bims-tuchim Biomed News
on Tumor-on-chip models
Issue of 2021–08–15
sixteen papers selected by
Philipp Albrecht, Friedrich Schiller University
  1. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy.
  2. Autophagy Inhibition Synergizes with Immunotherapy in Pancreatic Cancer.
  3. T cell-mediated anti-tumor immunity cooperatively induced by TGFβR1 antagonism and gemcitabine counteracts reformation of the stromal barrier in pancreatic cancer.
  4. Tumor Cells Induce Endothelial Cells to Secrete a Chemoattractant.
  5. Integrated computational and experimental pipeline for quantifying local cell-matrix interactions.
  6. PKCι regulates the expression of PDL1 through multiple pathways to modulate immune suppression of pancreatic cancer cells.
  7. The role of S100A9 in the interaction between pancreatic ductal adenocarcinoma cells and stromal cells.
  8. Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming.
  9. Fibroblast Activation Protein (FAP)-Targeted CAR-T Cells: Launching an Attack on Tumor Stroma.
  10. Next-generation cancer organoids.
  11. Specific Endothelial Cells Govern Nanoparticle Entry into Solid Tumors.
  12. Rapid spheroid assays in a 3-dimensional cell culture chip.
  13. CCL2: An Important Mediator Between Tumor Cells and Host Cells in Tumor Microenvironment.
  14. Analysis of Immune-Related Signatures Related to CD4+ T Cell Infiltration With Gene Co-Expression Network in Pancreatic Adenocarcinoma.
  15. Tumor-Infiltrating T Cells Mimic Tissue-Resident T-cell Heterogeneity.
  16. Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies.
  1. Cell. 2021 Aug 06. pii: S0092-8674(21)00879-5. [Epub ahead of print]
    Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy.
    Kazuhiro Koikawa, Shin Kibe, Futoshi Suizu, Nobufumi Sekino, Nami Kim, Theresa D Manz, Benika J Pinch, Dipikaa Akshinthala, Ana Verma, Giorgio Gaglia, Yutaka Nezu, Shizhong Ke, Chenxi Qiu, Kenoki Ohuchida, Yoshinao Oda, Tae Ho Lee, Babara Wegiel, John G Clohessy, Nir London, Sandro Santagata, Gerburg M Wulf, Manuel Hidalgo, Senthil K Muthuswamy, Masafumi Nakamura, Nathanael S Gray, Xiao Zhen Zhou, Kun Ping Lu.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance to current therapies attributed to inherent tumor heterogeneity and highly desmoplastic and immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1 regulates multiple cancer pathways, but its role in the TME and cancer immunotherapy is unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associated fibroblasts (CAFs) and correlates with poor survival in PDAC patients. Targeting Pin1 using clinically available drugs induces complete elimination or sustained remissions of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine in diverse model systems. Mechanistically, Pin1 drives the desmoplastic and immunosuppressive TME by acting on CAFs and induces lysosomal degradation of the PD-1 ligand PD-L1 and the gemcitabine transporter ENT1 in cancer cells, besides activating multiple cancer pathways. Thus, Pin1 inhibition simultaneously blocks multiple cancer pathways, disrupts the desmoplastic and immunosuppressive TME, and upregulates PD-L1 and ENT1, rendering PDAC eradicable by immunochemotherapy.
    Keywords:  Pin1; cancer immune evasion; cancer-associated fibroblasts; chemotherapy; combination therapy; immuni checkpoint therapy; pancreatic cancer; targeted therapy; tumor immune microenvironment; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cell.2021.07.020
  2. Cancer Discov. 2020 Jun;10(6): 760
    Autophagy Inhibition Synergizes with Immunotherapy in Pancreatic Cancer.
      Autophagy-mediated MHC-I degradation facilitated immune evasion in pancreatic ductal adenocarcinoma.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-063
  3. Mol Cancer Ther. 2021 Aug 10. pii: molcanther.0620.2020. [Epub ahead of print]
    T cell-mediated anti-tumor immunity cooperatively induced by TGFβR1 antagonism and gemcitabine counteracts reformation of the stromal barrier in pancreatic cancer.
