1932

Abstract

Pancreatic cancer is characterized by an extensive fibroinflammatory reaction that includes immune cells, fibroblasts, extracellular matrix, vascular and lymphatic vessels, and nerves. Overwhelming evidence indicates that the pancreatic cancer microenvironment regulates cancer initiation, progression, and maintenance. Pancreatic cancer treatment has progressed little over the past several decades, and the prognosis remains one of the worst for any cancer. The contribution of the microenvironment to carcinogenesis is a key area of research, offering new potential targets for treating the disease. Here, we explore the composition of the pancreatic cancer stroma, discuss the network of interactions between different components, and describe recent attempts to target the stroma therapeutically. We also discuss current areas of active research related to the tumor microenvironment.

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2019-02-10
2024-04-17
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Literature Cited

  1. 1.  Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM 2014. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74:2913–21
    [Google Scholar]
  2. 2.  Sener SF, Fremgen A, Menck HR, Winchester DP 1999. Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985–1995, using the National Cancer Database. J. Am. Coll. Surg. 189:1–7
    [Google Scholar]
  3. 3.  Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD et al. 2016. Pancreatic cancer. Nat. Rev. Dis. Primers 2:16022
    [Google Scholar]
  4. 4.  Smit VT, Boot AJM, Smits AMM, Fleuren GJ, Cornelisse CJ, Bos JL 1988. KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acids Res 16:7773–82
    [Google Scholar]
  5. 5.  Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M 1988. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–54
    [Google Scholar]
  6. 6.  Hong SM, Vincent A, Kanda M, Leclerc J, Omura N et al. 2012. Genome-wide somatic copy number alterations in low-grade PanINs and IPMNs from individuals with a family history of pancreatic cancer. Clin. Cancer Res. 18:4303–12
    [Google Scholar]
  7. 7.  Maitra A, Hruban RH 2008. Pancreatic cancer. Annu. Rev. Pathol. Mech. Dis. 3:157–88
    [Google Scholar]
  8. 8.  Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA 2006. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 20:1218–49
    [Google Scholar]
  9. 9.  Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C et al. 2003. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4:437–50
    [Google Scholar]
  10. 10.  Tuveson DA, Shaw AT, Willis NA, Silver DP, Jackson EL et al. 2004. Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5:375–87
    [Google Scholar]
  11. 11.  Collins MA, Brisset JC, Zhang Y, Bednar F, Pierre J et al. 2012. Metastatic pancreatic cancer is dependent on oncogenic Kras in mice. PLOS ONE 7:e49707
    [Google Scholar]
  12. 12.  Yadav D, Lowenfels AB 2013. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 144:1252–61
    [Google Scholar]
  13. 13.  Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG et al. 1993. Pancreatitis and the risk of pancreatic cancer. N. Engl. J. Med. 328:1433–37
    [Google Scholar]
  14. 14.  Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF et al. 2016. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 30:355–85
    [Google Scholar]
  15. 15.  Hruban RH, Goggins M, Parsons J, Kern SE 2000. Progression model for pancreatic cancer. Clin. Cancer Res. 6:82969–72
    [Google Scholar]
  16. 16.  Matthaei H, Schulick RD, Hruban RH, Maitra A 2011. Cystic precursors to invasive pancreatic cancer. Nat. Rev. Gastroenterol. Hepatol. 8:3141–50
    [Google Scholar]
  17. 17.  Vincent A, Herman J, Schulick R, Hruban RH, Goggins M 2011. Pancreatic cancer. Lancet 378:607–20
    [Google Scholar]
  18. 18.  Witkiewicz AK, McMillan EA, Balaji U, Baek G, Lin WC et al. 2015. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat. Commun. 6:6744
    [Google Scholar]
