Culprits of PDAC Resistance to Gemcitabine and Immune Checkpoint Inhibitor: Tumour Microenvironment Components

Overview

Journal Front Mol Biosci

Specialty Biology

Date 2022 Oct 27

PMID 36299300

Authors

Sheng-Kai Hsu

Mahendra Jadhao

Wei-Ting Liao

Wen-Tsan Chang

Chun-Tzu Hung

Chien-Chih Chiu

Affiliations

Soon will be listed here.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer with a dismal five-year survival rate of 11%. Despite remarkable advancements in cancer therapeutics, PDAC patients rarely benefit from it due to insurmountable treatment resistance. Notably, PDAC is pathologically characterized by an extensive desmoplastic reaction and an extremely immunosuppressive tumour microenvironment (TME). The PDAC TME consists of cell components (e.g., tumour, immune and stromal cells) and noncellular components (e.g., extracellular matrix), exhibiting high complexity and their interplay resulting in resistance to chemotherapeutics and immune checkpoint inhibitors. In our review, we shed light on how crosstalk of complex environmental components modulates PDAC drug resistance, and we summarize related clinical trials. Moreover, we extend our discussion on TME exploration and exosome analysis, providing new insights into clinical applications, including personalized medicine, disease monitoring and drug carriers.

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References

Porcelli L, Iacobazzi R, Di Fonte R, Serrati S, Intini A, Solimando A . CAFs and TGF-β Signaling Activation by Mast Cells Contribute to Resistance to Gemcitabine/Nabpaclitaxel in Pancreatic Cancer. Cancers (Basel). 2019; 11(3). PMC: 6468868. DOI: 10.3390/cancers11030330. View

Orth M, Metzger P, Gerum S, Mayerle J, Schneider G, Belka C . Pancreatic ductal adenocarcinoma: biological hallmarks, current status, and future perspectives of combined modality treatment approaches. Radiat Oncol. 2019; 14(1):141. PMC: 6688256. DOI: 10.1186/s13014-019-1345-6. View

Sohal D, Mangu P, Khorana A, Shah M, Philip P, OReilly E . Metastatic Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016; 34(23):2784-96. PMC: 5019760. DOI: 10.1200/JCO.2016.67.1412. View

Tempero M, Oh D, Tabernero J, Reni M, Van Cutsem E, Hendifar A . Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study. Ann Oncol. 2021; 32(5):600-608. DOI: 10.1016/j.annonc.2021.01.070. View

Francescone R, Vendramini-Costa D, Franco-Barraza J, Wagner J, Muir A, Lau A . Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast-Driven Nutritional Support and Immunosuppression. Cancer Discov. 2020; 11(2):446-479. PMC: 7858242. DOI: 10.1158/2159-8290.CD-20-0775. View

Katsuta E, Qi Q, Peng X, Hochwald S, Yan L, Takabe K . Pancreatic adenocarcinomas with mature blood vessels have better overall survival. Sci Rep. 2019; 9(1):1310. PMC: 6362082. DOI: 10.1038/s41598-018-37909-5. View

Zhang D, Li L, Jiang H, Li Q, Wang-Gillam A, Yu J . Tumor-Stroma IL1β-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemoresistance, and Poor Prognosis in Pancreatic Cancer. Cancer Res. 2018; 78(7):1700-1712. PMC: 5890818. DOI: 10.1158/0008-5472.CAN-17-1366. View

Apte M, Pirola R, Wilson J . Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol. 2012; 3:344. PMC: 3428781. DOI: 10.3389/fphys.2012.00344. View

Steele C, Karim S, Leach J, Bailey P, Upstill-Goddard R, Rishi L . CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2016; 29(6):832-845. PMC: 4912354. DOI: 10.1016/j.ccell.2016.04.014. View

10.

Tong D, Guan J, Sun J, Zhao C, Chen S, Zhang Z . Characterization of B cell-mediated PD-1/PD-L1 interaction in pancreatic cancer patients. Clin Exp Pharmacol Physiol. 2020; 47(8):1342-1349. DOI: 10.1111/1440-1681.13317. View

11.

Zhou W, Zhou Y, Chen X, Ning T, Chen H, Guo Q . Pancreatic cancer-targeting exosomes for enhancing immunotherapy and reprogramming tumor microenvironment. Biomaterials. 2020; 268:120546. DOI: 10.1016/j.biomaterials.2020.120546. View

12.

Ducreux M, Seufferlein T, Van Laethem J, Laurent-Puig P, Smolenschi C, Malka D . Systemic treatment of pancreatic cancer revisited. Semin Oncol. 2019; 46(1):28-38. DOI: 10.1053/j.seminoncol.2018.12.003. View

13.

Parra E, Zhai J, Tamegnon A, Zhou N, Pandurengan R, Barreto C . Identification of distinct immune landscapes using an automated nine-color multiplex immunofluorescence staining panel and image analysis in paraffin tumor tissues. Sci Rep. 2021; 11(1):4530. PMC: 7907283. DOI: 10.1038/s41598-021-83858-x. View

14.

Obaid G, Bano S, Mallidi S, Broekgaarden M, Kuriakose J, Silber Z . Impacting Pancreatic Cancer Therapy in Heterotypic Organoids and Tumors with Specificity-Tuned, NIR-Activable Photoimmunonanoconjugates: Towards Conquering Desmoplasia?. Nano Lett. 2019; 19(11):7573-7587. PMC: 6934365. DOI: 10.1021/acs.nanolett.9b00859. View

15.

Ene-Obong A, Clear A, Watt J, Wang J, Fatah R, Riches J . Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology. 2013; 145(5):1121-32. PMC: 3896919. DOI: 10.1053/j.gastro.2013.07.025. View

16.

Torphy R, Wang Z, True-Yasaki A, Volmar K, Rashid N, Yeh B . Stromal Content Is Correlated With Tissue Site, Contrast Retention, and Survival in Pancreatic Adenocarcinoma. JCO Precis Oncol. 2018; 2018. PMC: 6262879. DOI: 10.1200/PO.17.00121. View

17.

Zhou Y, Zhou W, Chen X, Wang Q, Li C, Chen Q . Bone marrow mesenchymal stem cells-derived exosomes for penetrating and targeted chemotherapy of pancreatic cancer. Acta Pharm Sin B. 2020; 10(8):1563-1575. PMC: 7488356. DOI: 10.1016/j.apsb.2019.11.013. View

18.

Blando J, Sharma A, Higa M, Zhao H, Vence L, Yadav S . Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. Proc Natl Acad Sci U S A. 2019; 116(5):1692-1697. PMC: 6358697. DOI: 10.1073/pnas.1811067116. View

19.

Samanta S, Rajasingh S, Drosos N, Zhou Z, Dawn B, Rajasingh J . Exosomes: new molecular targets of diseases. Acta Pharmacol Sin. 2017; 39(4):501-513. PMC: 5888687. DOI: 10.1038/aps.2017.162. View

20.

Seifert A, Reiche C, Heiduk M, Tannert A, Meinecke A, Baier S . Detection of pancreatic ductal adenocarcinoma with galectin-9 serum levels. Oncogene. 2020; 39(15):3102-3113. PMC: 7142017. DOI: 10.1038/s41388-020-1186-7. View