bims-tuchim Biomed News
on Tumor-on-chip models
Issue of 2021–09–19
sixteen papers selected by
Philipp Albrecht, Friedrich Schiller University
  1. A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids.
  2. Regulation of Extracellular Matrix Production in Activated Fibroblasts: Roles of Amino Acid Metabolism in Collagen Synthesis.
  3. PD-1/PD-L1-associated immunoarchitectural patterns stratify pancreatic cancer patients into prognostic/predictive subgroups.
  4. Targeting tumor-stromal IL-6/STAT3 signaling through IL-1 receptor inhibition in pancreatic cancer.
  5. Fabrication and Use of a Pumpless Microfluidic Lymphatic Vessel Chip.
  6. Cell-to-cell interaction analysis of prognostic ligand-receptor pairs in human pancreatic ductal adenocarcinoma.
  7. Nanowire Assisted Mechanotyping of Cellular Metastatic Potential.
  8. CCL2 produced by pancreatic ductal adenocarcinoma is essential for the accumulation and activation of monocytic myeloid-derived suppressor cells.
  9. Insights into the origins of pancreatic cancer.
  10. Organ-on-Chips for Studying Tissue Barriers: Standard Techniques and a Novel Method for Including Porous Membranes Within Microfluidic Devices.
  11. Genomic and molecular analyses identify molecular subtypes of pancreatic cancer recurrence.
  12. Decreasing hyaluronic acid combined with drug-loaded nanoprobes improve the delivery and efficacy of chemotherapeutic drugs for pancreatic cancer.
  13. Two opposing sub-populations of fibroblasts decide progression of pancreatic cancer.
  14. Acinar cell clonal expansion in pancreas homeostasis and carcinogenesis.
  15. Hypoxia increases KIAA1199/CEMIP expression and enhances cell migration in pancreatic cancer.
  16. TRAPPC4 regulates the intracellular trafficking of PD-L1 and antitumor immunity.
  1. Nat Mater. 2021 Sep 13.
    A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids.
    Christopher R Below, Joanna Kelly, Alexander Brown, Jonathan D Humphries, Colin Hutton, Jingshu Xu, Brian Y Lee, Celia Cintas, Xiaohong Zhang, Victor Hernandez-Gordillo, Linda Stockdale, Matthew A Goldsworthy, Joe Geraghty, Lucy Foster, Derek A O'Reilly, Barbara Schedding, Janet Askari, Jessica Burns, Nigel Hodson, Duncan L Smith, Catherine Lally, Garry Ashton, David Knight, Aleksandr Mironov, Antonia Banyard, Johannes A Eble, Jennifer P Morton, Martin J Humphries, Linda G Griffith, Claus Jørgensen.
      Experimental in vitro models that capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from genetically engineered murine models and human patients, essential adhesive cues were empirically defined and replicated in the hydrogel scaffold, revealing a functional role of laminin-integrin α3/α6 signalling in establishment and survival of pancreatic organoids. Altered tissue stiffness-a hallmark of pancreatic cancer-was recapitulated in culture by adjusting the hydrogel properties to engage mechano-sensing pathways and alter organoid growth. Pancreatic stromal cells were readily incorporated into the hydrogels and replicated phenotypic traits characteristic of the tumour environment in vivo. This model therefore recapitulates a pathologically remodelled tumour microenvironment for studies of normal and pancreatic cancer cells in vitro.
    DOI:  https://doi.org/10.1038/s41563-021-01085-1
  2. Front Oncol. 2021 ;11 719922
    Regulation of Extracellular Matrix Production in Activated Fibroblasts: Roles of Amino Acid Metabolism in Collagen Synthesis.
    Emily J Kay, Grigorios Koulouras, Sara Zanivan.
      Cancer associated fibroblasts (CAFs) are a major component of the tumour microenvironment in most tumours, and are key mediators of the response to tissue damage caused by tumour growth and invasion, contributing to the observation that tumours behave as 'wounds that do not heal'. CAFs have been shown to play a supporting role in all stages of tumour progression, and this is dependent on the highly secretory phenotype CAFs develop upon activation, of which extracellular matrix (ECM) production is a key element. A collagen rich, stromal ECM has been shown to influence tumour growth and metastasis, exclude immune cells and impede drug delivery, and is associated with poor prognosis in many cancers. CAFs also extensively remodel their metabolism to support cancer cells, however, it is becoming clear that metabolic rewiring also supports intrinsic functions of activated fibroblasts, such as increased ECM production. In this review, we summarise how fibroblasts metabolically regulate ECM production, focussing on collagen production, at the transcriptional, translational and post-translational level, and discuss how this can provide possible strategies for effectively targeting CAF activation and formation of a tumour-promoting stroma.
