REFERENCES
2. Madorsky Rowdo FP, Baron A, Urrutia M, Mordoh J. Immunotherapy in cancer: a combat between tumors and the immune system; you win some, you lose some. Front Immunol 2015;6:127.
3. Guler I, Askan G, Klostergaard J, Sahin IH. Precision medicine for metastatic colorectal cancer: an evolving era. Expert Rev Gastroenterol Hepatol 2019:1-13.
4. Sahin IH. Precision medicine for gastrointestinal cancers: a conference report. Future Sci 2020;6:FSO478.
5. Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 2019;381:317-27.
6. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509-20.
7. Cloyd JM, Katz MH, Wang H, Cuddy A, You YN. Clinical and genetic implications of DNA mismatch repair deficiency in patients with pancreatic ductal adenocarcinoma. JAMA surg 2017;152:1086-8.
8. Sahin I, Askan G, Hu Z, O’Reilly E. Immunotherapy in pancreatic ductal adenocarcinoma: an emerging entity? Ann Oncol 2017;28:2950-61.
9. Le DT, Picozzi VJ, Ko AH, Wainberg ZA, Kindler H, et al. Results from a phase IIb, randomized, multicenter study of GVAX pancreas and CRS-207 compared with chemotherapy in adults with previously treated metastatic pancreatic adenocarcinoma (ECLIPSE study). Clin Cancer Res 2019;25:5493-502.
10. O’Reilly EM, Oh DY, Dhani N, Renouf DJ, Lee MA, et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol 2019;5:1431-8.
11. Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015;518:495.
12. Hu ZI, Shia J, Stadler ZK, Varghese AM, Capanu M, et al. Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations. Clin Cancer Res 2018;24:1326-36.
13. Uzunparmak B, Sahin IH. Pancreatic cancer microenvironment: a current dilemma. Clin Transl Med 2019;8:2.
14. Bachem MG, Schünemann M, Ramadani M, Siech M, Beger H, et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterol 2005;128:907-21.
15. Apte MV, Haber PS, Darby SJ, Rodgers SC, McCaughan GW, et al. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut 1999;44:534-41.
16. Apte M, Park S, Phillips P, Santucci N, Goldstein D, et al. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 2004;29:179-87.
17. Bailey JM, Swanson BJ, Hamada T, Eggers JP, Singh PK, et al. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res 2008;14:5995-6004.
18. Spivak-Kroizman TR, Hostetter G, Posner R, Aziz M, Hu C, et al. Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer. Cancer Res 2013;73:3235-47.
19. Li X, Wang Z, Ma Q, Xu Q, Liu H, et al. Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer. Clin Cancer Res 2014;20:4326-38.
20. Sahin IH, Shama MA, Tanaka M, Abbruzzese JL, Curley SA, et al. Association of diabetes and perineural invasion in pancreatic cancer. Cancer Med 2012;1:357-62.
21. Bailey JM, Mohr AM, Hollingsworth MA. Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene 2009;28:3513-25.
22. Ene-Obong A, Clear AJ, Watt J, Wang J, Fatah R, et al. Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology 2013;145:1121-32.
23. Ostrand-Rosenberg S, Sinha P, Beury DW, Clements VK. Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression. Semin Cancer Biol 2012;22:275-81.
24. 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 2006;12:5423-34.
25. Vizio B, Novarino A, Giacobino A, Cristiano C, Prati A, et al. Potential plasticity of T regulatory cells in pancreatic carcinoma in relation to disease progression and outcome. Exp Ther Med 2012;4:70-8.
26. Zhang Y, Lazarus J, Steele NG, Yan W, Lee HJ, et al. Regulatory T-cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis. Cancer discov 2020;10:422-39.
27. Facciabene A, Motz GT, Coukos G. T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res 2012;72:2162-71.
28. Chen ML, Pittet MJ, Gorelik L, Flavell RA, Weissleder R, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals in vivo. Proc Natl Acad Sci U S A 2005;102:419-24.
29. Wang RF. CD8+ regulatory T cells, their suppressive mechanisms, and regulation in cancer. Human Immunol 2008;69:811-4.
30. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008;322:271-5.
31. Chaput N, Darrasse-Jèze G, Bergot AS, Cordier C, Ngo-Abdalla S, et al. Regulatory T cells prevent CD8 T cell maturation by inhibiting CD4 Th cells at tumor sites. J Immunol 2007;179:4969-78.
32. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Rev Immunol 2009;9:162-74.
33. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 2009;182:4499-506.
34. Marigo I, Dolcetti L, Serafini P, Zanovello P, Bronte V. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev 2008;222:162-79.
35. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 2007;67:4507-13.
36. Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer cell 2012;21:822-35.
37. Ostrand-Rosenberg S. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer immunol immunother 2010;59:1593-600.
38. Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 2014;74:5057-69.
39. Daurkin I, Eruslanov E, Stoffs T, Perrin GQ, Algood C, et al. Tumor-associated macrophages mediate immunosuppression in the renal cancer microenvironment by activating the 15-lipoxygenase-2 pathway. Cancer Res 2011;71:6400-9.
40. Liu J, Zhang N, Li Q, Zhang W, Ke F, et al. Tumor-associated macrophages recruit CCR6+ regulatory T cells and promote the development of colorectal cancer via enhancing CCL20 production in mice. PLoS One 2011;6:e19495.