  19. 19.  Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB et al. 2012. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491:399–405
    [Google Scholar]
  20. 20.  Kanda M, Matthaei H, Wu J, Hong SM, Yu J et al. 2012. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 142:730–33.e9
    [Google Scholar]
  21. 21.  Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M et al. 2011. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med. 17:500–3
    [Google Scholar]
  22. 22.  Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG et al. 2015. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47:1168–78
    [Google Scholar]
  23. 23.  Bailey P, Chang DK, Nones K, Johns AL, Patch AM et al. 2016. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531:47–52
    [Google Scholar]
  24. 24.  Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS et al. 2015. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518:495–501
    [Google Scholar]
  25. 25.  Bhagwat N, Dulmage K, Pletcher CH Jr.,, Wang L, DeMuth W et al. 2018. An integrated flow cytometry-based platform for isolation and molecular characterization of circulating tumor single cells and clusters. Sci. Rep. 8:5035
    [Google Scholar]
  26. 26.  Siveke JT, Einwächter H, Sipos B, Lubeseder-Martellato C, Klöppel G, Schmid RM 2007. Concomitant pancreatic activation of KrasG12D and Tgfa results in cystic papillary neoplasms reminiscent of human IPMN. Cancer Cell 12:266–79
    [Google Scholar]
  27. 27.  Izeradjene K, Combs C, Best M, Gopinathan A, Wagner A et al. 2007. KrasG12D and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 11:229–43
    [Google Scholar]
  28. 28.  Schofield HK, Tandon M, Park MJ, Halbrook CJ, Ramakrishnan SK et al. 2018. Pancreatic HIF2α stabilization leads to chronic pancreatitis and predisposes to mucinous cystic neoplasm. Cell Mol. Gastroenterol. Hepatol. 5:169–85.e2
    [Google Scholar]
  29. 29.  Kopp JL, von Figura G, Mayes E, Liu FF, Dubois CL et al. 2012. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22:737–50
    [Google Scholar]
  30. 30.  Guerra C, Schuhmacher AJ, Cañamero M, Grippo PJ, Verdaguer L et al. 2007. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11:291–302
    [Google Scholar]
  31. 31.  Morris JP 4th, Wang SC, Hebrok M 2010. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat. Rev. Cancer 10:683–95
    [Google Scholar]
  32. 32.  Lee AYL, Dubois CL, Sarai K, Zarei S, Schaeffer DF, Sander M, Kopp JL 2018. Cell of origin affects tumour development and phenotype in pancreatic ductal adenocarcinoma. Gut https://doi.org/10.1136/gutjnl-2017-314426
    [Crossref]
  33. 33.  Bailey JM, Hendley AM, Lafaro KJ, Pruski MA, Jones NC et al. 2016. p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells. Oncogene 35:4282–88
    [Google Scholar]
  34. 34.  Stanger BZ, Stiles B, Lauwers GY, Bardeesy N, Mendoza M et al. 2005. Pten constrains centroacinar cell expansion and malignant transformation in the pancreas. Cancer Cell 8:185–95
    [Google Scholar]
  35. 35.  Ying H, Elpek KG, Vinjamoori A, Zimmerman SM, Chu GC et al. 2011. Pten is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB-cytokine network. Cancer Discov 1:158–69
    [Google Scholar]
  36. 36.  Roy N, Malik S, Villanueva KE, Urano A, Lu X et al. 2015. Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation. Genes Dev 29:658–71
    [Google Scholar]
  37. 37.  Tsuda M, Fukuda A, Roy N, Hiramatsu Y, Leonhardt L et al. 2018. The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis. J Clin. Investig. 128:3475–89
    [Google Scholar]
  38. 38.  von Figura G, Fukuda A, Roy N, Liku ME, Morris JP 4th et al. 2014. The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma. Nat. Cell Biol. 16:255–67
    [Google Scholar]
  39. 39.  Ji B, Tsou L, Wang H, Gaiser S, Chang DZ et al. 2009. Ras activity levels control the development of pancreatic diseases. Gastroenterology 137:1072–82.e1–6
    [Google Scholar]