    Keywords:  CAF; amino acids; extracellular matrix; fibroblasts; metabolism; tumour microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.719922
  3. Cancer Immunol Res. 2021 Sep 15. pii: canimm.0144.2021. [Epub ahead of print]
    PD-1/PD-L1-associated immunoarchitectural patterns stratify pancreatic cancer patients into prognostic/predictive subgroups.
    Eva Karamitopoulou, Andreas Andreou, Aurélie Pahud de Mortanges, Marianne Tinguely, Beat Gloor, Aurel Perren.
      Immunotherapy, including PD-1/PD-L1 agonists, has shown limited efficacy in pancreatic ductal adenocarcinoma (PDAC). We examined the PD-1/PD-L1 expression and immunoarchitectural features by automated morphometric analysis using multiplex immunofluorescence and 118 microsatellite-stable, treatment-naïve, surgically resected PDACs (study cohort). Five microsatellite-instable cases were stained in parallel (MSI cohort). Molecular analysis was additionally performed. An independent PDAC-cohort (n=226) was immunostained for PD-L1and used as a validation cohort. PD-L1 expression on tumor cells (TCs) and/or immune cells (ICs) was present in 32% and 30% of the study and validation cohorts, respectively, and assigned into one of four patterns: "adaptive-1" (TC:0, IC>1%), "adaptive-2" (TC>1%-<25%, IC>1%), "constitutive" (TC{greater than or equal to}25%, IC:0), and "combined" (TC{greater than or equal to}25%, IC>1%). "Constitutive" tumors were characterized by reduced numbers of all immune cells and poor outcome. In contrast, "adaptive-1" tumors exhibited abundant T cells, including high counts of cytotoxic CD3+CD8+ and PD-1+CD3+CD8+ cells, but low counts of PD-L1+CD3+CD8+ cells and associated with the best outcome. "Adaptive-2" tumors (median OS:13 months) displayed higher proportions of PD-L1+CD3+CD8+ T cells and tumor-associated macrophages (CD68+, CD68+CD206+) compared to "adaptive-1" tumors. In the "combined" pattern, extensive PD-L1 expression on TCs was accompanied by increased numbers of T cells and improved OS. ICs were closer to PD-L1- than to PD-L1+ PDAC cells. TP53 and PIK3CA alterations tended to be more frequent in PD-L1+ tumors. The 5 MSI cases were PD-L1-. The distinct PD-1/PD-L1-associated immunoarchitectural patterns underpin the heterogeneity of the immunological responses and might be used to inform patient outcomes and therapeutic decisions in pancreatic cancer.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-21-0144
  4. Mol Cancer Ther. 2021 Sep 13. pii: molcanther.0083.2021. [Epub ahead of print]
    Targeting tumor-stromal IL-6/STAT3 signaling through IL-1 receptor inhibition in pancreatic cancer.
    Austin R Dosch, Samara Singh, Xizi Dai, Siddharth Mehra, Iago De Castro Silva, Anna Bianchi, Supriya Srinivasan, Zhen Gao, Yuguang Ban, Xi Chen, Sulagna Banerjee, Nagaraj S Nagathihalli, Jashodeep Datta, Nipun B Merchant.
