Abstract
Programmed death ligand-1 (PD-L1 or B7-H1) is well known for its role in immune checkpoint regulation, but its function inside the tumor cells has rarely been explored. Here we report that nuclear PD-L1 is important for cancer cell sister chromatid cohesion. We found that depletion of PD-L1 suppresses cancer cell proliferation, colony formation in vitro, and tumor growth in vivo in immune-deficient NSG mice independent of its role in immune checkpoint. Specifically, PD-L1 functions as a subunit of the cohesin complex, and its deficiency leads to formation of multinucleated cells and causes a defect in sister chromatid cohesion. Mechanistically, PD-L1 compensates for the loss of Sororin, whose expression is suppressed in cancer cells overexpressing PD-L1. PD-L1 competes with Wing Apart-Like (WAPL) for binding to PDS5B, and secures proper sister chromatid cohesion and segregation. Our findings suggest an important role for nuclear PD-L1 in cancer cells independent of its function in immune checkpoint.
Highlights
Immune checkpoints are cell surface receptors that are expressed in immune cells
PD-L1 is required for triple negative breast cancers (TNBCs) cell proliferation and tumor growth independent of PD1 We first suppressed PD-L1 expression in two TNBC cell lines that highly express PD-L1 to evaluate its effect on cellular phenotypes (Fig. 1a–d; Supplementary information, Fig. S1a, b)
Based on expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), breast cancer can be classified into three subtypes, including ER-positive breast cancer, HER2-positive breast cancer, and triple negative breast cancer (TNBC)
Summary
Immune checkpoints are cell surface receptors that are expressed in immune cells. They modulate the amplitude and quality of the adaptive and innate effectors, maintaining immune homeostasis and preventing autoimmunity.[1] Well-studied immune checkpoint proteins include cytotoxic T-lymphocyte protein 4. CTLA4 pathways restrict T cell activity at the early stage of immune response, whereas PD1 signaling plays roles in the later stage of immune response, protecting surrounding tissues at sites of chronic inflammation from damage.[2] Both immune checkpoints are utilized by cancer cells to evade immune surveillance. PD1, known as PDCD1 or CD279, is a membrane protein and expressed on T cells and pro-B cells.[3,4,5] Its ligand, PD-
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