Effects of Hypoxia in Pancreatic Cancer on Immune Cell Behavior in the Tumor Microenvironment
Abstract
Hypoxia serves as a fundamental component of the tumor microenvironment, exerting a crucial influence on tumor advancement. Nonetheless, a comprehensive examination of a prognostic signature linked to hypoxia in pancreatic cancer is notably absent, presenting an urgent necessity. Therefore, our objective was to create and authenticate a robust prognostic signature capable of predicting outcomes for pancreatic cancer.
Initially, the Gene Set Enrichment Analysis (GSEA) database was used to obtain hypoxia-related genes, and prognostic genes were analyzed. Following this, we utilized the Lasso Cox regression model to construct the hypoxia risk score model. Pancreatic cancer patients were subsequently categorized into high- and low-risk groups according to the median risk score. Finally, the CIBERSORT technique was used to assess immune cell infiltration while examining the relationship between hypoxia and immune-related genes.
Applying the Lasso Cox regression model, we pinpointed 2 significant genes, GYS1 and ALDOB. Following this, patients were categorized into hypoxia high-risk and low-risk groups. Notably, the low-risk cohort demonstrated a substantially heightened survival rate relative to the high-risk group. Further investigation into the immune microenvironment unveiled a greater prevalence of resting mast cells, monocytes, plasma cells, and naive CD4+ T cells in the low-risk category. In addition, we detected differences in the expression of 39 immune-related genes between the 2 groups.
In summary, our study has established a predictive signature comprising molecular markers for forecasting the prognosis of pancreatic cancer patients.
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14. Yuen VW, Wong CC. Hypoxia-inducible factors and innate immunity in liver cancer. J Clin Invest. 2020;130(10):5052-62.
15. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014-22.
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18. Ma S, Zhao Y, Lee WC, Ong LT, Lee PL, Jiang Z, et al. Hypoxia induces HIF1alpha-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy. Nat Commun. 2022;13(1):4118.
19. Geng S, Zhu L, Wang Y, Liu Q, Yu C, Shi S, et al. Co-Colorectal cancer stem cells employ the FADS1/DDA axis to evade NK cell-mediated immunosuppression after co-cultured with NK cells under hypoxia. Int Immunopharmacol. 2024;143(Pt 3):113535.
20. Khosravi GR, Mostafavi S, Bastan S, Ebrahimi N, Gharibvand RS, Eskandari N. Immunologic tumor microenvironment modulators for turning cold tumors hot. Cancer Commun. 2024;44(5):521-53.
21. Kawai T, Akira S. TLR signaling. Semin Immunol. 2007;19(1):24-32.
22. Lewis C, Murdoch C. Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am J Pathol. 2005;167(3):627-35.
23. Hypoxemia vs. hypoxia. New Engl J Med. 1966;274(16):908-9.
24. Darby IA, Hewitson TD. Hypoxia in tissue repair and fibrosis. Cell Tissue Res. 2016;365(3):553-62.
25. Multhoff G, Vaupel P. Hypoxia Compromises Anti-Cancer Immune Responses. Adv Exp Med Biol. 2020;1232:131-43.
26. Xie Y, Shi X, Sheng K, Han G, Li W, Zhao Q, et al. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review). Mol Med Rep. 2019;19(2):783-91.
27. Oikonomakos NG, Zographos SE, Skamnaki VT, Archontis G. The 1.76 A resolution crystal structure of glycogen phosphorylase B complexed with glucose, and CP320626, a potential antidiabetic drug. Bioorgan Med Chem. 2002;10(5):1313-9.
28. Roach PJ, Cheng C, Huang D, Lin A, Mu J, Skurat AV, et al. Novel aspects of the regulation of glycogen storage. J Basic Clin Physiol Pharmacol. 1998;9(2-4):139-51.
29. Rousset M, Zweibaum A, Fogh J. Presence of glycogen and growth-related variations in 58 cultured human tumor cell lines of various tissue origins. Cancer Res. 1981;41(3):1165-70.
30. Favaro E, Bensaad K, Chong MG, Tennant DA, Ferguson DJ, Snell C, et al. Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metab. 2012;16(6):751-64.
31. Samanta D, Semenza GL. Metabolic adaptation of cancer and immune cells mediated by hypoxia-inducible factors. Bba-Rev Cancer. 2018;1870(1):15-22.