      A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense, desmoplastic stroma and the consequent altered interactions between cancer cells and their surrounding tumor microenvironment (TME) that promote disease progression, metastasis, and chemoresistance. We have previously shown that IL-6 secreted from pancreatic stellate cells (PSCs) stimulates the activation of STAT3 signaling in tumor cells, an established mechanism of therapeutic resistance in PDAC. We have now identified the tumor cell-derived cytokine interleukin-1α (IL-1α) as an upstream mediator of IL-6 release from PSCs that is involved in STAT3 activation within the TME. Herein, we show that IL-1α is overexpressed in both murine and human PDAC tumors and engages with its cognate receptor IL-1R1 which is strongly expressed on stromal cells. Further, we show that IL-1R1 inhibition using anakinra (recombinant IL-1 receptor antagonist) significantly reduces stromal-derived IL-6, thereby suppressing IL-6-dependent STAT3 activation in human PDAC cell lines. Anakinra treatment results in significant reduction in IL-6 and activated STAT3 levels in pancreatic tumors from Ptf1aCre/+;LSL-KrasG12D/+; Tgfbr2flox/flox (PKT) mice. Additionally, the combination of anakinra with cytotoxic chemotherapy significantly extends overall survival compared with vehicle treatment or anakinra monotherapy in this aggressive genetic mouse model of PDAC. These data highlight the importance of IL-1 in mediating tumor-stromal IL-6/STAT3 crosstalk in the TME and provide preclinical rationale for targeting IL-1 signaling as a therapeutic strategy in PDAC.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-21-0083
  5. Methods Mol Biol. 2022 ;2373 177-199
    Fabrication and Use of a Pumpless Microfluidic Lymphatic Vessel Chip.
    Parinaz Fathi, Mandy B Esch.
      Pumpless microfluidic systems are easy-to-use devices that can be used to culture cells that are sensitive to mechanical shear, such as lymphatic endothelial cells. However, previously developed pumpless systems either provide unidirectional shear where the cell culture medium is discarded, or bidirectional shear that produces endothelial cell cultures with disease characteristics. Here, we describe a PDMS-based system that produces cyclically rising and falling shear that is unidirectional, similar to what has been reported in lymphatic vessels. The system can recirculate cell culture medium, making it possible for proteins and growth factors produced by the cell culture to remain in circulation. In addition, we describe the custom-made rotating platform that we used to create this unique flow pattern. Using this rotating platform, the microfluidic device can be used to grow confluent layers of lymphatic endothelial cells under physiologically relevant growth conditions.
    Keywords:  Endothelial lining; Endothelium; Gravity-driven flow; Lymph node; Lymphatic vessel; Organ-on-a-chip; Pumpless microfluidics; Rotating platform
    DOI:  https://doi.org/10.1007/978-1-0716-1693-2_11
  6. Biochem Biophys Rep. 2021 Dec;28 101126
    Cell-to-cell interaction analysis of prognostic ligand-receptor pairs in human pancreatic ductal adenocarcinoma.
    Sayaka R Suzuki, Akihiro Kuno, Haruka Ozaki.
      Cell-to-cell interactions (CCIs) through ligand-receptor (LR) pairs in the tumor microenvironment underlie the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). However, there is scant knowledge of the association of CCIs with PDAC prognosis, which is critical to the identification of potential therapeutic candidates. Here, we sought to identify the LR pairs associated with PDAC patient prognosis by integrating survival analysis and single-cell CCI prediction. Via survival analysis using gene expression from cancer cohorts, we found 199 prognostic LR pairs. CCI prediction based on single-cell RNA-seq data revealed the enriched LR pairs associated with poor prognosis. Notably, the CCIs involved epithelial tumor cells, cancer-associated fibroblasts, and tumor-associated macrophages through integrin-related and ANXA1-FPR pairs. Finally, we determined that CCIs involving 33 poor-prognostic LR pairs were associated with tumor grade. Although the clinical implication of the set of LR pairs must be determined, our results may provide potential therapeutic targets in PDAC.
    Keywords:  Cell-cell communication; Ligand-receptor pairs; Pancreatic ductal adenocarcinoma; Survival analysis; scRNA-seq
    DOI:  https://doi.org/10.1016/j.bbrep.2021.101126
  7. Adv Funct Mater. 2021 Jul 23. pii: 2101638. [Epub ahead of print]31(30):
    Nanowire Assisted Mechanotyping of Cellular Metastatic Potential.
    Debadrita Paria, Annalisa Convertino, Piyush Raj, Kristine Glunde, Yun Chen, Ishan Barman.