  40. 40.  Ardito CM, Grüner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N et al. 2012. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22:304–17
    [Google Scholar]
  41. 41.  Navas C, Hernandez-Porras I, Schuhmacher AJ, Sibilia M, Guerra C, Barbacid M 2012. EGF receptor signaling is essential for K-Ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 22:318–30
    [Google Scholar]
  42. 42.  Duell EJ, Lucenteforte E, Olson SH, Bracci PM, Li D et al. 2012. Pancreatitis and pancreatic cancer risk: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4). Ann. Oncol. 23:2964–70
    [Google Scholar]
  43. 43.  Niederau C, Ferrell LD, Grendell JH 1985. Caerulein-induced acute necrotizing pancreatitis in mice: protective effects of proglumide, benzotript, and secretin. Gastroenterology 88:1192–204
    [Google Scholar]
  44. 44.  Carrière C, Young AL, Gunn JR, Longnecker DS, Korc M 2009. Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras. Biochem. Biophys. Res. Commun. 382:561–65
    [Google Scholar]
  45. 45.  Morris JP 4th, Cano DA, Sekine S, Wang SC, Hebrok M 2010. β-Catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J. Clin. Investig. 120:508–20
    [Google Scholar]
  46. 46.  Guerra C, Collado M, Navas C, Schuhmacher AJ, Hernandez-Porras I et al. 2011. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19:728–39
    [Google Scholar]
  47. 47.  Collins MA, Yan W, Sebolt-Leopold JS, Pasca di Magliano M 2014. MAPK signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice. Gastroenterology 146:822–34.e7
    [Google Scholar]
  48. 56.  Collins MA, Bednar F, Zhang Y, Brisset JC, Galban S et al. 2012. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J. Clin. Investig. 122:639–53
    [Google Scholar]
  49. 48.  Stanger BZ, Hebrok M 2013. Control of cell identity in pancreas development and regeneration. Gastroenterology 144:1170–79
    [Google Scholar]
  50. 49.  Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D et al. 2009. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324:1457–61
    [Google Scholar]
  51. 50.  Hingorani SR, Tuveson DA 2003. Targeting oncogene dependence and resistance. Cancer Cell 3:414–17
    [Google Scholar]
  52. 51.  Neesse A, Michl P, Frese KK, Feig C, Cook N et al. 2011. Stromal biology and therapy in pancreatic cancer. Gut 60:861–68
    [Google Scholar]
  53. 52.  Yauch RL, Gould SE, Scales SJ, Tang T, Tian H et al. 2008. A paracrine requirement for hedgehog signalling in cancer. Nature 455:406–10
    [Google Scholar]
  54. 53.  Kalluri R, Zeisberg M 2006. Fibroblasts in cancer. Nature Rev. Cancer 6:392–401
    [Google Scholar]
  55. 54.  Bailey JM, Swanson BJ, Hamada T, Eggers JP, Singh PK et al. 2008. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin. Cancer Res. 14:5995–6004
    [Google Scholar]
  56. 55.  Principe DR, DeCant B, Mascarinas E, Wayne EA, Diaz AM et al. 2016. TGFβ signaling in the pancreatic tumor microenvironment promotes fibrosis and immune evasion to facilitate tumorigenesis. Cancer Res 76:2525–39
    [Google Scholar]
  57. 57.  Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L et al. 2010. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-α. Science 330:827–30
    [Google Scholar]
  58. 58.  Mathew E, Collins MA, Fernandez-Barrena MG, Holtz AM, Yan W et al. 2014. The transcription factor Gli1 modulates the inflammatory response during pancreatic tissue remodeling. J. Biol. Chem. 289:27727–743
    [Google Scholar]
  59. 59.  Öhlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS et al. 2017. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214:3579
    [Google Scholar]
  60. 60.  Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A et al. 2013. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. PNAS 110:20212–17
    [Google Scholar]
  61. 61.  Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC et al. 2014. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25:719–34
    [Google Scholar]
  62. 62.  Zhang Y, Yan W, Collins MA, Bednar F, Rakshit S et al. 2013. Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance. Cancer Res 73:6359–74
