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  • Review Article
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The tumour microenvironment in pancreatic cancer — clinical challenges and opportunities

Abstract

Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumours despite the use of multi-agent conventional chemotherapy regimens. Such poor outcomes have fuelled ongoing efforts to exploit the tumour microenvironment (TME) for therapy, but strategies aimed at deconstructing the surrounding desmoplastic stroma and targeting the immunosuppressive pathways have largely failed. In fact, evidence has now shown that the stroma is multi-faceted, which illustrates the complexity of exploring features of the TME as isolated targets. In this Review, we describe ways in which the PDAC microenvironment has been targeted and note the current understanding of the clinical outcomes that have unexpectedly contradicted preclinical observations. We also consider the more sophisticated therapeutic strategies under active investigation — multi-modal treatment approaches and exploitation of biologically integrated targets — which aim to remodel the TME against PDAC.

Key points

  • Therapeutic approaches to target stromal desmoplasia, a histopathological hallmark of pancreatic ductal adenocarcinoma, have classically focused on depleting the stromal constituents; results have been generally disappointing, owing to the multi-faceted nature of tumour stroma.

  • Isolated strategies to overcome specific immune targets have also met with limited success, likely owing to the presence of multiple immunoregulatory pathways within the pancreatic ductal adenocarcinoma microenvironment.

  • In recognition of the functional complexity of the tumour microenvironment (TME), combining complementary stromal-targeted and immune-targeted treatment modalities to leverage the changes in the TME offers a more rational treatment approach.

  • Points of biological convergence, such as stromal–immune crosstalk, including glutamine metabolism, focal adhesion kinase and transforming growth factor-β signalling, are promising targets for remodelling the TME into an antitumour milieu.

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Fig. 1: Targeting PDAC-associated stroma.
Fig. 2: Myeloid and Treg targeting strategies to treat PDAC.
Fig. 3: Remodelling the PDAC microenvironment.

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References

  1. Hidalgo, M. Pancreatic cancer. N. Engl. J. Med. 362, 1605–1617 (2010).

    CAS  PubMed  Google Scholar 

  2. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin. 69, 7–34 (2019).

    PubMed  Google Scholar 

  3. Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013).

    Google Scholar 

  4. Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817–1825 (2011).

    CAS  PubMed  Google Scholar 

  5. Moskaluk, C. A., Hruban, R. H. & Kern, S. E. p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res. 57, 2140–2143 (1997).

    CAS  PubMed  Google Scholar 

  6. DiGiuseppe, J. A., Redston, M. S., Yeo, C. J., Kern, S. E. & Hruban, R. H. p53-independent expression of the cyclin-dependent kinase inhibitor p21 in pancreatic carcinoma. Am. J. Pathol. 147, 884–888 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Hruban, R. H. et al. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am. J. Surg. Pathol. 25, 579–586 (2001).

    CAS  PubMed  Google Scholar 

  8. Foster, D. S., Jones, R. E., Ransom, R. C., Longaker, M. T. & Norton, J. A. The evolving relationship of wound healing and tumor stroma. JCI Insight 3, 99911 (2018).

    PubMed  Google Scholar 

  9. Flier, J. S., Underhill, L. H. & Dvorak, H. F. Tumors: wounds that do not heal. N. Engl. J. Med. 315, 1650–1659 (1986).

    Google Scholar 

  10. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Ramanathan, R. K. et al. Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313. J. Clin. Oncol. 37, 1062–1069 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Hingorani, S. R. et al. HALO 202: randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J. Clin. Oncol. 36, 359–366 (2018).

    CAS  PubMed  Google Scholar 

  13. Whatcott, C. J. et al. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin. Cancer Res. 21, 3561–3568 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Vonlaufen, A. et al. Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res. 68, 2085–2093 (2008).

    CAS  PubMed  Google Scholar 

  15. Apte, M. V. et al. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut 44, 534–541 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Bramhall, S. R., Neoptolemos, J. P., Stamp, G. W. H. & Lemoine, N. R. Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. J. Pathol. 182, 347–355 (1997).

    CAS  PubMed  Google Scholar 

  18. Jones, L. E., Humphreys, M. J., Campbell, F., Neoptolemos, J. P. & Boyd, M. T. Comprehensive analysis of matrix metalloproteinase and tissue inhibitor expression in pancreatic cancer: increased expression of matrix metalloproteinase-7 predicts poor survival. Clin. Cancer Res. 10, 2832–2845 (2004).