41. Royal RE, Levy C, Turner K, Mathur A, Hughes M, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010;33:828-33.
42. Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, et al. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-65.
43. Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 2015;21:4286-93.
44. O’Reilly EM, Oh DY, Dhani N, Renouf DJ, Lee MA, et al. A randomized phase 2 study of durvalumab monotherapy and in combination with tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): ALPS study. J Clin Oncol 2018;36:217.
45. Kamath SD, Kalyan A, Kircher S, Nimeiri H, Fought AJ, et al. Ipilimumab and gemcitabine for advanced pancreatic cancer: a phase Ib study. Oncologist 2020;25:e808-15.
46. Aglietta M, Barone C, Sawyer M, Moore J, Miller WH Jr, et al. A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. Ann Oncol 2014;25:1750-5.
47. Weiss GJ, Blaydorn L, Beck J, Bornemann-Kolatzki K, Urnovitz H, et al. Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma. Invest New Drugs 2018;36:96-102.
48. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felipet E, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018;378:2078-92.
49. Sahin IH, Akce M, Alese O, Shaib W, Lesinski GB, et al. Immune checkpoint inhibitors for the treatment of MSI-H/MMR-D colorectal cancer and a perspective on resistance mechanisms. Br J cancer 2019;121:809-18.
50. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-13.
51. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: Results from the phase II KEYNOTE-158 study. J Clin Oncol 2020;38:1-10.
52. Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, 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 2015;33:4284.
53. Madden JI. Infinity reports update from phase 2 study of saridegib plus gemcitabine in patients with metastatic pancreatic cancer. Available from: https://www.businesswire.com/news/home/20120127005146/en/Infinity-Reports-Update-Phase-2-Study-Saridegib. [Last accessed on 1 Sep 2020].
54. Hingorani SR, Zheng L, Bullock AJ, Seery TE, Harris WP, 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 2018;36:359-66.
55. Tempero MA, Van Cutsem E, Sigal D, Oh DY, Fazio N, et al. HALO 109-301: a randomized, double-blind, placebo-controlled, phase 3 study of pegvorhyaluronidase alfa (PEGPH20)+ nab-paclitaxel/gemcitabine (AG) in patients (pts) with previously untreated hyaluronan (HA)-high metastatic pancreatic ductal adenocarcinoma (mPDA). J Clin Oncol 2020;38:638.
56. Porembka MR, Mitchem JB, Belt BA, Hsieh CS, Lee HM, et al. Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol Immunother 2012;61:1373-85.
57. Mace TA, Ameen Z, Collins A, Wojcik S, Mair M, et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer res 2013;73:3007-18.
58. Panni RZ, Sanford DE, Belt BA, Mitchem JB, Worley LA, et al. Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer. Cancer Immunol Immunother 2014;63:513-28.
59. Papadopoulos KP, Naing A, Infante JR, Autio KA, Ott PA, et al. Anti-tumor activity of PEGylated human IL-10 (AM0010) in patients with pancreatic or colorectal cancer. J Clin Oncol 2016;34:3082.
60. Naing A, Infante JR, Papadopoulos KP, Chan IH, Shen C, et al. PEGylated IL-10 (Pegilodecakin) induces systemic immune activation, CD8+ T cell invigoration and polyclonal T cell expansion in cancer patients. Cancer Cell 2018;34:775-91.e3.
61. Hecht JR, Lonardi S, Bendell JC, SIM HW, Macarulla T, et al. Randomized phase III study of FOLFOX alone and with pegilodecakin as second-line therapy in patients with metastatic pancreatic cancer (SEQUOIA). J Clin Oncol 2020;38:637.
62. Le DT, Picozzi VJ, Ko AH, Wainberg ZA, Kindler H, et al. Results from a phase 2b, randomized, multicenter study of GVAX pancreas and CRS-207 compared to chemotherapy in adults with previously-treated metastatic pancreatic adenocarcinoma (ECLIPSE Study). J Clin Oncol 2017;35:345.
63. Sahin IH, Iacobuzio-Donahue CA, O’Reilly EM. Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy. Expert Opin Ther Targets 2016;20:341-59.
64. Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A 2013;110:20212-7.
65. Halama N, Pruefer U, Frömming A, Beyer D, Eulberg D, et al. Experience with CXCL12 inhibitor NOX-A12 plus pembrolizumab in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer. J Clin Oncol 2019;37:e14143.
66. Bockorny B, Semenisty V, Macarulla T, Borazanci E, Wolpin BM, et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat Med 2020;26:878-85.
67. Ternyila D. Cabiralizumab misses primary end point in phase II trial of advanced pancreatic cancer. Available from: https://www.targetedonc.com/view/cabiralizumab-misses-primary-end-point-in-phase-ii-trial-of-advanced-pancreatic-cancer. [Last acccessed on 1 Sep 2020].
68. Chow LQM, Gainor JF, Lakhani NJ, Lee KW, Chung HC, et al. A phase I study of ALX148, a CD47 blocker, in combination with standard anticancer antibodies and chemotherapy regimens in patients with advanced malignancy. J Clin Oncol 2020;38:3056.