    [Google Scholar]
  63. 63.  Mills LD, Zhang Y, Marler RJ, Herreros-Villanueva M, Zhang L et al. 2013. Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS-induced transformation. J. Biol. Chem. 288:11786–94
    [Google Scholar]
  64. 64.  Xu D, Matsuo Y, Ma J, Koide S, Ochi N et al. 2010. Cancer cell-derived IL-1α promotes HGF secretion by stromal cells and enhances metastatic potential in pancreatic cancer cells. J. Surg. Oncol. 102:469–77
    [Google Scholar]
  65. 65.  Charo C, Holla V, Arumugam T, Hwang R, Yang P et al. 2013. Prostaglandin E2 regulates pancreatic stellate cell activity via the EP4 receptor. Pancreas 42:467–74
    [Google Scholar]
  66. 66.  Pomianowska E, Sandnes D, Grzyb K, Schjølberg AR, Aasrum M et al. 2014. Inhibitory effects of prostaglandin E2 on collagen synthesis and cell proliferation in human stellate cells from pancreatic head adenocarcinoma. BMC Cancer 14:413
    [Google Scholar]
  67. 67.  Mace TA, Ameen Z, Collins A, Wojcik S, Mair M et al. 2013. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res 73:3007–18
    [Google Scholar]
  68. 68.  Tang D, Yuan Z, Xue X, Lu Z, Zhang Y et al. 2012. High expression of galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer. Int. J. Cancer 130:2337–48
    [Google Scholar]
  69. 69.  Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR 2012. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21:418–29
    [Google Scholar]
  70. 70.  Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N et al. 2013. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62:112–20
    [Google Scholar]
  71. 71.  Kim EJ, Sahai V, Abel EV, Griffith KA, Greenson JK et al. 2014. Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma. Clin. Cancer Res. 20:5937–45
    [Google Scholar]
  72. 72.  Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF et al. 2014. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25:735–47
    [Google Scholar]
  73. 73.  Ceyhan GO, Michalski CW, Demir IE, Muller MW, Friess H 2008. Pancreatic pain. Best Pract. Res. Clin. Gastroenterol. 22:31–44
    [Google Scholar]
  74. 74.  Freelove R, Walling AD 2006. Pancreatic cancer: diagnosis and management. Am. Fam. Physician 73:485–92
    [Google Scholar]
  75. 75.  Yi SQ, Miwa K, Ohta T, Kayahara M, Kitagawa H et al. 2003. Innervation of the pancreas from the perspective of perineural invasion of pancreatic cancer. Pancreas 27:225–29
    [Google Scholar]
  76. 76.  Stopczynski RE, Normolle DP, Hartman DJ, Ying H, DeBerry JJ et al. 2014. Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res 74:1718–27
    [Google Scholar]
  77. 77.  Saloman JL, Albers KM, Li D, Hartman DJ, Crawford HC et al. 2016. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. PNAS 113:3078–83
    [Google Scholar]
  78. 78.  Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH 2007. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 67:9518–27
    [Google Scholar]
  79. 79.  Zhang Y, Yan W, Mathew E, Bednar F, Wan S et al. 2014. CD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice. Cancer Immunol. Res. 2:423–35
    [Google Scholar]
  80. 80.  McAllister F, Bailey JM, Alsina J, Nirschl CJ, Sharma R et al. 2014. Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell 25:621–37
    [Google Scholar]
  81. 81.  Zhang Y, Zoltan M, Riquelme E, Xu H, Sahin I et al. 2018. Immune cell production of interleukin 17 induces stem cell features of pancreatic intraepithelial neoplasia cells. Gastroenterology 155:210–223.e3
    [Google Scholar]
  82. 82.  De Monte L, Reni M, Tassi E, Clavenna D, Papa I et al. 2011. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J. Exp. Med. 208:469–78
    [Google Scholar]
  83. 83.  Ochi A, Nguyen AH, Bedrosian AS, Mushlin HM, Zarbakhsh S et al. 2012. MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J. Exp. Med. 209:1671–87
    [Google Scholar]
