, exposition to chemotherapeutic agents, and an imbalance of antior proapoptotic proteins, along with the molecular phenotype of breast cancer [49]. Expression of PD-L1 by cells from the tumor microenvironment, as well as the number of TILs, have emerged as crucial determining factors for breast cancer therapy, impacting in patient survival [9, 64, 69]. We hypothesize that the majority of the immune cells inside the tumor might be rendered dysfunctional because breast cancer samples with a TN phenotype display high levels of PD-L1
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