    Dandan Li, Nicholas Schaub, Theresa M Guerin, Tashinga E Bapiro, Frances M Richards, Vicky Chen, Keyur Talsania, Parimal Kumar, Debra J Gilbert, Jerome J Schlomer, Seong-Jin Kim, Rebecca Sorber, Yaroslav Teper, Wendy Bautista, Claudia Palena, Chan-Young Ock, Duncan I Jodrell, Nathan Pate, Monika Mehta, Yongmei Zhao, Serguei V Kozlov, Udo Rudloff.
      The desmoplastic stroma of pancreatic cancers forms a physical barrier that impedes intratumoral drug delivery. Attempts to modulate the desmoplastic stroma to increase delivery of administered chemotherapy have not shown positive clinical results thus far, and preclinical reports in which chemotherapeutic drugs were co-administered with anti-stromal therapies did not universally demonstrate increased genotoxicity despite increased intratumoral drug levels. In this study, we tested whether TGFβ antagonism can break the stromal barrier, enhance perfusion and tumoral drug delivery, and interrogated cellular and molecular mechanisms by which the tumor prevents synergism with co-administered gemcitabine. TGFβ inhibition in genetically engineered murine models (GEMMs) of pancreas cancer enhanced tumoral perfusion and increased intratumoral gemcitabine levels. However, tumors rapidly adapted to TGFβ-dependent stromal modulation, and intratumoral perfusion returned to pre-treatment levels upon extended TGFβ inhibition. Perfusion was governed by the phenotypic identity and distribution of cancer-associated fibroblasts (CAFs) with the myelofibroblastic phenotype (myCAFs), and myCAFs which harbored unique genomic signatures rapidly escaped the restricting effects of TGFβ inhibition. Despite the reformation of the stromal barrier and reversal of initially increased intratumoral exposure levels, TGFβ inhibition in cooperation with gemcitabine effectively suppressed tumor growth via cooperative reprogramming of T regulatory cells and stimulation of CD8 T cell-mediated anti-tumor activity. The anti-tumor activity was further improved by the addition of anti-PD-L1 immune checkpoint blockade to offset adaptive PD-L1 upregulation induced by TGFβ inhibition. These findings support the development of combined anti-stroma anti-cancer therapies capable of impacting the tumor beyond the disruption of the desmoplastic stroma as a physical barrier to improve drug delivery.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-20-0620
  4. Cancer Discov. 2020 Dec;10(12): 1784
    Tumor Cells Induce Endothelial Cells to Secrete a Chemoattractant.
      Endothelial cell-produced SLIT2 drove tumor-cell migration to blood vessels to promote metastasis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-146
  5. Sci Rep. 2021 Aug 12. 11(1): 16465
    Integrated computational and experimental pipeline for quantifying local cell-matrix interactions.
    Hugh Xiao, Ryan Y Nguyen, Ryan LaRanger, Erica L Herzog, Michael Mak.
      Cellular interactions with the extracellular matrix (ECM) play a key role in modulating biological processes. While studies have identified key molecular factors of these interactions, the mechanical regulation associated with these interactions is not well characterized. To address this, we present an image analysis platform to analyze time-dependent dynamics observed in lung fibroblasts embedded in a 3D collagen matrix. Combining drug studies with quantitative analysis of cell-matrix interactions, our results are able to provide cellular level quantitative insights for mechanical and biophysical phenomena relevant to cell-ECM interactions. This system overall represents an initial pipeline for understanding cell mechanics in a 3D collagen gel and their implications in a physiologically relevant context.
    DOI:  https://doi.org/10.1038/s41598-021-95935-2
  6. Cell Signal. 2021 Aug 07. pii: S0898-6568(21)00204-7. [Epub ahead of print] 110115
    PKCι regulates the expression of PDL1 through multiple pathways to modulate immune suppression of pancreatic cancer cells.
    Hongmei Zhang, Yue Zhu, Junli Wang, Sijia Weng, Fengqiong Zuo, Changlong Li, Tongbo Zhu.
