Advances in the study of changes in the tumor microenvironment of pancreatic ductal adenocarcinoma during immunotherapy_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WANG Chi ¹ , REN Likun ¹ , CHEN Song ¹ , PAN Yaozhen ^1,2 ,  WANG Xing ^1,2

1. Clinical Medical College, Guizhou Medical University, Guiyang 550000, P. R. China;
2. Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guizhou Medical University, Guiyang 550000, P. R. China;

Corresponding author：

WANG Xing, Email: foxmulder180@gmc.edu.cn

Keywords：

pancreatic ductal adenocarcinoma; tumor microenvironment; immunotherapy; biomarker; review

DOI：

10.7507/1007-9424.202502028

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the changes in the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) in the context of immunotherapy and their impact on treatment outcomes. Methods A systematic review of recent studies on the TME of PDAC was carried out to analyze the immune properties, intercellular interactions, and biological functions of its cellular and non-cellular components, disclose the molecular mechanisms of immunotherapy affects on the TME, explore the advancements in targeted therapy and potential biomarkers, and analyze the challenges in clinical applications and their impacts on the quality of life of patients. Results The TME of PDAC exhibits highly immunosuppressive and heterogeneous characteristics, rich in diverse cells (such as pancreatic cancer cells, stellate cells, cancer-associated fibroblasts, immune cells) and non-cellular components (such as extracellular matrix). Immunotherapy is capable of regulating the immune balance in the TME and enhancing the anti-tumor response. Despite the progress made in multiple immunotherapy strategies (such as immune checkpoint inhibitors, chimeric antigen receptor cell therapy), challenges such as difficulty in selecting targets, drug resistance, and side effects still persist. Meanwhile, potential biomarkers such as programmed cell death-ligand 1, tumor-infiltrating lymphocytes, and leukemia inhibitory factor offer new directions for individualized treatment. Conclusions The TME of PDAC undergoes continuous changes during immunotherapy. In the future, it is requisite to integrate new technologies to deeply explore targets and biomarkers, optimize multimodal precise treatment strategies, enhance the safety and efficacy of immunotherapy, and improve the prognosis of patients.

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2. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
3. Zheng R, Liu X, Zhang Y, et al. Frontiers and future of immunotherapy for pancreatic cancer: from molecular mechanisms to clinical application. Front Immunol, 2024, 15: 1383978. doi: 10.3389/fimmu.2024.1383978.
4. Kamisawa T, Wood LD, Itoi T, et al. Pancreatic cancer. Lancet, 2016, 388(10039): 73-85.
5. Bockorny B, Grossman JE, Hidalgo M. Facts and hopes in immunotherapy of pancreatic cancer. Clin Cancer Res, 2022, 28(21): 4606-4617.
6. Sherman MH, Beatty GL. Tumor microenvironment in pancreatic cancer pathogenesis and therapeutic resistance. Annu Rev Pathol, 2023, 18: 123-148.
7. Flowers BM, Xu H, Mulligan AS, et al. Cell of origin influences pancreatic cancer subtype. Cancer Discov, 2021, 11(3): 660-677.
8. Guerra C, Collado M, Navas C, et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell, 2011, 19(6): 728-739.
9. Cortesi M, Zanoni M, Pirini F, et al. Pancreatic cancer and cellular senescence: tumor microenvironment under the spotlight. Int J Mol Sci, 2021, 23(1): 254. doi: 10.3390/ijms23010254.
10. Lelarge V, Capelle R, Oger F, et al. Senolytics: from pharmacological inhibitors to immunotherapies, a promising future for patients’ treatment. NPJ Aging, 2024, 10(1): 12. doi: 10.1038/s41514-024-00138-4.
11. Yamamoto K, Venida A, Yano J, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-Ⅰ. Nature, 2020, 581(7806): 100-105.
12. Shi X, Wang M, Zhang Y, et al. Hypoxia activated HGF expression in pancreatic stellate cells confers resistance of pancreatic cancer cells to EGFR inhibition. EBioMedicine, 2022, 86: 104352. doi: 10.1016/j.ebiom.2022.104352.
13. Derynck R, Turley SJ, Akhurst RJ. TGFβ biology in cancer progression and immunotherapy. Nat Rev Clin Oncol, 2021, 18(1): 9-34.
14. Zhou W, Zhou Y, Chen X, et al. Pancreatic cancer-targeting exosomes for enhancing immunotherapy and reprogramming tumor microenvironment. Biomaterials, 2021, 268: 120546. doi: 10.1016/j.biomaterials.2020.
15. Wood LD, Canto MI, Jaffee EM, et al. Pancreatic cancer: pathogenesis, screening, diagnosis, and treatment. Gastroenterology, 2022, 163(2): 386-402. e1.
16. Jin G, Hong W, Guo Y, et al. Molecular mechanism of pancreatic stellate cells activation in chronic pancreatitis and pancreatic cancer. J Cancer, 2020, 11(6): 1505-1515.
17. Ahmad RS, Eubank TD, Lukomski S, et al. Immune cell modulation of the extracellular matrix contributes to the pathogenesis of pancreatic cancer. Biomolecules, 2021, 11(6): 901. doi: 10.3390/biom11060901.
18. Froeling FE, Feig C, Chelala C, et al. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-β-catenin signaling to slow tumor progression. Gastroenterology, 2011, 141(4): 1486-1497, 1497. e1-14.
19. Wang Y, Chen K, Liu G, et al. Disruption of super-enhancers in activated pancreatic stellate cells facilitates chemotherapy and immunotherapy in pancreatic cancer. Adv Sci (Weinh), 2024, 11(16): e2308637. doi: 10.1002/advs.202308637.
20. Mace TA, Ameen Z, Collins A, et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res, 2013, 73(10): 3007-3018.
21. Li H, Liu D, Li K, et al. Pancreatic stellate cells and the interleukin family: linking fibrosis and immunity to pancreatic ductal adenocarcinoma (review). Mol Med Rep, 2024, 30(3): 159. doi: 10.3892/mmr.2024.13283.
22. Wartenberg M, Cibin S, Zlobec I, et al. Integrated genomic and immunophenotypic classification of pancreatic cancer reveals three distinct subtypes with prognostic/predictive significance. Clin Cancer Res, 2018, 24(18): 4444-4454.
23. Cheung PF, Yang J, Fang R, et al. Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCⅠ expression. Nat Commun, 2022, 13(1): 156. doi: 10.1038/s41467-021-27088-9.
24. Steele NG, Carpenter ES, Kemp SB, et al. Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer. Nat Cancer, 2020, 1(11): 1097-1112.
25. Dutta S, Ganguly A, Chatterjee K, et al. Targets of immune escape mechanisms in cancer: basis for development and evolution of cancer immune checkpoint inhibitors. Biology (Basel), 2023, 12(2): 218. doi: 10.3390/biology12020218.
26. Chen Q, Yin H, He J, et al. Tumor microenvironment responsive CD8⁺ T cells and myeloid-derived suppressor cells to Trigger CD73 inhibitor AB680-based synergistic therapy for pancreatic cancer. Adv Sci (Weinh), 2023, 10(33): e2302498. doi: 10.1002/advs.202302498.
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