  84. 84.  Protti MP, De Monte L 2012. Cross-talk within the tumor microenvironment mediates Th2-type inflammation in pancreatic cancer. Oncoimmunology 1:89–91
    [Google Scholar]
  85. 85.  Bellone G, Turletti A, Artusio E, Mareschi K, Carbone A et al. 1999. Tumor-associated transforming growth factor-β and interleukin-10 contribute to a systemic Th2 immune phenotype in pancreatic carcinoma patients. Am. J. Pathol. 155:537–47
    [Google Scholar]
  86. 86.  von Bernstorff W, Voss M, Freichel S, Schmid A, Vogel I et al. 2001. Systemic and local immunosuppression in pancreatic cancer patients. Clin. Cancer Res. 7:925s–32s
    [Google Scholar]
  87. 87.  Yamamoto M, Kamigaki T, Yamashita K, Hori Y, Hasegawa H et al. 2009. Enhancement of anti-tumor immunity by high levels of Th1 and Th17 with a combination of dendritic cell fusion hybrids and regulatory T cell depletion in pancreatic cancer. Oncol. Rep. 22:337–43
    [Google Scholar]
  88. 88.  Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V et al. 2002. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J. Immunol. 169:2756–61
    [Google Scholar]
  89. 89.  Pylayeva-Gupta Y, Lee KE, Hajdu CH, Miller G, Bar-Sagi D 2012. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21:836–47
    [Google Scholar]
  90. 90.  Hiraoka N, Onozato K, Kosuge T, Hirohashi S 2006. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin. Cancer Res. 12:5423–34
    [Google Scholar]
  91. 91.  Tang Y, Xu X, Guo S, Zhang C, Tian Y et al. 2014. An increased abundance of tumor-infiltrating regulatory T cells is correlated with the progression and prognosis of pancreatic ductal adenocarcinoma. PLOS ONE 9:e91551
    [Google Scholar]
  92. 92.  Mizukami Y, Kono K, Kawaguchi Y, Akaike H, Kamimura K et al. 2008. CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer. Int. J. Cancer 122:2286–93
    [Google Scholar]
  93. 93.  Iellem A, Mariani M, Lang R, Recalde H, Panina-Bordignon P et al. 2001. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4+CD25+ regulatory T cells. J. Exp. Med. 194:847–53
    [Google Scholar]
  94. 94.  Tan MC, Goedegebuure PS, Belt BA, Flaherty B, Sankpal N et al. 2009. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J. Immunol. 182:1746–55
    [Google Scholar]
  95. 95.  Viehl CT, Moore TT, Liyanage UK, Frey DM, Ehlers JP et al. 2006. Depletion of CD4+CD25+ regulatory T cells promotes a tumor-specific immune response in pancreas cancer-bearing mice. Ann. Surg. Oncol. 13:1252–58
    [Google Scholar]
  96. 96.  Byrne WL, Mills KH, Lederer JA, O'Sullivan GC 2011. Targeting regulatory T cells in cancer. Cancer Res 71:6915–20
    [Google Scholar]
  97. 97.  Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP 2009. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 206:1717–25
    [Google Scholar]
  98. 98.  Jang JE, Hajdu CH, Liot C, Miller G, Dustin ML, Bar-Sagi D 2017. Crosstalk between regulatory T cells and tumor-associated dendritic cells negates anti-tumor immunity in pancreatic cancer. Cell Rep 20:558–71
    [Google Scholar]
  99. 99.  Daley D, Zambirinis CP, Seifert L, Akkad N, Mohan N et al. 2016. γδ T cells support pancreatic oncogenesis by restraining αβ T cell activation. Cell 166:1485–99.e15
    [Google Scholar]
  100. 100.  Pylayeva-Gupta Y, Das S, Handler JS, Hajdu CH, Coffre M et al. 2016. IL35-producing B cells promote the development of pancreatic neoplasia. Cancer Discov 6:247–55
    [Google Scholar]
  101. 101.  Lee KE, Spata M, Bayne LJ, Buza EL, Durham AC et al. 2016. Hif1α deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia. Cancer Discov 6:256–69
    [Google Scholar]
  102. 102.  Gunderson AJ, Kaneda MM, Tsujikawa T, Nguyen AV, Affara NI et al. 2016. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov 6:270–85
    [Google Scholar]
  103. 103.  Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF 2008. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity 28:639–50
    [Google Scholar]