    CAS  PubMed  Google Scholar 

  19. Matsuyama, Y., Takao, S. & Aikou, T. Comparison of matrix metalloproteinase expression between primary tumors with or without liver metastasis in pancreatic and colorectal carcinomas. J. Surg. Oncol. 80, 105–110 (2002).

    CAS  PubMed  Google Scholar 

  20. Okada, Y. et al. Nerve growth factor stimulates MMP-2 expression and activity and increases invasion by human pancreatic cancer cells. Clin. Exp. Metastasis 21, 285–292 (2004).

    CAS  PubMed  Google Scholar 

  21. Schnelderhan, W. et al. Pancreatic stellate cells are an important source of MMP-2 in human pancreatic cancer and accelerate tumor progression in a murine xenograft model and CAM assay. J. Cell Sci. 120, 512–519 (2007).

    Google Scholar 

  22. Gress, T. M. et al. Expression and in-situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancer. Int. J. Cancer 62, 407–413 (1995).

    CAS  PubMed  Google Scholar 

  23. Ellenrieder, V. et al. Role of MT-MMPs and MMP-2 in pancreatic cancer progression. Int. J. Cancer 85, 14–20 (2000).

    CAS  PubMed  Google Scholar 

  24. Yamamoto, H. et al. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human pancreatic adenocarcinomas: clinicopathologic and prognostic significance of matrilysin expression. J. Clin. Oncol. 19, 1118–1127 (2001).

    CAS  PubMed  Google Scholar 

  25. Crawford, H. C., Scoggins, C. R., Washington, M. K., Matrisian, L. M. & Leach, S. D. Matrix metalloproteinase-7 is expressed by pancreatic cancer precursors and regulates acinar-to-ductal metaplasia in exocrine pancreas. J. Clin. Invest. 109, 1437–1444 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Fukuda, A. et al. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 19, 441–455 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Tang, Y., Kesavan, P., Nakada, M. T. & Yan, L. Tumor-stroma interaction: positive feedback regulation of extracellular matrix metalloproteinase inducer (EMMPRIN) expression and matrix metalloproteinase-dependent generation of soluble EMMPRIN. Mol. Cancer Res. 2, 73–80 (2004).

    CAS  PubMed  Google Scholar 

  28. Chirvi, R. G. S. et al. Inhibition of the metastatic spread and growth of B16-BL6 murine melanoma by a synthetic matrix metalloproteinase inhibitor. Int. J. Cancer 58, 460–464 (1994).

    Google Scholar 

  29. Watson, S. A. et al. Inhibition of organ invasion by the matrix metalloproteinase inhibitor batimastat (BB-94) in two human colon carcinoma metastasis models. Cancer Res. 55, 3629–3633 (1995).

    CAS  PubMed  Google Scholar 

  30. Watson, S. A. et al. Inhibition of tumour growth by marimastat in a human xenograft model of gastric cancer: relationship with levels of circulating CEA. Br. J. Cancer 81, 19–23 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Bramhall, S. R. et al. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br. J. Cancer 87, 161–167 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Bramhall, S. R. et al. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J. Clin. Oncol. 19, 3447–3455 (2001).

    CAS  PubMed  Google Scholar 

  33. Moore, M. J. et al. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 21, 3296–3302 (2003).

    CAS  PubMed  Google Scholar 

  34. Jacobetz, M. A. et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62, 112–120 (2013).

    CAS  PubMed  Google Scholar 

  35. HemOnc today. Phase 3 trial of pancreatic cancer therapy misses primary endpoint https://www.healio.com/hematology-oncology/gastrointestinal-cancer/news/online/%7Be57ffed4-505b-40e5-ac9a-21f050ee850e%7D/phase-3-trial-of-pancreatic-cancer-therapy-misses-primary-endpoint (2019).

  36. Hebrok, M., Kim, S. K. & Melton, D. A. Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev. 12, 1705–1713 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Kim, S. K. & Melton, D. A. Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor. Proc. Natl Acad. Sci. USA 95, 13036–13041 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Strobel, O. et al. Pancreatic duct glands are distinct ductal compartments that react to chronic injury and mediate Shh-induced metaplasia. Gastroenterology 138, 1166–1177 (2010).