      To investigate the impact of oncogenic protein kinase C isoform ι (PKCι) on the microenvironment and the immunogenic properties of pancreatic tumors, we prohibit PKCι activity in various pancreatic ductal adenocarcinoma (PDAC) cell lines and co-culture them with human natural killer NK92 cells. The results demonstrate that PKCι suppression enhances the susceptibility of PDAC to NK cytotoxicity and promotes the degranulation and cytolytic activity of co-cultured NK92 cells. Mechanistic studies pinpoint that downstream of KRAS, both YAP1 and STAT3 are recruited by oncogenic PKCι to elevate the expression of PDL1, contributing to constitute an immune suppressive microenvironment in PDAC. Co-culture with NK92 further induces PDL1 upregulation via STAT3 to stimulate immune escape of PDAC cells. Subsequently, inhibition of PKCι in PDAC alleviates the immune suppression and enhances the cytotoxicity of NK92 towards PDAC through restraining PDL1 overexpression. Combined with PD1/PDL1 blocker, PKCι inhibitor remarkably elevates the cytotoxicity of NK92 against PDAC cells in vitro, establishing PKCι inhibitor as a promising candidate for boosting the immunotherapy of PDAC.
    Keywords:  Immune evasion; Immunotherapy; Natural killer cell; PDL1; PKCι; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.cellsig.2021.110115
  7. Cancer Immunol Immunother. 2021 Aug 10.
    The role of S100A9 in the interaction between pancreatic ductal adenocarcinoma cells and stromal cells.
    Pin-Jui Kung, Ting-Yu Lai, Jerry Cao, Li-Chung Hsu, Tsai-Chen Chiang, Pu Ou-Yang, Ching-Yi Tsai, Yi-Fen Tsai, Chih-Wen Lin, Chien-Chia Chen, Meng-Kun Tsai, Yu-Wen Tien, Chih-Yuan Lee.
       BACKGROUND: A major feature of the microenvironment in pancreatic ductal adenocarcinoma (PDAC) is the significant amount of extracellular matrix produced by pancreatic stellate cells (PSCs), which have been reported to enhance the invasiveness of pancreatic cancer cells and negatively impact the prognosis.
    METHODS: We analyzed the data from two publicly available microarray datasets deposited in the Gene Expression Omnibus and found candidate genes that were differentially expressed in PDAC cells with metastatic potential and PDAC cells cocultured with PSCs. We studied the interaction between PDAC cells and PSCs in vitro and verified our finding with the survival data of patients with PDAC from the website of The Human Protein Atlas.
    RESULTS: We found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC.
    CONCLUSIONS: PSCs stimulated PDAC cells to secrete S100A9, which acts as a chemoattractant to attract circulatory monocytes into cancer microenvironment and induces expression of PD-L1 on macrophages. High expression of S100A9 and PD-L1 was associated with worse overall survival in a cohort of patients with PDAC.
    Keywords:  PD-L1; PSC; Pancreatic ductal adenocarcinoma; S100A9
    DOI:  https://doi.org/10.1007/s00262-021-03026-y
  8. Theranostics. 2021 ;11(17): 8322-8336
    Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming.
    Zhenzhen Li, Chanjun Sun, Zhihai Qin.
      Cancer cells are well-known for adapting their metabolism to maintain high proliferation rates and survive in unfavorable environments with low oxygen and nutritional deficiency. Metabolic reprogramming most commonly arises from the tumor microenvironment (TME). The events of metabolic pathways include the Warburg effect, shift in Krebs cycle metabolites, and increase rate of oxidative phosphorylation that provides the energy for the development and invasion of cancer cells. The TME and shift in tumor metabolism shows a close relationship through bidirectional signaling pathways between the stromal and tumor cells. Cancer-associated fibroblasts (CAFs) are the main type of stromal cells in the TME and consist of a heterogeneous and plastic population that play key roles in tumor growth and metastatic capacity. Emerging evidence suggests that CAFs act as major regulators in shaping tumor metabolism especially through the dysregulation of several metabolic pathways, including glucose, amino acid, and lipid metabolism. The arrangement of these metabolic switches is believed to shape distinct CAF behavior and change tumor cell behavior by the CAFs. The crosstalk between cancer cells and CAFs is associated with cell metabolic reprogramming that contributes to cancer cell growth, progression, and evasion from cancer therapies. But the mechanism and process of this interaction remain unclear. This review aimed to highlight the metabolic couplings between tumor cells and CAFs. We reviewed the recent literature supporting an important role of CAFs in the regulation of cancer cell metabolism, and the relevant pathways, which may serve as targets for therapeutic interventions.