      Nanotechnology has provided tools for next generation biomedical devices which rely on nanostructure interfaces with living cells. In vitro biomimetic structures have enabled observation of cell response to various mechanical and chemical cues, and there is a growing interest in isolating and harnessing the specific cues that three-dimensional microenvironments can provide without the requirement for such culture and the experimental drawbacks associated with it. Here we report a randomly oriented gold coated Si nanowire substrate with patterned hydrophobic-hydrophilic areas for differentiation of isogenic breast cancer cells of varying metastatic potential. When considering synthetic surfaces for the study of cell-nanotopography interfaces, randomly oriented nanowires more closely resemble the isotropic architecture of natural extracellular matrix as compared to currently more widely used vertical nanowire arrays. In the study reported here, we show that primary cancer cells preferably attach to the hydrophilic region of randomly oriented nanowire substrate while secondary cancer cells do not adhere. Using machine learning analysis of fluorescence images, cells were found to spread and elongate on the nanowire substrates as compared to a flat substrate, where they mostly remain round, when neither surface was coated with extracellular matrix (ECM) proteins. Such platforms can not only be used for developing bioassays but also as stepping stones for tissue printing technologies where cells can be selectively patterned at desired locations.
    Keywords:  Metastatic cells; hydrophilic-hydrophobic surface; machine learning; microfabrication; silicon nanowires
    DOI:  https://doi.org/10.1002/adfm.202101638
  8. Immun Inflamm Dis. 2021 Sep 15.
    CCL2 produced by pancreatic ductal adenocarcinoma is essential for the accumulation and activation of monocytic myeloid-derived suppressor cells.
    Haitao Gu, Wensheng Deng, Zhong Zheng, Ke Wu, Feng Sun.
       INTRODUCTION: The development of pancreatic ductal adenocarcinoma (PDAC) is closely tied with the immune system. C-C motif chemokine ligands (CCL) were proved to lead to immune recruitment and training. Thus, we reckoned CCL2 to be the kernel of immune suppression in PDAC tissues.
    METHODS: We compared normal pancreatic tissues with PDAC tissues according to The Cancer Genome Atlas (TCGA) and clinical samples. Flow cytometry was used to identify M-MDSCs. We further demonstrated immune suppression of M-MDSCs according to proliferation rates of CD8+ T cells/CD4+ T cells. Levels of reactive oxygen species (ROS) and Arginase were also tested by flow cytometry, enzyme-linked immunosorbent assay, and western blot analysis. We also analyzed the specific mechanisms by cluster analysis after CCL2 stimulating M-MDSCs.
    RESULTS: We found that CCL2 highly increased in PDAC tissues. CCL2 is positively related to CD33 and CD14, markers of monocytic myeloid-derived suppressor cells (M-MDSCs). We have demonstrated that CCL2 recruited M-MDSCs into PDAC tissues both in vitro and in vivo. M-MDSCs recruitment is accompanied by sustained immune suppression. Furthermore, we have found that M-MDSCs impeded T cell proliferation and produced high levels of ROS and Arginase, which can be enhanced by CCL2. Mechanistically, CCL2 stimulated M-MDSCs led to a significant upregulation of genes, a large part of which accumulated in the mitogen-activated protein kinase signaling pathway. Treatment of aloesin, MAPK signaling inhibitor, relieved the associated immunosuppressive phenotype induced by CCL2.
    CONCLUSIONS: Our study indicates that PDAC cells produced CCL2, which promoted localized M-MDSC recruitment and immune suppression, thereby promoting tumor progression.
    Keywords:  CCL2; M-MDSCs; immune suppression; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1002/iid3.523
  9. Nature. 2021 Sep 15.
    Insights into the origins of pancreatic cancer.
    Laura D Wood, Anirban Maitra.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-021-02435-4
  10. Methods Mol Biol. 2022 ;2373 21-38
    Organ-on-Chips for Studying Tissue Barriers: Standard Techniques and a Novel Method for Including Porous Membranes Within Microfluidic Devices.
    Mattia Ballerini, Mohammad Jouybar, Andrea Mainardi, Marco Rasponi, Giovanni Stefano Ugolini.
      A relevant number of organ-on-chips is aimed at modeling epithelial/endothelial interfaces between tissue compartments. These barriers help tissue function either by protecting (e.g., endothelial blood-brain barrier) or by orchestrating relevant molecular exchanges (e.g., lung alveolar interface) in human organs. Models of these biological systems are aimed at characterizing the transport of molecules, drugs or drug carriers through these specific barriers. Multilayer microdevices are particularly appealing to this goal and techniques for embedding porous membranes within organ-on-chips are therefore at the basis of the development and use of such systems. Here, we discuss and provide procedures for embedding porous membranes within multilayer organ-on-chips. We present standard techniques involving both custom-made polydimethylsiloxane (PDMS) membranes and commercially available plastic membranes. In addition, we present a novel method for fabricating and bonding PDMS porous membranes by using a cost-effective epoxy resin in place of microfabricated silicon wafers as master molds.
