PD-L1 (B7-H1) Competes with the RNA Exosome to Regulate the DNA Damage Response and Can Be Targeted to Sensitize to Radiation or Chemotherapy

Tu, Xinyi; Qin, Bo; Zhang, Yong; Zhang, Cheng; Kahila, Mohamed M.; Nowsheen, Somaira; Yin, Ping; Yuan, Jian; Pei, Huadong; Hu, Li; Yu, Jia; Song, Zhiwang; Zhou, Qin; Zhao, Fei; Liu, Jiaqi; Zhang, Chao; Dong, Haidong; Mutter, Robert W.; Lou, Zhenkun

doi:10.1016/j.molcel.2019.04.005

Cited by 188 publications

(166 citation statements)

References 39 publications

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“…A PD-L1 antibody, H1A, was developed to destabilize PD-L1 by disrupting the PD-L1 stabilizer CMTM6. This disruption resulted in PD-L1 degradation through the lysosome and increased sensitivity to radiotherapy and cisplatin (4). These studies indicate that targeting intracellular PDL1 may enhance the efficacy of chemotherapy or radiotherapy by overcoming PDL1 mediated drug resistance (Figure 2).…”

Section: Crosstalk Between the Dna Damage Response And Immune Checkpomentioning

confidence: 92%

“…PD-L1 has been well-known as immune checkpoint inhibition to the activation of T cells by interacting with PD1. PD-L1 was recently found as a novel RNA binding protein to increase drug resistance in cancer cells by increasing mRNA stability of various mRNAs encoding for proteins involved in DDR and repair (4). Luo lab reported that PD-L1 acts as an RNA binding protein to protect target RNAs from degradation by interacting with EXOSC10 and EXOSC4, which are key components of the RNA exosome (4).…”

Section: Crosstalk Between the Dna Damage Response And Immune Checkpomentioning

confidence: 99%

“…PD-L1 knockdown on the alteration of gene expression in genome wide was identified by comparing control and PD-L1 knockdown cells by RNA sequencing (RNA-seq). About 135 genes were found to be enriched in both datasets of the RNA-seq analysis and RIP-seq analysis, including ATM, BRCA1, and FANCL and other genes involved in cellular responses to DNA damage metabolic, transcriptional, and protein modification pathways (4). A PD-L1 antibody, H1A, was developed to destabilize PD-L1 by disrupting the PD-L1 stabilizer CMTM6.…”

Section: Crosstalk Between the Dna Damage Response And Immune Checkpomentioning

confidence: 99%

“…Many observations indicate that there are connections between DNA damage and immune system activation. Intracellular immune checkpoint protein PD-L1 was fond to regulate DNA damage response by acting as RNA binding proteins to regulate many DNA repair proteins (4). DNA damage also can activate immune system (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

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The Interplay Between the DNA Damage Response, RNA Processing and Extracellular Vesicles

2020

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RNA processing was recently found to affect DNA damage response. The RNA processing factors THRAP3 and BCLAF1 play critical role in keeping DNA genomic stability by regulating the transcription, mRNA splicing and export of DNA repair proteins BRCA2, PALB2, Rad51, FANCD2, and FANCL in response to DNA damage. RNA processing factors THRAP3 and BCLAF1 play critical roles in maintaining DNA genomic stability. These factors regulate transcription, mRNA splicing and nuclear RNA export of DNA repair proteins BRCA2, PALB2, Rad51, FANCD2, and FANCL in response to DNA damage. Splicing factors SRSF10 and Sam68 were found to control the DNA damage agent-induced mRNA splicing of transcripts including BCLAF1, BRCA1, BCL2L1, CASP8, CHK2, and RBBP8 to regulate apoptosis, cell-cycle transition and DNA repair. Splicing factors and RNA binding proteins (RBPs) were also found to play a critical role in DNA/RNA hybrids (R-loops) formed during transcription and RNA processing to prevent RNA-induced genome instability. At the same time, DNA repair proteins FANCI and FANCD2 were found to regulate the nuclear localization of splicing factors SF3B1 in the DNA damage response. In addition, tumor-derived extracellular vesicles (Evs) enhanced by chemotherapeutic agents in cancer were found to promote cancer metastasis and drug resistance. Inhibiting Evs from cancer cells significantly reduced cancer metastasis and drug resistance. Furthermore, cross-talk between the DNA damage response and the immune response was observed including the enhancement of the efficacy of immune checkpoint blockade by PARP inhibitors and the effect of PD-L1 on mRNA stability of various mRNAs involved in DNA damage response by acting as a novel RNA binding protein to increase drug resistance in cancer cells. This review will introduce recent progress on the interplay of the DNA damage response, the RNA processing and the extracellular vesicles mediated metastasis.

