Pancreatic ductal adenocarcinoma (PDAC) is commonly known as the "king of cancers" because of its exceptionally aggressive nature and poor prognosis for patients. Moreover, the pancreas, being a retroperitoneal organ, presents a lack of specific markers, making early identification difficult. The tumor microenvironment (TME) consists of tumor cells, stromal cells, immune cells and cytokines, etc. together. Antitumor medications cannot penetrate PDAC due to its high mesenchymal component content, which also restricts immune cells to infiltrate the tumor tissue. At the same time, the TME of PDAC lacks anti-tumor immune cell infiltration and has strong immunosuppressive properties, and the components of TME play an important role in tumor growth, angiogenesis, immunosuppression, and resistance to chemotherapy and targeted drugs. In this paper, we provide an overview of the composition, biological properties and research progress of immunotherapy of TME in PDAC, in the hope of bringing new ideas for the treatment of PDAC.

Xinyue Guo, Zheng Jiang. Current Status and Perspectives of Pancreatic Cancer Tumor Microenvironment and Therapy. International Journal of Frontiers in Medicine (2024), Vol. 6, Issue 2: 38-44. https://doi.org/10.25236/IJFM.2024.060206.

[1] R. L. Siegel, K. D. Miller, H. E. Fuchs, et al. "Cancer Statistics, 2022". CA Cancer J Clin, vol.72, no.1, pp.7–33, 2022.

[2] H. Sung, J. Ferlay, R. L. Siegel, et al. "Global Cancer Statistics 2020: GLOBOCAN Estimates Of Incidence And Mortality Worldwide For 36 Cancers In 185 Countries". CA A Cancer J Clinicians, vol.71, no.3, pp.209–249, 2021.

[3] K. A. Brune, B. Lau, E. Palmisano, et al. "Importance Of Age Of Onset In Pancreatic Cancer Kindreds". JNCI Journal of the National Cancer Institute, vol.102, no.2, pp.119–126, 2010.

[4] A. N. Hosein, S. K. Dougan, A. J. Aguirre, et al. "Translational Advances In Pancreatic Ductal Adenocarcinoma Therapy". Nat Cancer, vol.3, no.3, pp.272–286, 2022.

[5] E. Versteijne, J. A. Vogel, M. G. Besselink, et al. "Meta-Analysis Comparing Upfront Surgery With Neoadjuvant Treatment In Patients With Resectable Or Borderline Resectable Pancreatic Cancer". British Journal of Surgery, vol.105, no.8, pp.946–958, 2018.

[6] J. Chen, Q. Hua, H. Wang, et al. "Meta-Analysis And Indirect Treatment Comparison Of Modified FOLFIRINOX And Gemcitabine Plus Nab-Paclitaxel As First-Line Chemotherapy In Advanced Pancreatic Cancer". BMC Cancer, vol.21, no.1, pp.853, 2021.

[7] S. Ay, M. M. Atcı, R. Arıkan, et al. "FOLFIRINOX Versus Gemcitabine Plus Nab-Paclitaxel As The First-Line Chemotherapy In Metastatic Pancreatic Cancer". Journal of Chemotherapy, vol.34, no.7, pp.465–471, 2022.

[8] N. Merza, S. K. Farooqui, S. H. Dar, et al. "Folfirinox Vs. Gemcitabine + Nab-Paclitaxel As The First-Line Treatment For Pancreatic Cancer: A Systematic Review And Meta-Analysis". World J Oncol, vol.14, no.5, pp.325–339, 2023.

[9] A. Marabelle, D. T. Le, P. A. Ascierto, et al. "Efficacy Of Pembrolizumab In Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From The Phase II KEYNOTE-158 Study". JCO, vol.38, no.1, pp.1–10, 2020.

[10] M. Binnewies, E. W. Roberts, K. Kersten, et al. "Understanding The Tumor Immune Microenvironment (TIME) For Effective Therapy". Nat Med, vol.24, no.5, pp.541–550, 2018.

[11] A. Neesse, P. Michl, K. K. Frese, et al. "Stromal Biology And Therapy In Pancreatic Cancer". Gut, vol.60, no.6, pp.861–868, 2011.

[12] A. Fukunaga, M. Miyamoto, Y. Cho, et al. "CD8+ Tumor-Infiltrating Lymphocytes Together With CD4+ Tumor-Infiltrating Lymphocytes And Dendritic Cells Improve The Prognosis Of Patients With Pancreatic Adenocarcinoma:". Pancreas, vol.28, no.1, pp.e26–e31, 2004.