    PubMed  Google Scholar 

  39. Bailey, J. M. et al. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin. Cancer Res. 14, 5995–6004 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Feldmann, G. et al. Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Gut 57, 1420–1430 (2008).

    CAS  PubMed  Google Scholar 

  41. Olive, K. P. et al. Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Madden, J. Infinity Reports Update from Phase 2 Study of Saridegib Plus Gemcitabine in Patients with Metastatic Pancreatic Cancer. https://www.businesswire.com/news/home/20120127005146/en/Infinity-Reports-Update-Phase-2-Study-Saridegib (2012).

  43. Catenacci, D. V. et al. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J. Clin. Oncol. 33, 4284–4292 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. De Jesus-Acosta, A. et al. A phase II study of vismodegib, a hedgehog (Hh) pathway inhibitor, combined with gemcitabine and nab-paclitaxel (nab-P) in patients (pts) with untreated metastatic pancreatic ductal adenocarcinoma (PDA). J. Clin. Oncol. 32, 257 (2014).

    Google Scholar 

  45. Hingorani, S. R. et al. Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer. Clin. Cancer Res. 22, 2848–2854 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Lee, J. J. et al. Stromal response to hedgehog signaling restrains pancreatic cancer progression. Proc. Natl Acad. Sci. USA 111, E3091–E3100 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Xiao, Q. et al. Cancer-associated fibroblasts in pancreatic cancer are reprogrammed by tumor-induced alterations in genomic DNA methylation. Cancer Res. 76, 5395–5404 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).

    PubMed  PubMed Central  Google Scholar 

  50. Öhlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579–596 (2017).

    PubMed  PubMed Central  Google Scholar 

  51. Torphy, R. J. et al. Stromal content is correlated with tissue site, contrast retention, and survival in pancreatic adenocarcinoma. JCO Precis. Oncol. 2018, 1–12 (2018).

    Google Scholar 

  52. Moffitt, R. A. et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47, 1168–1178 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ligorio, M. et al. Stromal microenvironment shapes the intratumoral architecture of pancreatic. Cancer Cell 178, 160–175 (2019).

    CAS  Google Scholar 

  54. Mahadevan, K. K. et al. Quasimesenchymal phenotype predicts systemic metastasis in pancreatic ductal adenocarcinoma. Mod. Pathol. 32, 844–854 (2019).

    PubMed  PubMed Central  Google Scholar 

  55. Chen, X. & Song, E. Turning foes to friends: targeting cancer-associated fibroblasts. Nat. Rev. Drug Discov. 18, 99–115 (2019).

    CAS  PubMed  Google Scholar 

  56. Hofheinz, R. D. et al. Stromal antigen targeting by a humanised monoclonal antibody: an early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer. Onkologie 26, 44–48 (2003).

    CAS  PubMed  Google Scholar 

  57. Gunderson, A. J. et al. Blockade of fibroblast activation protein in combination with radiation treatment in murine models of pancreatic adenocarcinoma. PLoS One 14, e0211117 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Nugent, F. W. et al. Phase 2 study of talabostat/gemcitabine in stage IV pancreatic cancer. J. Clin. Oncol. 25, 4616 (2007).

    Google Scholar 

  59. Özdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).

    PubMed  PubMed Central  Google Scholar 

  60. Ohuchida, K. et al. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res. 64, 3215–3222 (2004).

    CAS  PubMed  Google Scholar 

  61. Lo, A. et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 75, 2800–2810 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Kakarla, S. et al. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol. Ther. 21, 1611–1620 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Hosein, A. N. et al. Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution. JCI Insight 4, e129212 (2019).

    PubMed Central  Google Scholar 

  64. Biffi, G. et al. Il1-induced Jak/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 9, 282–301 (2019).

    PubMed  Google Scholar 

  65. Blair, A. B. et al. Dissecting the stromal signaling and regulation of myeloid cells and memory effector T cells in pancreatic cancer. Clin. Cancer Res. 25, 5351–5363 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Hidalgo, M. et al. A multi-center phase IIA trial to assess the safety and efficacy of BL-8040 (a CXCR4 inhibitor) in combination with pembrolizumab and chemotherapy in patients with metastatic pancreatic adenocarcinoma (PDAC). Ann. Oncol. 30, xi33 (2019).