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Section: Crosstalk Between the Dna Damage Response And Immune Checkpomentioning

confidence: 92%

Section: Crosstalk Between the Dna Damage Response And Immune Checkpomentioning

confidence: 99%

Section: Crosstalk Between the Dna Damage Response And Immune Checkpomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Interplay Between the DNA Damage Response, RNA Processing and Extracellular Vesicles

2020

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“…As a regulatory molecule of PD-L1, CMTM6 enhances the cell surface expression of PD-L1. The upstream and downstream relationship between CMTM6 and PD-L1 may participate in the formation of tumor related pathways [14]. Few studies have examined CMTM6 and PD-L1 in GC.…”

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confidence: 99%

Co-expression of CMTM6 and PD-L1: a novel prognostic indicator of gastric cancer

Zhang¹,

An²,

Tan³

et al. 2020

Preprint

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Background CKLF Like MARVEL Transmembrane Domain Containing 6 (CMTM6) is involved in the epigenetic regulation of genes and tumorigenesis. Programmed cell death ligand 1 (PD-L1) is closely related to the prognosis of some human cancers. CMTM6 is a key regulator of PD-L1 in many cancers. The purpose of this study was to investigate the expressions of these proteins in gastric cancer and the correlations with clinicopathological features and survival. Methods The expression levels of CMTM6 and PD-L1 were examined in 185 gastric cancer specimens by immunohistochemistry. Chi-square test was used to analyze the relationship between CMTM6 and PD-L1 expressions and clinicopathological characteristics. Kaplan-Meier method and log-rank test were used to analyze the survival data of patients.Results The positive expression rates of CMTM6 and PD-L1 were 78.38% (145/185) and 75.68% (140/185), respectively. High expression of CMTM6 and PD-L1 was correlated with Borrmann type ( P < 0.001), N stage ( P = 0.002), peritoneal metastasis ( P = 0.007) and TNM stage ( P = 0.038). The expression of CMTM6 and PD-L1 in gastric cancer tissues was positively correlated (Pearson's coefficient test, r = 0.260; P < 0.001). High expression of CMTM6 was correlated with poor prognosis (HR = 1.668; 95% CI = 1.032–2.695; P = 0.037). High expression of both CMTM6 and PD-L1 could be used as an independent factor for overall survival (HR = 1.554; 95% CI = 1.011–2.389; P = 0.044). Conclusions The combined detection of CMTM6 and PD-L1 may be used as an indicator for judging the prognosis of gastric cancer.

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Subcellular localization of PD‐L1 and cell‐cycle‐dependent expression of nuclear PD‐L1 variants: implications for head and neck cancer cell functions and therapeutic efficacy

Schulz,

Feulner,

Santos Rubenich

et al. 2023

Molecular Oncology

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The programmed cell death 1 ligand 1 (PD‐L1)/programmed cell death protein 1 (PD‐1) axis is primarily associated with immunosuppression in cytotoxic T lymphocytes (CTLs). However, mounting evidence is supporting the thesis that PD‐L1 not only functions as a ligand but mediates additional cellular functions in tumor cells. Moreover, it has been demonstrated that PD‐L1 is not exclusively localized at the cellular membrane. Subcellular fractionation revealed the presence of PD‐L1 in various cellular compartments of six well‐characterized head and neck cancer (HNC) cell lines, including the nucleus. Via Western blotting, we detected PD‐L1 in its well‐known glycosylated/deglycosylated state at 40–55 kDa. In addition, we detected previously unknown PD‐L1 variants with a molecular weight at approximately 70 and > 150 kDa exclusively in nuclear protein fractions. These in vitro findings were confirmed with primary tumor samples from head and neck squamous cell carcinoma (HNSCC) patients. Furthermore, we demonstrated that nuclear PD‐L1 variant expression is cell‐cycle‐dependent. Immunofluorescence staining of PD‐L1 in different cell cycle phases of synchronized HNC cells supported these observations. Mechanisms of nuclear PD‐L1 trafficking remain less understood; however, proximity ligation assays showed a cell‐cycle‐dependent interaction of the cytoskeletal protein vimentin with PD‐L1, whereas vimentin could serve as a potential shuttle for nuclear PD‐L1 transportation. Mass spectrometry after PD‐L1 co‐immunoprecipitation, followed by gene ontology analysis, indicated interaction of nuclear PD‐L1 with proteins involved in DNA remodeling and messenger RNA (mRNA) splicing. Our results in HNC cells suggest a highly complex regulation of PD‐L1 and multiple tumor cell‐intrinsic functions, independent of immune regulation. These observations bear significant implications for the therapeutic efficacy of immune checkpoint inhibition.

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PD-L1 (B7-H1) Competes with the RNA Exosome to Regulate the DNA Damage Response and Can Be Targeted to Sensitize to Radiation or Chemotherapy

Cited by 188 publications

References 39 publications

The Interplay Between the DNA Damage Response, RNA Processing and Extracellular Vesicles

The Interplay Between the DNA Damage Response, RNA Processing and Extracellular Vesicles

Co-expression of CMTM6 and PD-L1: a novel prognostic indicator of gastric cancer

Subcellular localization of PD‐L1 and cell‐cycle‐dependent expression of nuclear PD‐L1 variants: implications for head and neck cancer cell functions and therapeutic efficacy

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