Rational Combination of Immunotherapy for Triple Negative Breast Cancer Treatment

Chia-Wei Li; Seung-Oe Lim; Jennifer L. Hsu; Mien-Chie Hung

Disclosures

Chin Clin Oncol. 2017;6(5) 

In This Article

Abstract and Introduction

Abstract

Recent evidence indicates that tumor infiltrating lymphocytes (TILs), including cytotoxic T cells, are present in the tumor microenvironment of triple-negative breast cancers (TNBC). Despite the presence of cytotoxic T cells, these tumors still develop, progress, and metastasize, suggesting evasion of immune response. One mechanism of immunosuppression is the presence of the T cell inhibitory molecule, programmed death protein 1 (PD-1), on infiltrating T cells and its cognate ligand programmed death ligand 1 (PD-L1) on tumor cells, myeloid dendritic cells (DCs), and macrophages, in the tumor microenvironment. Because TNBC is immunologically insensitive, combinatorial strategies may be ideal to increase both anti-proliferation activity and cytotoxic T cells activity in TNBC. On the basis of two recently discovered regulatory mechanisms of PD-L1, we discuss the potential interactions to boost anti-tumor immunity against TNBC in this review and propose therapeutic strategies that could reduce PD-L1 expression by chemotherapeutic drugs or targeted therapies and sensitize TNBC to immunotherapies.

Introduction

Triple-negative breast cancers (TNBC) is a subtype of breast cancer that lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Because TNBC lacks well-defined molecular targets, it is still the most challenging type of breast cancer for which no effective treatments exist.[1,2] TNBC is further classified into several subtypes based on its gene expression profiles, suggesting TNBC is highly heterogeneous.[2] Approximately half of TNBC is initially sensitive to conventional chemotherapy, but the disease eventually recurs 3–5 years after the initial treatment and develops resistance. Similar to chemotherapy, TNBC has been considered immunologically silent as results from clinical trials indicated that breast cancer, among all cancer types, demonstrates the worse response to inhibitor against immune checkpoint protein cytotoxic T lymphocyte associated antigen 4 (CTLA4).[3,4] Although a significant number of tumor infiltrating lymphocytes (TILs) exist in TNBC, they are frequently inhibited by secreted lactate[5] or expression of co-inhibitory ligands, such as programmed death ligand 1 (PD-L1) and B7H family, by cancer cells.[6–8] Cancer cells hijack T cell activation by overexpressing co-inhibitory ligands to engage co-inhibitory receptors on the T cells.[9] Thus, inhibition of cancer cell signaling together with immune checkpoint blockade can induce effective anti-tumor immunity to eliminate cancer.[10,11]

Post-translational modifications control critical biological activity of proteins, e.g., glycosylation, and occur on approximately two third of all proteins.[12] N-linked glycosylation represents a type of oligosaccharide attached to the asparagine residue (Asn, N) in the NXT/S motif.[13] Compared with non-TNBC cells, PD-L1 in TNBC cells is more substantially glycosylated.[14] Indeed, TNBC demonstrated stronger T cell inhibition than non-TNBC. Glycosylation has been shown to prevent PD-L1 from undergoing 26S proteasome-mediated degradation and enhanced association with programmed death protein 1 (PD-1), all of which lead to the suppression of the T cell immune response.[14] A recent study also suggested that chronic inflammation induces PD-L1 stabilization through CSN5-mediated de-ubiquitination in TNBC.[15] Macrophage-secreted TNFα also induces TNBC immunosuppression via NF-κB signaling. These findings suggested that targeting PD-L1 glycosylation, phosphorylation, or ubiquitination is a novel strategy to enhance anti-tumor immunity against TNBC. In this review, we summarize the current understanding of PD-L1 regulation in TNBC, e.g., the EGF/GSK3β/PD-L1[14] or TNFα/p65/CSN5/PD-L1[15] signaling axis, with the goal of assisting clinicians design effective combinatorial strategies to combat TNBC. In principle, drugs that downregulate PD-L1 expression are suitable for combining with other types of monoclonal antibody (mAb) immunotherapy, such as anti-CTLA-4, anti-TIM-3, or anti-PD-L1/PD1. Likewise, drugs that induce PD-L1 expression may be appropriate for combination with anti-PD1 or anti-PD-L1. In this regard, the proposed combinations may lead to maximal therapeutic efficacy with minimal toxicity.

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