    Google Scholar 

  68. Yadav, D. & Lowenfels, A. B. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 144, 1252–1261 (2013).

    PubMed  Google Scholar 

  69. Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).

    CAS  PubMed  Google Scholar 

  70. Guerra, C. et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728–739 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. DuPage, M. et al. Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression. Cancer Cell 19, 72–85 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Fossum, B., Olsen, A. C., Thorsby, E. & Gaudernack, G. CD8+ T cells from a patient with colon carcinoma, specific for a mutant p21-Ras-derived peptide (GLY13→ASP), are cytotoxic towards a carcinoma cell line harbouring the same mutation. Cancer Immunol. Immunother. 40, 165–172 (1995).

    CAS  PubMed  Google Scholar 

  73. Qin, H. et al. CD4+ T-cell immunity to mutated ras protein in pancreatic and colon cancer patients. Cancer Res. 55, 2984–2987 (1995).

    CAS  PubMed  Google Scholar 

  74. Kubuschok, B. et al. Naturally occurring T-cell response against mutated p21 Ras oncoprotein in pancreatic cancer. Clin. Cancer Res. 12, 1365–1372 (2006).

    CAS  PubMed  Google Scholar 

  75. Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).

    CAS  PubMed  Google Scholar 

  76. Danilova, L. et al. Programmed cell death ligand-1 (PD-L1) and CD8 expression profiling identify an immunologic subtype of pancreatic ductal adenocarcinomas with favorable survival. Cancer Immunol. Res. 7, 886–895 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9, 34 (2017).

    PubMed  PubMed Central  Google Scholar 

  80. Osipov, A. et al. Tumor mutational burden (TMB) and response rates to immune checkpoint inhibitors (ICIs) targeting PD-1, CTLA-4, and combination. J. Clin. Oncol. 37, 2578–2578 (2019).

    Google Scholar 

  81. Yarchoan, M., Hopkins, A. & Jaffee, E. M. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med. 377, 2500–2501 (2017).

    PubMed  PubMed Central  Google Scholar 

  82. Salman, B., Zhou, D., Jaffee, E. M., Edil, B. H. & Zheng, L. Vaccine therapy for pancreatic cancer. Oncoimmunology 2, 1–8 (2013).

    Google Scholar 

  83. Bernhardt, S. L. et al. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study. Br. J. Cancer 95, 1474–1482 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Gjertsen, M. K. et al. Vaccination with mutant ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation. Lancet 346, 1399–1400 (1995).

    CAS  PubMed  Google Scholar 

  85. Gjertsen, M. K. et al. Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: clinical and immunological responses in patients with pancreatic adenocarcinoma. Int. J. Cancer 92, 441–450 (2001).

    CAS  PubMed  Google Scholar 

  86. Gilliam, A. D. et al. An international multicenter randomized controlled trial of G17DT in patients with pancreatic cancer. Pancreas 41, 374–379 (2012).

    CAS  PubMed  Google Scholar 

  87. Kaufman, H. L. et al. Poxvirus-based vaccine therapy for patients with advanced pancreatic cancer. J. Transl Med. 5, (2007).

  88. Lepisto, A. J. et al. A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Ther. 6, 955–964 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Laheru, D. et al. Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin. Cancer Res. 14, 1455–1463 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Le, D. T. et al. A live-attenuated listeria vaccine (ANZ-100) and a live-attenuated listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. Clin. Cancer Res. 18, 858–868 (2012).

    CAS  PubMed  Google Scholar 

  91. Gatti-Mays, M. E. et al. A phase I dose-escalation trial of BN-CV301, a recombinant poxviral vaccine targeting MUC1 and CEA with costimulatory molecules. Clin. Cancer Res. 25, 4933–4944 (2019).

    PubMed  PubMed Central  Google Scholar 

  92. Hu, Z., Ott, P. A. & Wu, C. J. Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nat. Rev. Immunol. 18, 168–182 (2018).

    CAS  PubMed  Google Scholar 

  93. Kinkead, H. L. et al. Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer. JCI Insight 3, 122857 (2018).

    PubMed  Google Scholar 

  94. Jaffee, E. M. et al. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J. Clin. Oncol. 19, 145–156 (2001).

    CAS  PubMed  Google Scholar 

  95. Eric, L. et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma: a phase II trial of safety, efficacy, and immune activation. Ann. Surg. 253, 328–335 (2011).

