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Activation and acetylation of tumor-intrinsic PD-L1 via HBXIP accelerates breast cancer growth

ABSTRACT: Programmed death ligand-1 (PD-L1) is a well-known transmembrane protein, which antibodies present effective clinical therapy in multiple human cancers. However, the function of tumor cell-intrinsic PD-L1 and its related mechanism in breast cancer remains incompletely studied. Programmed death ligand 1 (PD-L1) on the membrane of tumor cells strengthens tumor immune escape. Tumor cell-intrinsic PD-L1 is also involved in tumorigenesis and development, but the mechanism in regulating PD-L1 expression remains incompletely studied. Here, we report a novel mechanism for PD-L1 that can be induced by hepatitis B X-interacting protein (HBXIP), an oncogenic transcriptional coactivator, promoting breast cancer growth. Overexpression of PD-L1 increases breast cancer proliferation in vitro and in vivo. Transcriptomic analysis also reveals that PD-L1 plays a critical role in cancer development. Furthermore, we find that the expression of PD-L1 is positively associated with HBXIP in breast cancer clinical tissues as well as in cell lines, PD-L1 and HBXIP expression have higher levels in tumor. Mechanistically, HBXIP predominantly stimulates the promoter activity of PD-L1 through coactivating transcription factor ETS2. Especially, HBXIP induced PD-L1 acetylation with the acetyltransferase p300 at lysine 270 (K270), enhancing PD-L1 protein stability. Functionally, depletion of HBXIP markedly attenuates PD-L1-induced breast tumor growth in vitro and in vivo. Moreover, aspirin decreased breast cancer growth via targeting PD-L1 and HBXIP. Taken together, our results extend a new mechanism of PD-L1 functions, expound non-immune effects of PD-L1 and imply broader uses for PD-L1 as a target in breast cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158696 | GEO | 2022/02/02

REPOSITORIES: GEO

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Gene-expression profiles of PD-L1-affected CD8+ T cells

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2012-07-09 | E-GEOD-39205 | biostudies-arrayexpress

RNA-Seq analysis to compare myeloid cells from PD-L1-LysMCre mice with littermate Wild-type controls

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2022-03-07 | GSE190715 | GEO

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2012-07-09 | E-GEOD-39204 | biostudies-arrayexpress

Human RKO cells LC-MSMS (gel-based proteomics)

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| phs001469 | dbGaP

Gene-expression profiles of PD-L1-affected CD8+ T cells

2012-07-10 | GSE39205 | GEO

Transcriptomic analysis of PD-L1 positive and negative hot lung adenocarcinomas identifies a different molecular immunogenic landscape

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2021-09-27 | GSE180347 | GEO

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Project description:Programmed death-ligand 1 (PD-L1), a critical immune checkpoint ligand, is a transmembrane protein synthesized in the endoplasmic reticulum of tumor cells and transported to the plasma membrane to interact with programmed death 1 (PD-1) expressed on T cell surface. This interaction delivers co-inhibitory signals to T cells, thereby suppressing their function and evading antitumor immunity. Most companion or complementary diagnostic devices for PD-L1 expression levels in tumor cells used in the clinic or clinical trials require membranous staining. However, the mechanism driving PD-L1 translocation to the plasma membrane after de novo synthesis is poorly understood. Herein, we showed that mind bomb homolog 2 (MIB2) is required for PD-L1 transportation from the trans-Golgi network (TGN) to the plasma membrane of cancer cells. MIB2 deficiency leaded to fewer PD-L1 proteins on the tumor cell surface and promotes antitumor immunity in mice.We performed a single-cell RNA sequencing (scRNA-seq) of B16-F10 tumors from C57BL/6 syngeneic mice. Knockdown of MIB2 resulted in an increase in the percentage of CD8+ CTLs (approximately 5-fold) and CD4+/CD8+ effector/activated T cells (approximately 2-fold), indicating that MIB2 downregulation enhanced the antitumor immune activity centered on CD8+ CTLs and changed their transcriptional profile. Our findings demonstrate that non-proteolytic ubiquitination of PD-L1 by MIB2 is required for its transportation to the plasma membrane and tumor cells' immune evasion.

2023-12-31 | GSE218906 | GEO

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Project description:Cancer cells express high levels of PD-L1, a ligand of the PD-1 receptor on T cells, allowing tumors to suppress T cell activity 1-3. Clinical trials utilizing monoclonal antibodies that disrupt the PD-1/PD-L1 immune checkpoint have yielded remarkable results, with PD-1 immunotherapy approved as a first-line therapy for human lung cancer patients 4-6. Despite significant progress in targeting this pathway, the mechanisms through which PD-L1 is upregulated in non-small cell lung cancer (NSCLC) and other tumor types remain incompletely understood. Here we used CRISPR-based screening to identify regulators of PDL1 in human lung cancer cells, revealing potent induction of PD-L1 levels upon disruption of the heme biosynthesis pathway. Impairment of heme production activates the integrated stress response (ISR), allowing bypass of inhibitory upstream open reading frames in the PD-L1 5¢ UTR, resulting in enhanced PD-L1 translation and suppression of anti-tumor immunity. We further demonstrated that ISR-dependent translation of PD-L1 requires the translation initiation factor EIF5B. EIF5B overexpression, which is frequent in human lung cancers and is associated with poor prognosis, is sufficient to induce PD-L1. These findings uncover a new mechanism of immune checkpoint activation and suggest novel targets for therapeutic intervention.

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