NPM1 upregulates the transcription of PD-L1 and suppresses T cell activity in triple-negative breast cancer

Abstract

Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction plays a crucial role in tumor-associated immune escape. Here, we verify that triple-negative breast cancer (TNBC) has higher PD-L1 expression than other subtypes. We then discover that nucleophosmin (NPM1) binds to PD-L1 promoter specifically in TNBC cells and activates PD-L1 transcription, thus inhibiting T cell activity in vitro and in vivo. Furthermore, we demonstrate that PARP1 suppresses PD-L1 transcription through its interaction with the nucleic acid binding domain of NPM1, which is required for the binding of NPM1 at PD-L1 promoter. Consistently, the PARP1 inhibitor olaparib elevates PD-L1 expression in TNBC and exerts a better effect with anti-PD-L1 therapy. Together, our research has revealed NPM1 as a transcription regulator of PD-L1 in TNBC, which could lead to potential therapeutic strategies to enhance the efficacy of cancer immunotherapy.

Expression and clinical significance of PD-L1, B7-H3, B7-H4 and VISTA in craniopharyngioma

“…Immunohistochemistry, digital pathology and scoring system Immunohistochemical (IHC) staining was performed on TMAs using the following primary antibodies: PD-L1 (1:200, 4.37 µg/mL, 13684, Cell Signaling Technology), B7-H3 (1:400, 1.49 µg/mL, 14 058S, Cell Signaling Technology), B7-H4 (1:400, 0.66 µg/mL, 14572, Cell Signaling Technology) and VISTA (1:200, 0.05 µg/mL, 54979, Cell Signaling Technology). [15][16][17][18] TMA slides were stained using standard immunohistochemistry techniques as previously described. 15 The IHC staining was scanned using Pannoramic MIDI (3D HISTECH).…”

Autophagy deficiency promotes triple-negative breast cancer resistance to T cell-mediated cytotoxicity by blocking tenascin-C degradation

“…An improved understanding of the immunogenicity of TNBC has provided therapeutic options for patients with TNBC. Compared with hormone receptor-positive breast cancers, TNBCs show higher expression of PD-L1, levels of prognosis-related tumour-infiltrating lymphocytes (TILs), rates of genomic instability and rates of genetic mutation, highlighting the potential of immunotherapy in treating this malignancy 1 , 2 . Among the immunotherapeutic strategies are currently being tested in preclinical studies or clinical trials involving TNBC patients 3 , the use of immune checkpoint inhibitors is particularly attractive, and atezolizumab plus nab-paclitaxel is approved in advanced TNBC 4 .…”

Chemoproteomics Maps Glycolytic Targetome in Cancer Cells

“…3g). Besides TRIM28, we also noticed lactate affected chemical accessibility and hence likely the conformations and functions of other transcriptional proteins that execute cancer malignant phenotypes exempli ed by YBX1, a core regulator of MEK/ERK signaling-dependent gene expression signatures 28 , and NPM1, a multifunctional phosphoprotein implicated in tumorigenesis and immune escape 29 . Together with recent discovery of lactate as an epigenetic regulator by lactylation, our identi cation of lactate as a transcriptional regulator sheds light in understanding why the Warburg effect, characterized with lactate overproduction, is fundamental for cancer development and progression.…”