    Google Scholar 

  96. Hopkins, A. C. et al. T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma. JCI Insight 3, 122092 (2018).

    PubMed  Google Scholar 

  97. Lutz, E. R. et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol. Res. 2, 616–631 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G. & Bar-Sagi, D. Oncogenic kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21, 836–847 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Clark, C. E. et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 67, 9518–9527 (2007).

    CAS  PubMed  Google Scholar 

  100. Zhao, F. et al. Increase in frequency of myeloid-derived suppressor cells in mice with spontaneous pancreatic carcinoma. Immunology 128, 141–149 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Hiraoka, N., Onozato, K., Kosuge, T. & Hirohashi, S. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin. Cancer Res. 12, 5423–5434 (2006).

    CAS  PubMed  Google Scholar 

  102. Joshi, N. S. et al. Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses. Immunity 43, 579–590 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Gabrilovich, D. I. Myeloid-derived suppressor cells. Cancer Immunol. Res. 5, 3–8 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Liou, G. Y. et al. Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. Cancer Discov. 5, 52–63 (2015).

    CAS  PubMed  Google Scholar 

  105. Liou, G. Y. et al. Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-kB and MMPs. J. Cell Biol. 202, 563–577 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Lesina, M. et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19, 456–469 (2011).

    CAS  PubMed  Google Scholar 

  107. Liou, G. Y. et al. The presence of interleukin-13 at pancreatic ADM/PanIN lesions alters macrophage populations and mediates pancreatic tumorigenesis. Cell Rep. 19, 1322–1333 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Ries, C. H. et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25, 846–859 (2014).

    CAS  PubMed  Google Scholar 

  109. Reid, M. D. et al. Tumor-infiltrating neutrophils in pancreatic neoplasia. Mod. Pathol. 24, 1612–1619 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Shen, M. et al. Tumor-associated neutrophils as a new prognostic factor in cancer: a systematic review and meta-analysis. PLoS One 9, e98259 (2014).

    PubMed  PubMed Central  Google Scholar 

  111. Chao, T., Furth, E. E. & Vonderheide, R. H. CXCR2-dependent accumulation of tumor-associated neutrophils regulates T-cell immunity in pancreatic ductal adenocarcinoma. Cancer Immunol. Res. 4, 968–982 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Le, D. T. & Jaffee, E. M. Regulatory T-cell modulation using cyclophosphamide in vaccine approaches: a current perspective. Cancer Res. 72, 3439–3444 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Kim, V. M. et al. Anti-pancreatic tumor efficacy of a listeria-based, annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies. J. Immunother. Cancer 7, 132 (2019).

    PubMed  PubMed Central  Google Scholar 

  114. Selby, M. J. et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol. Res. 1, 32–42 (2013).

    CAS  PubMed  Google Scholar 

  115. Jang, J. E. et al. Crosstalk between regulatory T cells and tumor-associated dendritic cells negates anti-tumor immunity in pancreatic cancer. Cell Rep. 20, 558–571 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Cannarile, M. A. et al. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J. Immunother. Cancer 5, 53 (2017).

    PubMed  PubMed Central  Google Scholar 

  117. Zhu, Y. et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 74, 5057–5069 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Saung, M. T. et al. Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer. J. Immunother. Cancer 6, 118 (2018).

    PubMed  PubMed Central  Google Scholar 

  119. Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Vonderheide, R. H. CD40 agonist antibodies in cancer immunotherapy. Annu. Rev. Med. 71, 47–58 (2020).

    CAS  PubMed  Google Scholar 

  121. Fu, J. et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci. Transl Med. 7, 283ra52 (2015).

    PubMed  PubMed Central  Google Scholar 

  122. Harrington, K. J. et al. Preliminary results of the first-in-human (FIH) study of MK-1454, an agonist of stimulator of interferon genes (STING), as monotherapy or in combination with pembrolizumab (pembro) in patients with advanced solid tumors or lymphomas. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 29, viii712 (2018).

    Google Scholar 

  123. Quaratino, S. et al. A first-in-human study of KY1044, a fully human anti-ICOS IgG1 antibody as monotherapy and in combination with atezolizumab in patients with selected advanced malignancies. J. Clin. Oncol. 37, TPS2644–TPS2644 (2019).