  104. 104.  Horikawa M, Weimer ET, DiLillo DJ, Venturi GM, Spolski R et al. 2013. Regulatory B cell (B10 cell) expansion during Listeria infection governs innate and cellular immune responses in mice. J. Immunol. 190:1158–68
    [Google Scholar]
  105. 105.  Nowarski R, Gagliani N, Huber S, Flavell RA 2013. Innate immune cells in inflammation and cancer. Cancer Immunol. Res. 1:77–84
    [Google Scholar]
  106. 106.  Stromnes IM, Brockenbrough JS, Izeradjene K, Carlson MA, Cuevas C et al. 2014. Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut 63:1769–81
    [Google Scholar]
  107. 107.  Rambaldi A, Young DC, Griffin JD 1987. Expression of the M-CSF (CSF-1) gene by human monocytes. Blood 69:1409–13
    [Google Scholar]
  108. 108.  Murdoch C, Giannoudis A, Lewis CE 2004. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 104:2224–34
    [Google Scholar]
  109. 109.  Monti P, Leone BE, Marchesi F, Balzano G, Zerbi A et al. 2003. The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: regulation of expression and potential mechanisms of antimalignant activity. Cancer Res 63:7451–61
    [Google Scholar]
  110. 110.  Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW et al. 2014. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41:14–20
    [Google Scholar]
  111. 111.  Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y et al. 2013. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 73:1128–41
    [Google Scholar]
  112. 112.  Helm O, Held-Feindt J, Grage-Griebenow E, Reiling N, Ungefroren H et al. 2014. Tumor-associated macrophages exhibit pro- and anti-inflammatory properties by which they impact on pancreatic tumorigenesis. Int. J. Cancer 135:843–61
    [Google Scholar]
  113. 113.  Gardian K, Janczewska S, Olszewski WL, Durlik M 2012. Analysis of pancreatic cancer microenvironment: role of macrophage infiltrates and growth factors expression. J. Cancer 3:285–91
    [Google Scholar]
  114. 114.  Kurahara H, Shinchi H, Mataki Y, Maemura K, Noma H et al. 2011. Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J. Surg. Res. 167:e211–19
    [Google Scholar]
  115. 115.  Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL et al. 2014. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 74:185057–69
    [Google Scholar]
  116. 116.  Sanford DE, Belt BA, Panni RZ, Mayer A, Deshpande AD et al. 2013. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin. Cancer Res. 19:3404–15
    [Google Scholar]
  117. 117.  Biswas SK, Mantovani A 2010. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11:889–96
    [Google Scholar]
  118. 118.  Bronte V, Zanovello P 2005. Regulation of immune responses by l-arginine metabolism. Nat. Rev. Immunol. 5:641–54
    [Google Scholar]
  119. 119.  Noy R, Pollard JW 2014. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41:49–61
    [Google Scholar]
  120. 120.  Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B 2007. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat. Immunol. 8:1086–94
    [Google Scholar]
  121. 121.  Savage ND, de Boer T, Walburg KV, Joosten SA, van Meijgaarden K et al. 2008. Human anti-inflammatory macrophages induce Foxp3+GITR+CD25+ regulatory T cells, which suppress via membrane-bound TGFβ-1. J. Immunol. 181:2220–26
    [Google Scholar]
  122. 122.  Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M 2004. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–86
    [Google Scholar]
  123. 123.  Gundra UM, Girgis NM, Ruckerl D, Jenkins S, Ward LN et al. 2014. Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct. Blood 123:e110–22
    [Google Scholar]
  124. 124.  Rey-Giraud F, Hafner M, Ries CH 2012. In vitro generation of monocyte-derived macrophages under serum-free conditions improves their tumor promoting functions. PLOS ONE 7:e42656
    [Google Scholar]
  125. 125.  Pardoll DM. 2012. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12:252–64
    [Google Scholar]
  126. 126.  Duraiswamy J, Freeman GJ, Coukos G 2013. Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. Cancer Res 73:6900–12
    [Google Scholar]