32. Pescador N, Villar D, Cifuentes D, Garcia-Rocha M, Ortiz-Barahona A, Vazquez S, et al. Hypoxia promotes glycogen accumulation through hypoxia inducible factor (HIF)-mediated induction of glycogen synthase 1. Plos One. 2010;5(3):e9644.
33. Chen SL, Huang QS, Huang YH, Yang X, Yang MM, He YF, et al. GYS1 induces glycogen accumulation and promotes tumor progression via the NF-kappaB pathway in Clear Cell Renal Carcinoma. Theranostics. 2020;10(20):9186-99.
34. Chang YC, Yang YC, Tien CP, Yang CJ, Hsiao M. Roles of Aldolase Family Genes in Human Cancers and Diseases. Trends Endocrin Met. 2018;29(8):549-59.
35. He X, Li M, Yu H, Liu G, Wang N, Yin C, et al. Loss of hepatic aldolase B activates Akt and promotes hepatocellular carcinogenesis by destabilizing the Aldob/Akt/PP2A protein complex. Plos Biol. 2020;18(12):e3000803.
36. Lian J, Xia L, Chen Y, Zheng J, Ma K, Luo L, et al. Aldolase B impairs DNA mismatch repair and induces apoptosis in colon adenocarcinoma. Pathol Res Pract. 2019;215(11):152597.
37. Bu P, Chen KY, Xiang K, Johnson C, Crown SB, Rakhilin N, et al. Aldolase B-Mediated Fructose Metabolism Drives Metabolic Reprogramming of Colon Cancer Liver Metastasis. Cell Metab. 2018;27(6):1249-62.
38. He J, Jin Y, Chen Y, Yao HB, Xia YJ, Ma YY, et al. Downregulation of ALDOB is associated with poor prognosis of patients with gastric cancer. Oncotargets Ther. 2016;9(8):6099-109.
2. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-86.
3. Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF, Maitra A, et al. Genetics and biology of pancreatic ductal adenocarcinoma. Gene Dev. 2016;30(4):355-85.
4. Ansari D, Tingstedt B, Andersson B, Holmquist F, Sturesson C, Williamsson C, et al. Pancreatic cancer: yesterday, today and tomorrow. Future Oncol. 2016;12(16):1929-46.
5. Zhang L, Sanagapalli S, Stoita A. Challenges in diagnosis of pancreatic cancer. World J Gastroentero. 2018;24(19):2047-60.
6. Heinrich S, Lang H. Neoadjuvant Therapy of Pancreatic Cancer: Definitions and Benefits. Int J Mol Sci. 2017;18(8)
7. Eltzschig HK, Carmeliet P. Hypoxia and inflammation. New Engl J Med. 2011;364(7):656-65.
8. Gilkes DM, Semenza GL, Wirtz D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat Rev Cancer. 2014;14(6):430-9.
9. Dengler VL, Galbraith M, Espinosa JM. Transcriptional regulation by hypoxia inducible factors. Crit Rev Biochem Mol. 2014;49(1):1-15.
10. Lu X, Kang Y. Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res. 2010;16(24):5928-35.
11. Daniel SK, Sullivan KM, Labadie KP, Pillarisetty VG. Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma. Clin Transl Med. 2019;8(1):10.
12. You L, Wu W, Wang X, Fang L, Adam V, Nepovimova E, et al. The role of hypoxia-inducible factor 1 in tumor immune evasion. Med Res Rev. 2021;41(3):1622-43.
13. Mennerich D, Kubaichuk K, Kietzmann T. DUBs, Hypoxia, and Cancer. Trends Cancer. 2019;5(10):632-53.
14. Yuen VW, Wong CC. Hypoxia-inducible factors and innate immunity in liver cancer. J Clin Invest. 2020;130(10):5052-62.
15. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014-22.
16. Garcia GC, Huang Y, Fuentes NR, Turner MC, Monberg ME, Lin D, et al. Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment. Gastroenterology. 2022;162(7):2018-31.
17. Konen JM, Wu H, Gibbons DL. Immune checkpoint blockade resistance in lung cancer: emerging mechanisms and therapeutic opportunities. Trends Pharmacol Sci. 2024;45(6):520-36.
18. Ma S, Zhao Y, Lee WC, Ong LT, Lee PL, Jiang Z, et al. Hypoxia induces HIF1alpha-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy. Nat Commun. 2022;13(1):4118.
19. Geng S, Zhu L, Wang Y, Liu Q, Yu C, Shi S, et al. Co-Colorectal cancer stem cells employ the FADS1/DDA axis to evade NK cell-mediated immunosuppression after co-cultured with NK cells under hypoxia. Int Immunopharmacol. 2024;143(Pt 3):113535.