    Google Scholar 

  124. Solinas, C., Gu-Trantien, C. & Willard-Gallo, K. The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy. ESMO Open 5, e000544 (2020).

    PubMed  PubMed Central  Google Scholar 

  125. Mitchem, J. B. et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 73, 1128–1141 (2013).

    CAS  PubMed  Google Scholar 

  126. Janson, C. et al. Inhibition of CCR2 potentiates checkpoint inhibitor immunotherapy in murine model of pancreatic cancer [abstract 5655]. Cancer Res. https://doi.org/10.1158/1538-7445.am2017-5655 (2017).

    Article  Google Scholar 

  127. Linehan, D. et al. Overall survival in a trial of orally administered CCR2 inhibitor CCX872 in locally advanced/metastatic pancreatic cancer: correlation with blood monocyte counts. J. Clin. Oncol. 36, 92–92 (2018).

    Google Scholar 

  128. Wang-Gillam, A. et al. Phase IB study of FOLFIRINOX plus PF-04136309 in patients with borderline resectable and locally advanced pancreatic adenocarcinoma (PC). J. Clin. Oncol. 33, 338–338 (2015).

    Google Scholar 

  129. Noel, M. et al. Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma. Invest. New Drugs https://doi.org/10.1007/s10637-019-00830-3 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Steele, C. W. et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell 29, 832–845 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Nywening, T. M. et al. Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut 67, 1112–1123 (2018).

    CAS  PubMed  Google Scholar 

  132. Eriksson, E. et al. Shaping the tumor stroma and sparking immune activation by CD40 and 4-1BB signaling induced by an armed oncolytic virus. Clin. Cancer Res. 23, 5846–5857 (2017).

    CAS  PubMed  Google Scholar 

  133. Carew, J. S. et al. Reolysin is a novel reovirus-based agent that induces endoplasmic reticular stress-mediated apoptosis in pancreatic cancer. Cell Death Dis. 4, e728 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Andtbacka, R. H. I. et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33, 2780–2788 (2015).

    CAS  PubMed  Google Scholar 

  135. Christmas, B. J. et al. Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs. Cancer Immunol. Res. 6, 1561–1577 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Dahlén, E., Veitonmäki, N. & Norlén, P. Bispecific antibodies in cancer immunotherapy. Ther. Adv. Vaccines Immunother. 6, 3–17 (2018).

    PubMed  PubMed Central  Google Scholar 

  137. Naing, A. et al. PEGylated IL-10 (Pegilodecakin) induces systemic immune activation, CD8+ T cell invigoration and polyclonal T cell expansion in cancer patients. Cancer Cell 34, 775–791 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    CAS  PubMed  Google Scholar 

  139. Altman, B. J., Stine, Z. E. & Dang, C. V. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat. Rev. Cancer 16, 619–634 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013–1021 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Weigel, P. H. Hyaluronan Synthase: The Mechanism of Initiation at the Reducing End and a Pendulum Model for Polysaccharide Translocation to the Cell Exterior. Int. J. Cell Biol. 2015, 1–15 (2015).

    Google Scholar 

  143. Vigetti, D., Viola, M., Karousou, E., De Luca, G. & Passi, A. Metabolic control of hyaluronan synthases. Matrix Biol. 35, 8–13 (2014).

    CAS  PubMed  Google Scholar 

  144. Chanmee, T. et al. Hyaluronan production regulates metabolic and cancer stem-like properties of breast cancer cells via hexosamine biosynthetic pathway-coupled HIF-1 signaling. J. Biol. Chem. 291, 24105–24120 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Sharma, N. S. et al. Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy. J. Clin. Invest. 130, 451–465 (2020).

    CAS  PubMed  Google Scholar 

  146. Wang, W. et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569, 270–274 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Lemberg, K. M., Vornov, J. J., Rais, R. & Slusher, B. S. We’re not ‘don’ yet: optimal dosing and prodrug delivery of 6-diazo-5-oxo-L-norleucine. Mol. Cancer Therapeutics 17, 1824–1832 (2018).

    CAS  Google Scholar 

  148. Allard, B., Longhi, M. S., Robson, S. C. & Stagg, J. The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol. Rev. 276, 121–144 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Loo, J. M. et al. Extracellular metabolic energetics can promote cancer progression. Cell 160, 393–406 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Kurth, I. et al. RGX-202, a first-in-class small-molecule inhibitor of the creatine transporter SLC6a8, is a robust suppressor of cancer growth and metastatic progression [abstract 5863]. Cancer Res. https://doi.org/10.1158/1538-7445.am2018-5863 (2018).