    Keywords:  Microfluidics; Multilayer microdevices; Organ-on-chip; Porous membranes; Replica molding
    DOI:  https://doi.org/10.1007/978-1-0716-1693-2_2
  11. Gastroenterology. 2021 Sep 14. pii: S0016-5085(21)03522-8. [Epub ahead of print]
    Genomic and molecular analyses identify molecular subtypes of pancreatic cancer recurrence.
    Stephan B Dreyer, Rosie Upstill-Goddard, Assya Legrini, Andrew V Biankin, Nigel B Jamieson, David K Chang.
      
    DOI:  https://doi.org/10.1053/j.gastro.2021.09.022
  12. Cancer Lett. 2021 Sep 13. pii: S0304-3835(21)00463-8. [Epub ahead of print]
    Decreasing hyaluronic acid combined with drug-loaded nanoprobes improve the delivery and efficacy of chemotherapeutic drugs for pancreatic cancer.
    Ying-Fang Fan, Wen-Ting Shang, Guan-Hua Lu, Kun-Xiong Guo, Han Deng, Xin-Hong Zhu, Cun-Chuan Wang, Jie Tian.
      Pancreatic cancer is one of the common malignant tumors of the digestive system, and its clinical treatment is still very challenging. Most of the pancreatic cancer chemotherapeutic drugs have poor plasma stability, low cell uptake efficiency, and are prone to developing drug resistance and toxic side effects. Besides, pancreatic cancer often has a dense extracellular matrix, which consists of collagens, hyaluronic acid, and other proteoglycans. Among them, hyaluronic acid is a key component of the dense matrix, which results in vascular compression and insufficient perfusion, and hinders the delivery of chemotherapeutic drugs. In this study, we explore using hyaluronidase in tumor-bearing mice to eliminate the hyaluronic acid barrier, to reduce blood vessel compression and reshape the tumor microenvironment. In addition, we evaluate using doxorubicin-loaded nanoprobes to improve the stability and local tumor-killing effect of the drug. The nanoprobes have the characteristics of near-infrared optical imaging, which are used to monitor the tumor size in real-time during the treatment process, and dynamically observe the tumor inhibitory effect. The results show that elimination of the hyaluronic acid barrier combined with the doxorubicin-loaded nanoprobes can greatly increase drug penetration into tumor tissue and improve the effectiveness of chemotherapy drugs. This study provides a novel strategy for the treatment of pancreatic cancer.
    Keywords:  Drug-loaded nanoprobes; Hyaluronic acid; Hyaluronidase; Near-infrared optical imaging; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.canlet.2021.09.016
  13. Cancer Cell. 2021 Sep 13. pii: S1535-6108(21)00401-3. [Epub ahead of print]39(9): 1175-1177
    Two opposing sub-populations of fibroblasts decide progression of pancreatic cancer.
    Emily J Kay, Sara Zanivan.
      Fibroblasts are a major non-neoplastic component of solid tumors, yet it is unclear whether they promote or oppose cancer. In this issue of Cancer Cell, Hutton et al. report two distinct fibroblast subpopulations that are defined by a single marker, one subpopulation that is tumor permissive and the other that is tumor suppressive and supports anti-tumor immunity.
    DOI:  https://doi.org/10.1016/j.ccell.2021.07.022
  14. Nature. 2021 Sep 15.
    Acinar cell clonal expansion in pancreas homeostasis and carcinogenesis.