  127. 127.  Porembka MR, Mitchem JB, Belt BA, Hsieh CS, Lee HM et al. 2012. Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol. Immunother. 61:1373–85
    [Google Scholar]
  128. 128.  Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD et al. 2012. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21:822–35
    [Google Scholar]
  129. 129.  Müller-Decker K, Fürstenberger G, Annan N, Kucher D, Pohl-Arnold A et al. 2006. Preinvasive duct-derived neoplasms in pancreas of keratin 5-promoter cyclooxygenase-2 transgenic mice. Gastroenterology 130:2165–78
    [Google Scholar]
  130. 130.  Colby JK, Klein RD, McArthur MJ, Conti CJ, Kiguchi K et al. 2008. Progressive metaplastic and dysplastic changes in mouse pancreas induced by cyclooxygenase-2 overexpression. Neoplasia 10:782–96
    [Google Scholar]
  131. 131.  Hasan S, Satake M, Dawson DW, Funahashi H, Angst E et al. 2008. Expression analysis of the prostaglandin E2 production pathway in human pancreatic cancers. Pancreas 37:121–27
    [Google Scholar]
  132. 132.  Itakura J, Ishiwata T, Friess H, Fujii H, Matsumoto Y et al. 1997. Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin. Cancer Res. 3:1309–16
    [Google Scholar]
  133. 133.  Blogowski W, Deskur A, Budkowska M, Salata D, Madej-Michniewicz A et al. 2014. Selected cytokines in patients with pancreatic cancer: a preliminary report. PLOS ONE 9:e97613
    [Google Scholar]
  134. 134.  Basso D, Plebani M, Fogar P, Panozzo MP, Meggiato T et al. 1995. Insulin-like growth factor-I, interleukin-1 α and β in pancreatic cancer: role in tumor invasiveness and associated diabetes. Int. J. Clin. Lab. Res. 25:40–43
    [Google Scholar]
  135. 135.  Friess H, Yamanaka Y, Büchler M, Ebert M, Beger HG et al. 1993. Enhanced expression of transforming growth factor β isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 105:1846–56
    [Google Scholar]
  136. 136.  Friess H, Yamanaka Y, Büchler M, Berger HG, Kobrin MS et al. 1993. Enhanced expression of the type II transforming growth factor beta receptor in human pancreatic cancer cells without alteration of type III receptor expression. Cancer Res 53:2704–7
    [Google Scholar]
  137. 137.  Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, Kalinski P 2011. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood 118:5498–505
    [Google Scholar]
  138. 138.  Vernon PJ, Loux TJ, Schapiro NE, Kang R, Muthuswamy R et al. 2013. The receptor for advanced glycation end products promotes pancreatic carcinogenesis and accumulation of myeloid-derived suppressor cells. J. Immunol. 190:1372–79
    [Google Scholar]
  139. 139.  Kumar V, Donthireddy L, Marvel D, Condamine T, Wang F et al. 2017. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 32:654–68.e5
    [Google Scholar]
  140. 140.  Criscimanna A, Coudriet GM, Gittes GK, Piganelli JD, Esni F 2014. Activated macrophages create lineage-specific microenvironments for pancreatic acinar- and β-cell regeneration in mice. Gastroenterology 147:1106–18.e11
    [Google Scholar]
  141. 141.  Liou GY, Bastea L, Fleming A, Doppler H, Edenfield BH et al. 2017. The presence of interleukin-13 at pancreatic ADM/PanIN lesions alters macrophage populations and mediates pancreatic tumorigenesis. Cell Rep 19:1322–33
    [Google Scholar]
  142. 142.  Zhang Y, Velez-Delgado A, Mathew E, Li D, Mendez FM et al. 2017. Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer. Gut 66:124–36
    [Google Scholar]
  143. 143.  Vonderheide RH. 2018. The immune revolution: a case for priming, not checkpoint. Cancer Cell 33:563–69
    [Google Scholar]
  144. 144.  Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL et al. 2012. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366:2455–65
    [Google Scholar]
  145. 145.  Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, Noelle RJ 2009. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol. Rev. 229:152–72
    [Google Scholar]
  146. 146.  Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR et al. 2011. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331:1612–16