20. Khosravi GR, Mostafavi S, Bastan S, Ebrahimi N, Gharibvand RS, Eskandari N. Immunologic tumor microenvironment modulators for turning cold tumors hot. Cancer Commun. 2024;44(5):521-53.
21. Kawai T, Akira S. TLR signaling. Semin Immunol. 2007;19(1):24-32.
22. Lewis C, Murdoch C. Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am J Pathol. 2005;167(3):627-35.
23. Hypoxemia vs. hypoxia. New Engl J Med. 1966;274(16):908-9.
24. Darby IA, Hewitson TD. Hypoxia in tissue repair and fibrosis. Cell Tissue Res. 2016;365(3):553-62.
25. Multhoff G, Vaupel P. Hypoxia Compromises Anti-Cancer Immune Responses. Adv Exp Med Biol. 2020;1232:131-43.
26. Xie Y, Shi X, Sheng K, Han G, Li W, Zhao Q, et al. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review). Mol Med Rep. 2019;19(2):783-91.
27. Oikonomakos NG, Zographos SE, Skamnaki VT, Archontis G. The 1.76 A resolution crystal structure of glycogen phosphorylase B complexed with glucose, and CP320626, a potential antidiabetic drug. Bioorgan Med Chem. 2002;10(5):1313-9.
28. Roach PJ, Cheng C, Huang D, Lin A, Mu J, Skurat AV, et al. Novel aspects of the regulation of glycogen storage. J Basic Clin Physiol Pharmacol. 1998;9(2-4):139-51.
29. Rousset M, Zweibaum A, Fogh J. Presence of glycogen and growth-related variations in 58 cultured human tumor cell lines of various tissue origins. Cancer Res. 1981;41(3):1165-70.
30. Favaro E, Bensaad K, Chong MG, Tennant DA, Ferguson DJ, Snell C, et al. Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metab. 2012;16(6):751-64.
31. Samanta D, Semenza GL. Metabolic adaptation of cancer and immune cells mediated by hypoxia-inducible factors. Bba-Rev Cancer. 2018;1870(1):15-22.
32. Pescador N, Villar D, Cifuentes D, Garcia-Rocha M, Ortiz-Barahona A, Vazquez S, et al. Hypoxia promotes glycogen accumulation through hypoxia inducible factor (HIF)-mediated induction of glycogen synthase 1. Plos One. 2010;5(3):e9644.
33. Chen SL, Huang QS, Huang YH, Yang X, Yang MM, He YF, et al. GYS1 induces glycogen accumulation and promotes tumor progression via the NF-kappaB pathway in Clear Cell Renal Carcinoma. Theranostics. 2020;10(20):9186-99.
34. Chang YC, Yang YC, Tien CP, Yang CJ, Hsiao M. Roles of Aldolase Family Genes in Human Cancers and Diseases. Trends Endocrin Met. 2018;29(8):549-59.
35. He X, Li M, Yu H, Liu G, Wang N, Yin C, et al. Loss of hepatic aldolase B activates Akt and promotes hepatocellular carcinogenesis by destabilizing the Aldob/Akt/PP2A protein complex. Plos Biol. 2020;18(12):e3000803.
36. Lian J, Xia L, Chen Y, Zheng J, Ma K, Luo L, et al. Aldolase B impairs DNA mismatch repair and induces apoptosis in colon adenocarcinoma. Pathol Res Pract. 2019;215(11):152597.
37. Bu P, Chen KY, Xiang K, Johnson C, Crown SB, Rakhilin N, et al. Aldolase B-Mediated Fructose Metabolism Drives Metabolic Reprogramming of Colon Cancer Liver Metastasis. Cell Metab. 2018;27(6):1249-62.
38. He J, Jin Y, Chen Y, Yao HB, Xia YJ, Ma YY, et al. Downregulation of ALDOB is associated with poor prognosis of patients with gastric cancer. Oncotargets Ther. 2016;9(8):6099-109.
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| Issue | Articles in Press | |
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| Keywords | ||
| Bioinformatics Hypoxia Immune cell infiltration Pancreatic cancer Tumor microenvironment | ||
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How to Cite
1.
Wen X, Fan Z, Yu H. Effects of Hypoxia in Pancreatic Cancer on Immune Cell Behavior in the Tumor Microenvironment. Iran J Allergy Asthma Immunol. 2025;:1-11.