    Patrick Neuhöfer, Caitlin M Roake, Stewart J Kim, Ryan J Lu, Robert B West, Gregory W Charville, Steven E Artandi.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer deaths worldwide1. Studies in human tissues and in mouse models have suggested that for many cancers, stem cells sustain early mutations driving tumour development2,3. For the pancreas, however, mechanisms underlying cellular renewal and initiation of PDAC remain unresolved. Here, using lineage tracing from the endogenous telomerase reverse transcriptase (Tert) locus, we identify a rare TERT-positive subpopulation of pancreatic acinar cells dispersed throughout the exocrine compartment. During homeostasis, these TERThigh acinar cells renew the pancreas by forming expanding clones of acinar cells, whereas randomly marked acinar cells do not form these clones. Specific expression of mutant Kras in TERThigh acinar cells accelerates acinar clone formation and causes transdifferentiation to ductal pre-invasive pancreatic intraepithelial neoplasms by upregulating Ras-MAPK signalling and activating the downstream kinase ERK (phospho-ERK). In resected human pancreatic neoplasms, we find that foci of phospho-ERK-positive acinar cells are common and frequently contain activating KRAS mutations, suggesting that these acinar regions represent an early cancer precursor lesion. These data support a model in which rare TERThigh acinar cells may sustain KRAS mutations, driving acinar cell expansion and creating a field of aberrant cells initiating pancreatic tumorigenesis.
    DOI:  https://doi.org/10.1038/s41586-021-03916-2
  15. Sci Rep. 2021 Sep 14. 11(1): 18193
    Hypoxia increases KIAA1199/CEMIP expression and enhances cell migration in pancreatic cancer.
    Takuya Oba, Norihiro Sato, Yasuhiro Adachi, Takao Amaike, Yuzan Kudo, Atsuhiro Koga, Shiro Kohi, Keiji Hirata.
      Pancreatic ductal adenocarcinoma (PDAC) is characterised by dense desmoplasia and hypoxic microenvironment. Our previous reports demonstrated that hyaluronan (HA), especially low-molecular-weight HA, provides a favourable microenvironment for PDAC progression. However, the effect of hypoxia on HA metabolism remains unknown. Using quantitative real-time RT-PCR and western blot analysis, we analysed the changes in the expression of HA-synthesizing enzymes (HAS2 and HAS3) and HA-degrading enzymes (HYAL1, KIAA1199/CEMIP) in PDAC cell lines under hypoxic conditions. Hypoxia increased the mRNA and protein expression of KIAA1199, whereas it decreased HYAL1 expression. The expression of HAS3 was increased and HAS2 remained unchanged in response to hypoxia. The effect of KIAA1199 on hypoxia-induced cell migration was determined using a transwell migration assay and small-interfering RNA (siRNA). Hypoxia enhanced the migratory ability of PDAC cells, which was inhibited by KIAA1199 knockdown. We also used immunohistochemistry to analyse the protein expression of hypoxia inducible factor (HIF) 1α and KIAA1199 in PDAC tissues. There was a significant immunohistochemically positive correlation between KIAA1199 and HIF1α. These findings suggest that hypoxia-induced KIAA1199 expression may contribute to enhanced motility in PDAC.
    DOI:  https://doi.org/10.1038/s41598-021-97752-z
  16. Nat Commun. 2021 Sep 13. 12(1): 5405
    TRAPPC4 regulates the intracellular trafficking of PD-L1 and antitumor immunity.
    Yimeng Ren, Yun Qian, Luoyan Ai, Yile Xie, Yaqi Gao, Ziyan Zhuang, Jinxian Chen, Ying-Xuan Chen, Jing-Yuan Fang.
      Tumor cells evade T cell-mediated immunosurveillance via the interaction between programmed death-1 (PD-1) ligand 1 (PD-L1) on tumor cells and PD-1 on T cells. Strategies disrupting PD-1/PD-L1 have shown clinical benefits in various cancers. However, the limited response rate prompts us to investigate the molecular regulation of PD-L1. Here, we identify trafficking protein particle complex subunit 4 (TRAPPC4), a major player in vesicular trafficking, as a crucial PD-L1 regulator. TRAPPC4 interacts with PD-L1 in recycling endosomes, acting as a scaffold between PD-L1 and RAB11, and promoting RAB11-mediated recycling of PD-L1, thus replenishing its distribution on the tumor cell surface. TRAPPC4 depletion leads to a significant reduction of PD-L1 expression in vivo and in vitro. This reduction in PD-L1 facilitates T cell-mediated cytotoxicity. Overexpression of Trappc4 sensitizes tumor cells to checkpoint therapy in murine tumor models, suggesting TRAPPC4 as a therapeutic target to enhance anti-tumor immunity.
    DOI:  https://doi.org/10.1038/s41467-021-25662-9
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