    [Google Scholar]
  147. 147.  Beatty GL, Torigian DA, Chiorean EG, Saboury B, Brothers A et al. 2013. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin. Cancer Res. 19:6286–95
    [Google Scholar]
  148. 148.  Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D 2011. RAS oncogenes: weaving a tumorigenic web. Nat. Rev. Cancer 11:761–74
    [Google Scholar]
  149. 149.  El-Jawhari JJ, El-Sherbiny YM, Scott GB, Morgan RS, Prestwich R et al. 2014. Blocking oncogenic RAS enhances tumour cell surface MHC class I expression but does not alter susceptibility to cytotoxic lymphocytes. Mol. Immunol. 58:160–68
    [Google Scholar]
  150. 150.  Zhang Y, Yan W, Mathew E, Kane KT, Brannon A et al. 2017. Epithelial-myeloid cell crosstalk regulates acinar cell plasticity and pancreatic remodeling in mice. eLife 6:e27388
    [Google Scholar]
  151. 151.  Wu CY, Carpenter ES, Takeuchi KK, Halbrook CJ, Peverley LV et al. 2014. PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. Gastroenterology 147:1405–16.e7
    [Google Scholar]
  152. 152.  Ancrile BB, O'Hayer KM, Counter CM 2008. Oncogenic Ras-induced expression of cytokines: a new target of anti-cancer therapeutics. Mol. Interv. 8:22–27
    [Google Scholar]
  153. 153.  Sparmann A, Bar-Sagi D 2004. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6:447–58
    [Google Scholar]
  154. 154.  Yang G, Rosen DG, Zhang Z, Bast RC Jr., Mills GB et al. 2006. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. PNAS 103:16472–77
    [Google Scholar]
  155. 155.  Okumura T, Ericksen RE, Takaishi S, Wang SS, Dubeykovskiy Z et al. 2010. K-ras mutation targeted to gastric tissue progenitor cells results in chronic inflammation, an altered microenvironment, and progression to intraepithelial neoplasia. Cancer Res 70:8435–45
    [Google Scholar]
  156. 156.  Keir ME, Butte MJ, Freeman GJ, Sharpe AH 2008. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26:677–704
    [Google Scholar]
  157. 157.  Dong H, Zhu G, Tamada K, Chen L 1999. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat. Med. 5:1365–69
    [Google Scholar]
  158. 158.  Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T et al. 2000. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192:1027–34
    [Google Scholar]
  159. 159.  Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M et al. 2001. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2:261–68
    [Google Scholar]
  160. 160.  Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A et al. 2008. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin. Cancer Res. 14:3044–51
    [Google Scholar]
  161. 161.  McDermott DF, Atkins MB 2013. PD-1 as a potential target in cancer therapy. Cancer Med 2:662–73
    [Google Scholar]
  162. 162.  Zou W, Chen L 2008. Inhibitory B7-family molecules in the tumour microenvironment. Nat. Rev. Immunol. 8:467–77
    [Google Scholar]
  163. 163.  Nomi T, Sho M, Akahori T, Hamada K, Kubo A et al. 2007. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin. Cancer Res. 13:2151–57
    [Google Scholar]
  164. 164.  Balachandran VP, Luksza M, Zhao JN, Makarov V, Moral JA et al. 2017. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551:512–16
    [Google Scholar]
  165. 165.  Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB et al. 2005. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7:469–83
    [Google Scholar]
  166. 166.  Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J et al. 2006. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev 20:3130–46
    [Google Scholar]
  167. 167.  Aguirre AJ, Bardeesy N, Sinha M, Lopez L, Tuveson DA et al. 2003. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 17:3112–26
    [Google Scholar]
  168. 168.  Corbett TH, Roberts BJ, Leopold WR, Peckham JC, Wilkoff LJ et al. 1984. Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice. Cancer Res 44:717–26
    [Google Scholar]
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