    Keywords:  Cancer; Cancer-associated fibroblasts; Metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.7150/thno.62378
  9. Immunotargets Ther. 2021 ;10 313-323
    Fibroblast Activation Protein (FAP)-Targeted CAR-T Cells: Launching an Attack on Tumor Stroma.
    Reyisa Bughda, Paraskevi Dimou, Reena R D'Souza, Astero Klampatsa.
      Fibroblast activation protein (FAP) is a membrane protease that is highly expressed by cancer-associated fibroblasts (CAFs). FAP can modulate the tumor microenvironment (TME) by remodeling the extracellular matrix (ECM), and its overexpression on CAFs is associated with poor prognosis in various cancers. The TME is in part accountable for the limited efficacy of chimeric antigen receptor (CAR)-T cell therapy in treatment of solid tumors. Targeting FAP with CAR-T cells is one of the strategies being researched to overcome the challenges in the TME. This review describes the role of FAP in the TME and its potential as a target in CAR-T cell immunotherapy, summarizes the preclinical studies and clinical trials of anti-FAP-CAR-T cells to date, and reviews possible optimizations to augment their cytotoxic efficiency in solid tumors.
    Keywords:  CAR T-cells; fibroblast-activating-protein; fibroblasts; immunotherapy; solid tumors; stroma; tumor microenvironment
    DOI:  https://doi.org/10.2147/ITT.S291767
  10. Nat Mater. 2021 Aug 12.
    Next-generation cancer organoids.
    Bauer L LeSavage, Riley A Suhar, Nicolas Broguiere, Matthias P Lutolf, Sarah C Heilshorn.
      Organotypic models of patient-specific tumours are revolutionizing our understanding of cancer heterogeneity and its implications for personalized medicine. These advancements are, in part, attributed to the ability of organoid models to stably preserve genetic, proteomic, morphological and pharmacotypic features of the parent tumour in vitro, while also offering unprecedented genomic and environmental manipulation. Despite recent innovations in organoid protocols, current techniques for cancer organoid culture are inherently uncontrolled and irreproducible, owing to several non-standardized facets including cancer tissue sources and subsequent processing, medium formulations, and animal-derived three-dimensional matrices. Given the potential for cancer organoids to accurately recapitulate the intra- and intertumoral biological heterogeneity associated with patient-specific cancers, eliminating the undesirable technical variability accompanying cancer organoid culture is necessary to establish reproducible platforms that accelerate translatable insights into patient care. Here we describe the current challenges and recent multidisciplinary advancements and opportunities for standardizing next-generation cancer organoid systems.
    DOI:  https://doi.org/10.1038/s41563-021-01057-5
  11. ACS Nano. 2021 Aug 12.
    Specific Endothelial Cells Govern Nanoparticle Entry into Solid Tumors.
    Benjamin R Kingston, Zachary P Lin, Ben Ouyang, Presley MacMillan, Jessica Ngai, Abdullah Muhammad Syed, Shrey Sindhwani, Warren C W Chan.
      The successful delivery of nanoparticles to solid tumors depends on their ability to pass through blood vessels and into the tumor microenvironment. Here, we discovered a subset of tumor endothelial cells that facilitate nanoparticle transport into solid tumors. We named these cells nanoparticle transport endothelial cells (N-TECs). We show that only 21% of tumor endothelial cells located on a small number of vessels are involved in transporting nanoparticles into the tumor microenvironment. N-TECs have an increased expression of genes related to nanoparticle transport and vessel permeability compared to other tumor endothelial cells. The N-TECs act as gatekeepers that determine the entry point, distribution, cell accessibility, and number of nanoparticles that enter the tumor microenvironment.