    Article  Google Scholar 

  151. Blair, A. B. et al. IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma. J. Clin. Invest. 129, 1742–1755 (2019).

    PubMed  PubMed Central  Google Scholar 

  152. Jiang, H. et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med. 22, 851–860 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Jiang, H. et al. Development of resistance to FAK inhibition in pancreatic cancer is linked to stromal depletion. Gut 69, 122–132 (2020).

    CAS  PubMed  Google Scholar 

  154. Mizuno, S., Matsumoto, K., Li, M. Y. & Nakamura, T. HGF reduces advancing lung fibrosis in mice: a potential role for MMP-dependent myofibroblast apoptosis. FASEB J. 19, 580–582 (2005).

    PubMed  Google Scholar 

  155. Iekushi, K. et al. Hepatocyte growth factor attenuates renal fibrosis through TGF-b1 suppression by apoptosis of myofibroblasts. J. Hypertens. 28, 2454–2461 (2010).

    CAS  PubMed  Google Scholar 

  156. Zhao, X. K. et al. Focal adhesion kinase regulates hepatic stellate cell activation and liver fibrosis. Sci. Rep. 7, (2017).

  157. Wong, V. W. et al. Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nat. Med. 18, 148–152 (2012).

    CAS  Google Scholar 

  158. Gates, R. E., King, L. E., Hanks, S. K. & Nanney, L. B. Potential role for focal adhesion kinase in migrating and proliferating keratinocytes near epidermal wounds and in culture. Cell Growth Differ. 5, 891–899 (1994).

    CAS  PubMed  Google Scholar 

  159. Lal, H. et al. Stretch-induced MAP kinase activation in cardiac myocytes: differential regulation through β1-integrin and focal adhesion kinase. J. Mol. Cell. Cardiol. 43, 137–147 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Kanteti, R. et al. Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma. Cancer Biol. Ther. 19, 316–327 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Hochwald, S. N. et al. A novel small molecule inhibitor of FAK decreases growth of human pancreatic cancer. Cell Cycle 8, 2435–2443 (2009).

    CAS  PubMed  Google Scholar 

  162. Stokes, J. B. et al. Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. Mol. Cancer Ther. 10, 2135–2145 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Zheng, D. et al. A novel strategy to inhibit FAK and IGF-1R decreases growth of pancreatic cancer xenografts. Mol. Carcinog. 49, 200–209 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Zhang, J., He, D.-H., Zajac-Kaye, M. & Hochwald, S. N. A small molecule FAK kinase inhibitor, GSK2256098, inhibits growth and survival of pancreatic ductal adenocarcinoma cells. Cell Cycle 13, 3143–3149 (2014).

    PubMed  PubMed Central  Google Scholar 

  165. Begum, A. et al. The extracellular matrix and focal adhesion kinase signaling regulate cancer stem cell function in pancreatic ductal adenocarcinoma. PLoS One 12, e0180181 (2017).

    PubMed  PubMed Central  Google Scholar 

  166. Vannini, A. et al. αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion. Proc. Natl Acad. Sci. USA 116, 20141–20150 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Serrels, A. et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell 163, 160–173 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Serrels, B. et al. IL-33 and ST2 mediate FAK-dependent antitumor immune evasion through transcriptional networks. Sci. Signal. 10, eaan8355 (2017).

    PubMed  PubMed Central  Google Scholar 

  169. Shi, Y.-K., Hao, X. Z., Xing, P., Hu, B. & Sun, Y. Phase I study of safety and pharmacokinetics for CT-707 in ALK-positive advanced non-small cell lung cancer. Ann. Oncol. 28, x132 (2017).

  170. Mak, G. et al. A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours. Br. J. Cancer 120, 975–981 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Wang-Gillam, A. et al. Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer. J. Clin. Oncol. 36, 380–380 (2018).

    Google Scholar 

  172. Principe, D. R. et al. TGF-β: duality of function between tumor prevention and carcinogenesis. J. Natl. Cancer Inst. 106, djt369 (2014).

    PubMed  PubMed Central  Google Scholar 

  173. Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Principe, D. R. et al. TGFb blockade augments PD-1 inhibition to promote T-cell–mediated regression of pancreatic cancer. Mol. Cancer Ther. 18, 613–620 (2019).