[13] J. J. Lee, V. Bernard, A. Semaan, et al. "Elucidation Of Tumor-Stromal Heterogeneity And The Ligand-Receptor Interactome By Single-Cell Transcriptomics In Real-World Pancreatic Cancer Biopsies". Clin Cancer Res, vol.27, no.21, pp.5912–5921, 2021.

[14] N. Hiraoka, K. Onozato, T. Kosuge, et al. "Prevalence Of FOXP3+ Regulatory T Cells Increases During The Progression Of Pancreatic Ductal Adenocarcinoma And Its Premalignant Lesions". Clin Cancer Res, vol.12, no.18, pp.5423–5434, 2006.

[15] J.-E. Jang, C. H. Hajdu, C. Liot, et al. "Crosstalk Between Regulatory T Cells And Tumor-Associated Dendritic Cells Negates Anti-Tumor Immunity In Pancreatic Cancer". Cell Reports, vol.20, no.3, pp.558–571, 2017.

[16] Y. Zhang, J. Lazarus, N. G. Steele, et al. "Regulatory T-Cell Depletion Alters The Tumor Microenvironment And Accelerates Pancreatic Carcinogenesis". Cancer Discovery, vol.10, no.3, pp.422–439, 2020.

[17] M. Heiduk, I. Plesca, J. Glück, et al. "Neoadjuvant Chemotherapy Drives Intratumoral T Cells Toward A Proinflammatory Profile In Pancreatic Cancer". JCI Insight, vol.7, no.22, pp.e152761, 2022.

[18] Y. Pylayeva-Gupta, S. Das, J. S. Handler, et al. "IL35-Producing B Cells Promote The Development Of Pancreatic Neoplasia". Cancer Discov, vol.6, no.3, pp.247–255, 2016.

[19] C. Minici, S. Testoni, and E. Della-Torre. "B-Lymphocytes In The Pathophysiology Of Pancreatic Adenocarcinoma". Front Immunol, vol.13pp.867902, 2022.

[20] B. Mirlekar, Y. Wang, S. Li, et al. "Balance Between Immunoregulatory B Cells And Plasma Cells Drives Pancreatic Tumor Immunity". Cell Rep Med, vol.3, no.9, pp.100744, 2022.

[21] Z. N. Senturk, I. Akdag, B. Deniz, et al. "Pancreatic Cancer: Emerging Field Of Regulatory B-Cell-Targeted Immunotherapies". Front Immunol, vol.14pp.1152551, 2023.

[22] D. Michaud, B. Mirlekar, C. Steward, et al. "B Cell Receptor Signaling And Protein Kinase D2 Support Regulatory B Cell Function In Pancreatic Cancer". Front Immunol, vol.12pp.745873, 2022.

[23] S. R. Nielsen, J. E. Strøbech, E. R. Horton, et al. "Suppression Of Tumor-Associated Neutrophils By Lorlatinib Attenuates Pancreatic Cancer Growth And Improves Treatment With Immune Checkpoint Blockade". Nat Commun, vol.12pp.3414, 2021.

[24] T. M. Nywening, B. A. Belt, D. R. Cullinan, et al. "Targeting Both Tumour-Associated CXCR2+ Neutrophils And CCR2+ Macrophages Disrupts Myeloid Recruitment And Improves Chemotherapeutic Responses In Pancreatic Ductal Adenocarcinoma". Gut, vol.67, no.6, pp.1112–1123, 2018.

[25] L. Kalafati, I. Mitroulis, P. Verginis, et al. "Neutrophils As Orchestrators In Tumor Development And Metastasis Formation". Front Oncol, vol.10pp.581457, 2020.

[26] Z. G. Fridlender, J. Sun, S. Kim, et al. "Polarization Of Tumor-Associated Neutrophil Phenotype By TGF-Beta: “N1” Versus “N2” TAN". Cancer Cell, vol.16, no.3, pp.183–194, 2009.

[27] J. Deng, Y. Kang, C.-C. Cheng, et al. "DDR1-Induced Neutrophil Extracellular Traps Drive Pancreatic Cancer Metastasis". JCI Insight, vol.6, no.17, pp.e146133, 2021.

[28] Y. Zhu, J. M. Herndon, D. K. Sojka, et al. "Tissue-Resident Macrophages In Pancreatic Ductal Adenocarcinoma Originate From Embryonic Hematopoiesis And Promote Tumor Progression". Immunity, vol.47, no.2, pp.323-338.e6, 2017.

[29] C. Shi and E. G. Pamer. "Monocyte Recruitment During Infection And Inflammation". Nat Rev Immunol, vol.11, no.11, pp.762–774, 2011.