    Keywords:  blood vessels; cancer; drug delivery; endothelial cells; image analysis; nanoparticles
    DOI:  https://doi.org/10.1021/acsnano.1c04510
  12. BMC Res Notes. 2021 Aug 13. 14(1): 310
    Rapid spheroid assays in a 3-dimensional cell culture chip.
    Jia Lin Teh, Siti Fairus Abdul Rahman, Gregory Domnic, Lengishwarra Satiyasilan, Nelson Jeng Yeou Chear, Darshan Singh, Nethia Mohana-Kumaran.
       OBJECTIVE: The spheroid model provides a physiological platform to study cancer cell biology and drug sensitivity. Usage of bovine collagen I for spheroid assays is costly especially when experiments are conducted in 24-well plates, as high volume of bovine collagen I is needed. The aim of the study was to downsize spheroid assays to a microfluidic 3D cell culture chip and compare the growth, invasion and response to drug/compound of spheroids embedded in the 3D chip to spheroids embedded in 24-well plates.
    RESULTS: Spheroids generated from nasopharyngeal carcinoma cell line HK-1 continuously grew and invaded into collagen matrix in a 24-well plate. Similar observations were noticed with spheroids embedded in the 3D chip. Large spheroids in both 24-well plate and the 3D chip disintegrated and invaded into the collagen matrix. Preliminary drug sensitivity assays showed that the growth and invasion of spheroids were inhibited when spheroids were treated with combination of cisplatin and paynantheine at high concentrations, in a 24-well plate. Comparable findings were obtained when spheroids were treated with the same drug combination in the 3D chip. Moving forward, spheroid assays could be performed in the 3D chip in a more high-throughput manner with minimal time and cost.
    Keywords:  3D cell culture chip; Bovine collagen I; Cisplatin; Mitragyna alkaloid; Nasopharyngeal carcinoma; Paynantheine; Spheroids
    DOI:  https://doi.org/10.1186/s13104-021-05727-0
  13. Front Oncol. 2021 ;11 722916
    CCL2: An Important Mediator Between Tumor Cells and Host Cells in Tumor Microenvironment.
    Jiakang Jin, Jinti Lin, Ankai Xu, Jianan Lou, Chao Qian, Xiumao Li, Yitian Wang, Wei Yu, Huimin Tao.
      Tumor microenvironment (TME) formation is a major cause of immunosuppression. The TME consists of a considerable number of macrophages and stromal cells that have been identified in multiple tumor types. CCL2 is the strongest chemoattractant involved in macrophage recruitment and a powerful initiator of inflammation. Evidence indicates that CCL2 can attract other host cells in the TME and direct their differentiation in cooperation with other cytokines. Overall, CCL2 has an unfavorable effect on prognosis in tumor patients because of the accumulation of immunosuppressive cell subtypes. However, there is also evidence demonstrating that CCL2 enhances the anti-tumor capability of specific cell types such as inflammatory monocytes and neutrophils. The inflammation state of the tumor seems to have a bi-lateral role in tumor progression. Here, we review works focusing on the interactions between cancer cells and host cells, and on the biological role of CCL2 in these processes.
    Keywords:  chemokine receptors; chemokines; inflammation; stroma; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.722916
  14. Front Oncol. 2021 ;11 674897
    Analysis of Immune-Related Signatures Related to CD4+ T Cell Infiltration With Gene Co-Expression Network in Pancreatic Adenocarcinoma.
    Zhen Tan, Yubin Lei, Bo Zhang, Si Shi, Jiang Liu, Xianjun Yu, Jin Xu, Chen Liang.
       Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most invasive solid malignancies. Immunotherapy and targeted therapy confirmed an existing certain curative effect in treating PDAC. The aim of this study was to develop an immune-related molecular marker to enhance the ability to predict Stages III and IV PDAC patients.
