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Breast Cancer Editorial Immune Checkpoint Inhibition for Triple-negative Breast Cancer Poornima Saha and Rita Nanda Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, US Abstract Triple-negative breast cancer remains an important clinical challenge with no targeted therapy available for treatment. Recently, drugs targeting the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) axis have been investigated, with promising responses across multiple tumor types. Two drugs—pembrolizumab and atezolizumab—have recently been explored in advanced triple-negative breast cancer and have demonstrated promising responses. Keywords Triple-negative breast cancer, immune therapy, immune checkpoint inhibitors Disclosure: Poornima Saha and Rita Nanda have nothing to declare in relation to this article. No funding was received in the publication of this article. This article is a short opinion piece and has not been submitted to external peer reviewers. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: February 15, 2016 Published Online: April 8, 2016 Citation: Oncology & Hematology Review, 2016;12(1):31–2 Correspondence: Rita Nanda, 5841 S Maryland Avenue, MC 2115, Chicago, IL 60637-1470, US. E: Breast cancers which lack expression of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)—so-called triple-negative breast cancers (TNBC)—make up 15–20% of the more than 230,000 cases of breast cancer diagnosed in the US each year. 1 Metastatic TNBC remains an important clinical challenge as it is associated with a median survival of under 12 months. While breast cancer has not historically been thought of as an immunogenic tumor, there have been a number of observations made over the past decade that have provided the rationale for investigating immunotherapy as a viable therapeutic option for TNBC. Loi and colleagues have observed that ER-negative breast cancers have a higher density of tumor infiltrating lymphocytes (TILs) than their ER-positive counterparts. 2 The ability to profile breast tumors on a molecular level has led to two key observations: first, that programmed death ligand 1 (PD-L1) gene expression is significantly greater in TNBCs compared with non-TNBCs, 3 and second, that a subset of TNBC tumors—the immunomodulatory subtype—is characterized by elevated expression of genes involved in T-cell function. 4 Furthermore, TNBCs are genomically unstable and have high rates of genetic mutations, which can in turn lead to neo-antigen presentation and induction of an immune response through activation of the cancer-immunity cycle. 5,6 The cancer-immunity cycle is a complex, multi-step, self-propagating cycle, which allows for the identification and eradication of cancer cells through the induction and amplification of T-cell responses. Key steps in the process include: TOU CH MED ICA L MEDIA • • • • • • • release of cancer cell antigens; presentation of these antigens by antigen presenting cells; priming and activation of the T-cell response; trafficking of T-cells to tumors; infiltration of the tumor by T-cells; T-cell recognition of cancer cells; and cancer cell death, which in turn leads to antigen release (step 1), and propagation of the cycle. Each step of this cycle is tightly regulated by both stimulatory and inhibitory factors, which lead to a delicate balance between immunity and unrestrained autoimmunity. For many human cancers, the cancer-immunity cycle is intact up to the point of tumor cell killing by T-cells. Programmed death 1 (PD-1) is expressed primarily by activated T-cells, and binding of PD-1 to its ligands PD-L1 or PD-L2 has been show to impair T-cell function. PD-L1 is overexpressed by tumor cells and macrophages, and tumors can coop the PD-1/PD-L1 pathway to evade immune surveillance. Once the PD-1/PD-L1 interaction is blocked, preexisting anticancer T-cells can have their effector function rapidly restored. 6 This concept has led to the development of a number of checkpoint inhibitors that target the interactions between PD-1 and PD- L1. These anti-PD-1 and PD-L1 agents have now been tested in multiple tumor types with promising efficacy being seen in several tumor types, including melanoma and lung cancer. The PD-1 inhibitor pembrolizumab, and the PD-L1 inhibitor atezolizumab have both been studied for the treatment of PD-L1-positive TNBC. 31