    CAS  PubMed  Google Scholar 

  175. Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).

    CAS  PubMed  Google Scholar 

  176. Soares, K. C. et al. TGF-β blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner. Oncotarget 6, 43005–43015 (2015).

    PubMed  PubMed Central  Google Scholar 

  177. Melisi, D. et al. Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer. Br. J. Cancer 119, 1208–1214 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Melisi, D. et al. A phase Ib dose-escalation and cohort-expansion study of safety and activity of the transforming growth factor (TGF) β receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer. J. Clin. Oncol. 37, 4124–4124 (2019).

    Google Scholar 

  179. Taylor, N. P. Lilly puts two-thirds of midphase cancer pipeline up for sale in major shake-up of R&D priorities. FierceBiotech https://www.fiercebiotech.com/biotech/lilly-puts-two-thirds-mid-phase-cancer-pipeline-up-for-sale-major-shake-up-r-d-priorities (2017).

  180. Akhurst, R. J. Targeting TGF-β signaling for therapeutic gain. Cold Spring Harb. Perspect. Biol. 9, a022301 (2017).

    PubMed  PubMed Central  Google Scholar 

  181. Ravi, R. et al. Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat. Commun. 9, 741 (2018).

    PubMed  PubMed Central  Google Scholar 

  182. Diop-Frimpong, B., Chauhan, V. P., Krane, S., Boucher, Y. & Jain, R. K. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc. Natl Acad. Sci. USA 108, 2909–2914 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Cohn, R. D. et al. Angiotensin II type 1 receptor blockade attenuates TGF-β-induced failure of muscle regeneration in multiple myopathic states. Nat. Med. 13, 204–210 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Chauhan, V. P. et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 4, 1–11 (2013).

    Google Scholar 

  185. Murphy, J. E. et al. Total neoadjuvant therapy with FOLFIRINOX in combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer. JAMA Oncol. 5, 1020 (2019).

    PubMed  PubMed Central  Google Scholar 

  186. Corbett, T. H. et al. Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice. Cancer Res. 44, 717–726 (1984).

    CAS  PubMed  Google Scholar 

  187. Bhadury, J., López, M. D., Muralidharan, S. V., Nilsson, L. M. & Nilsson, J. A. Identification of tumorigenic and therapeutically actionable mutations in transplantable mouse tumor cells by exome sequencing. Oncogenesis 2, e44 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Raphael, B. J. et al. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32, 185–203 (2017).

    Google Scholar 

  189. Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).

    CAS  PubMed  Google Scholar 

  190. Soares, K. C. et al. A preclinical murine model of hepatic metastases. J. Vis. Exp. https://doi.org/10.3791/51677 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

W.J.H. is the recipient of an ASCO Young Investigator Award and an AACR Incyte Immuno-Oncology Research Fellowship, and is supported by NIH T32CA00971-38.

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Correspondence to Lei Zheng.

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W.J.H. could potentially receive patent-related royalties from Rodeo Therapeutics. E.M.J. receives commercial research grants from Aduro Biotech, Amgen, Bristol–Myers Squibb, Corvus and Hertix, has ownership interest in Aduro Biotech, and is a consultant and/or advisory board member for Achilles Therapeutics, Adaptive Biotechnologies, CStone Pharmaceuticals, Dragonfly Therapeutics, Genocea and the Parker Institute for Cancer Immunotherapy. She is a member of the National Cancer Advisory Board and the Chief Medical Advisor for the Lustgarten Foundation. L.Z. receives grant support from Amgen, Bristol–Myers Squibb, Halozyme, Inxmed, iTeos, Merck and NovaRock, and received royalties for licensing GVAX to Aduro Biotech. He is a paid consultant and/or advisory board member for Akrevia, Alphamab, Biosion, Datarevive, Foundation Medicine, Fusun Biopharmaceutical, Mingruzhiyao, NovaRock and Sound Biologics, and holds shares in Alphamab and Mingruzhiyao.

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Ho, W.J., Jaffee, E.M. & Zheng, L. The tumour microenvironment in pancreatic cancer — clinical challenges and opportunities. Nat Rev Clin Oncol 17, 527–540 (2020). https://doi.org/10.1038/s41571-020-0363-5

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