[30] T. Wu and Y. Dai. "Tumor Microenvironment And Therapeutic Response". Cancer Lett, vol.387pp.61–68, 2017.

[31] P. Dong, Y. Yan, Y. Fan, et al. "The Role Of Myeloid-Derived Suppressor Cells In The Treatment Of Pancreatic Cancer". Technol Cancer Res Treat, vol.21pp.15330338221142472, 2022.

[32] M.-Y. Park, B.-G. Lim, S.-Y. Kim, et al. "GM-CSF Promotes The Expansion And Differentiation Of Cord Blood Myeloid-Derived Suppressor Cells, Which Attenuate Xenogeneic Graft-Vs.-Host Disease". Front Immunol, vol.10pp.183, 2019.

[33] Q. Liu, H. Wu, Y. Li, et al. "Combined Blockade Of TGf-Β1 And GM-CSF Improves Chemotherapeutic Effects For Pancreatic Cancer By Modulating Tumor Microenvironment". Cancer Immunol Immunother, vol.69, no.8, pp.1477–1492, 2020.

[34] Y. Kajiwara, H. Tazawa, M. Yamada, et al. "Oncolytic Virus-Mediated Reducing Of Myeloid-Derived Suppressor Cells Enhances The Efficacy Of PD-L1 Blockade In Gemcitabine-Resistant Pancreatic Cancer". Cancer Immunol Immunother, vol.72, no.5, pp.1285–1300, 2023.

[35] Y. Qiu, Y. Cao, G. Tu, et al. "Myeloid-Derived Suppressor Cells Alleviate Renal Fibrosis Progression Via Regulation Of CCL5-CCR5 Axis". Front Immunol, vol.12pp.698894, 2021.

[36] V. Tjomsland, P. Sandström, A. Spångeus, et al. "Pancreatic Adenocarcinoma Exerts Systemic Effects On The Peripheral Blood Myeloid And Plasmacytoid Dendritic Cells: An Indicator Of Disease Severity?". BMC Cancer, vol.10pp.87, 2010.

[37] J. R. Conejo-Garcia, M. R. Rutkowski, and J. R. Cubillos-Ruiz. "State-Of-The-Art Of Regulatory Dendritic Cells In Cancer". Pharmacol Ther, vol.164pp.97–104, 2016.

[38] J. Guo, M. Liao, X. Hu, et al. "Tumour-Derived Reg3A Educates Dendritic Cells To Promote Pancreatic Cancer Progression". Mol Cells, vol.44, no.9, pp.647–657, 2021.

[39] M. Katsuda, M. Miyazawa, T. Ojima, et al. "A Double-Blind Randomized Comparative Clinical Trial To Evaluate The Safety And Efficacy Of Dendritic Cell Vaccine Loaded With WT1 Peptides (TLP0-001) In Combination With S-1 In Patients With Advanced Pancreatic Cancer Refractory To Standard Chemotherapy". Trials, vol.20, no.1, pp.242, 2019.

[40] S.-W. Cai, S.-Z. Yang, J. Gao, et al. "Prognostic Significance Of Mast Cell Count Following Curative Resection For Pancreatic Ductal Adenocarcinoma". Surgery, vol.149, no.4, pp.576–584, 2011.

[41] J. Dudeck, S. M. Ghouse, C. H. K. Lehmann, et al. "Mast-Cell-Derived TNF Amplifies CD8(+) Dendritic Cell Functionality And CD8(+) T Cell Priming". Cell Rep, vol.13, no.2, pp.399–411, 2015.

[42] V. Longo, R. Tamma, O. Brunetti, et al. "Mast Cells And Angiogenesis In Pancreatic Ductal Adenocarcinoma". Clin Exp Med, vol.18, no.3, pp.319–323, 2018.

[43] Y. Ma, R. F. Hwang, C. D. Logsdon, et al. "Dynamic Mast Cell-Stromal Cell Interactions Promote Growth Of Pancreatic Cancer". Cancer Res, vol.73, no.13, pp.3927–3937, 2013.

[44] X. Guo, L. Zhai, R. Xue, et al. "Mast Cell Tryptase Contributes To Pancreatic Cancer Growth Through Promoting Angiogenesis Via Activation Of Angiopoietin-1". Int J Mol Sci, vol.17, no.6, pp.834, 2016.

[45] V. P. Groot, G. Gemenetzis, A. B. Blair, et al. "Defining And Predicting Early Recurrence In 957 Patients With Resected Pancreatic Ductal Adenocarcinoma". Ann Surg, vol.269, no.6, pp.1154–1162, 2019.