    Method: In this study, weighted gene co-expression network (WGCNA) analysis and a deconvolution algorithm (CIBERSORT) that evaluated the cellular constituent of immune cells were used to evaluate PDAC expression data from the GEO (Gene Expression Omnibus) datasets, and identify modules related to CD4+ T cells. LASSO Cox regression analysis and Kaplan-Meier curve were applied to select and build prognostic multi-gene signature in TCGA Stages III and IV PDAC patients (N = 126). This was followed by independent Stages III and IV validation of the gene signature in the International Cancer Genome Consortium (ICGC, N = 62) and the Fudan University Shanghai Cancer Center (FUSCC, N = 42) cohort. Inherited germline mutations and tumor immunity exploration were applied to elucidate the molecular mechanisms in PDAC. Univariate and Multivariate Cox regression analyses were applied to verify the independent prognostic factors. Finally, a prognostic nomogram was created according to the TCGA-PDAC dataset.
    Results: A four-gene signature comprising NAPSB, ZNF831, CXCL9 and PYHIN1 was established to predict overall survival of PDAC. This signature also robustly predicted survival in two independent validation cohorts. The four-gene signature could divide patients into high and low-risk groups with disparity overall survival verified by a Log-rank test. Expression of four genes positively correlated with immunosuppression activity (PD-L1 and PD1). Immune-related genes nomogram and corresponding calibration curves showed significant performance for predicting 3-year survival in TCGA-PDAC dataset.
    Conclusion: We constructed a novel four-gene signature to predict the prognosis of Stages III and IV PDAC patients by applying WGCNA and CIBERSORT algorithm scoring to transcriptome data different from traditional methods of filtrating for differential genes in cancer and healthy tissues. The findings may provide reference to predict survival and was beneficial to individualized management for advanced PDAC patients.
    Keywords:  CIBERSORT; WGCNA; bioinformatics; immunocytes infiltration; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.3389/fonc.2021.674897
  15. Cancer Discov. 2020 Jul;10(7): 902
    Tumor-Infiltrating T Cells Mimic Tissue-Resident T-cell Heterogeneity.
      Tissue-resident memory T cells and tumor-infiltrating lymphocytes (TIL) partitioned into two types.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-080
  16. Elife. 2021 Aug 11. pii: e67106. [Epub ahead of print]10
    Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies.
    S Jordan Kerns, Chaitra Belgur, Debora Petropolis, Marianne Kanellias, Riccardo Barrile, Johannes Sam, Tina Weinzierl, Tanja Fauti, Anne Freimoser-Grundschober, Jan Eckmann, Carina Hage, Martina Geiger, Patrick Ray Ng, William Tien-Street, Dimitris V Manatakis, Virginie Micallef, Regine Gerard, Michael Bscheider, Ekaterina Breous-Nystrom, Anneliese Schneider, Anna Maria Giusti, Cristina Bertinetti-Lapatki, Heather Shannon Grant, Adrian B Roth, Geraldine A Hamilton, Thomas Singer, Katia Karalis, Annie Moisan, Peter Bruenker, Christian Klein, Marina Bacac, Nikolce Gjorevski, Lauriane Cabon.
      Traditional drug safety assessment often fails to predict complications in humans, especially when the drug targets the immune system. Here, we show the unprecedented capability of two human Organs-on-Chips to evaluate the safety profile of T-cell bispecific antibodies (TCBs) targeting tumor antigens. Although promising for cancer immunotherapy, TCBs are associated with an on-target, off-tumor risk due to low levels of expression of tumor antigens in healthy tissues. We leveraged in vivo target expression and toxicity data of TCBs targeting folate receptor 1 (FOLR1) or carcinoembryonic antigen (CEA) to design and validate human immunocompetent Organs-on-Chips safety platforms. We discovered that the Lung-Chip and Intestine-Chip could reproduce and predict target-dependent TCB safety liabilities, based on sensitivity to key determinants thereof, such as target expression and antibody affinity. These novel tools broaden the research options available for mechanistic understandings of engineered therapeutic antibodies and assessing safety in tissues susceptible to adverse events.
    Keywords:  cancer biology; human; medicine
    DOI:  https://doi.org/10.7554/eLife.67106
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