JAK-STAT-mediated chronic inflammation impairs cytotoxic T lymphocyte activation to decrease anti-PD-1 immunotherapy efficacy in pancreatic cancer

OncoImmunology

Volumn 6, Issue 3, 2017, Pages

  Lu, Chunwan ^a,b   Talukder, Asif ^a   Savage, Natasha M ^a   Singh, Nagendra ^a   Liu, Kebin ^a,b  

^a MEDICAL COLLEGE OF GEORGIA   (United States)

^b VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

Cytotoxic T Lymphocytes; FasL; PD 1; PD L1; Ruxolitinib; STAT1; STAT3

Indexed keywords

CD11B ANTIGEN; CD3 ANTIGEN; CELL SURFACE PROTEIN; CYTOKINE; GAMMA INTERFERON; JANUS KINASE; PROGRAMMED DEATH 1 RECEPTOR; RUXOLITINIB; STAT PROTEIN; STAT1 PROTEIN; STAT3 PROTEIN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CANCER INHIBITION; CELL INFILTRATION; CELL PROLIFERATION; CELL VIABILITY; CHRONIC INFLAMMATION; CONTROLLED STUDY; CYTOTOXICITY; FLOW CYTOMETRY; GENE EXPRESSION; IMMUNE RESPONSE; IMMUNOHISTOCHEMISTRY; MOUSE; MTT ASSAY; NONHUMAN; PANCREAS CANCER; PROTEIN EXPRESSION; REAL TIME POLYMERASE CHAIN REACTION; T LYMPHOCYTE ACTIVATION; TH1 CELL; THYMIDINE INCORPORATION ASSAY; TUMOR GROWTH; TUMOR MICROENVIRONMENT; UPREGULATION; WESTERN BLOTTING;

EID: 85016620961     PISSN: 21624011     EISSN: 2162402X     Source Type: Journal    
DOI: 10.1080/2162402X.2017.1291106     Document Type: Article

References (70)

1. Seufferlein T, Bachet JB, Van Cutsem E, Rougier P. Pancreatic adenocarcinoma:ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 Suppl 7:vii33-vii40; PMID:22997452; http://dx.doi.org/10.1093/annonc/mds224
2. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369:1691-1703; PMID:24131140; http://dx.doi.org/10.1056/NEJMoa1304369
3. Ho MY, Kennecke HF, Renouf DJ, Cheung WY, Lim HJ, Gill S. Defining eligibility of FOLFIRINOX for first-line metastatic pancreatic adenocarcinoma (MPC) in the province of British Columbia:A population-based retrospective study. J Clin Oncol 30, 2012 (suppl; abstr e14588); PMID:26165420; http://dx.doi.org/10.1097/COC.0000000000000205
4. Rahma OE, Duffy A, Liewehr DJ, Steinberg SM, Greten TF. Second-line treatment in advanced pancreatic cancer:A comprehensive analysis of published clinical trials. Ann Oncol 2013; 24:1972-1979; PMID:23670093; http://dx.doi.org/10.1093/annonc/mdt166
5. Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer:Past, present, and future. J Clin Invest 2015; 125:3384-3391; PMID:26325035; http://dx.doi.org/10.1172/JCI80011
6. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366:2455-2465; PMID:22658128; http://dx.doi.org/10.1056/NEJMoa1200694
7. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366:2443-2454; PMID:22658127; http://dx.doi.org/10.1056/NEJMoa1200690
8. Winograd R, Byrne KT, Evans RA, Odorizzi PM, Meyer AR, Bajor DL, Clendenin C, Stanger BZ, Furth EE, Wherry EJ, et al. Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. Cancer Immunol Res 2015; 3:399-3411; PMID:25678581; http://dx.doi.org/10.1158/2326-6066.CIR-14-0215
9. Hutcheson J, Balaji U, Porembka MR, Wachsmann MB, McCue PA, Knudsen ES, Witkiewicz AK. Immunologic and metabolic features of pancreatic ductal adenocarcinoma define prognostic subtypes of disease. Clin Cancer Res 2016; 22:3606-3617; PMID:26858311; http://dx.doi.org/10.1158/1078-0432.CCR-15-1883
10. Luheshi NM, Coates-Ulrichsen J, Harper J, Mullins S, Sulikowski MG, Martin P, Brown L, Lewis A, Davies G, Morrow M, et al. Transformation of the tumour microenvironment by a CD40 agonist antibody correlates with improved responses to PD-L1 blockade in a mouse orthotopic pancreatic tumour model. Oncotarget 2016; 7:18508-18520; PMID:26918344; http://dx.doi.org/10.18632/oncotarget.7610
11. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer:Crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 2013; 13:759-771; PMID:24154716; http://dx.doi.org/10.1038/nrc3611
12. Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol 2014; 15:e493-e503; PMID:25281468; http://dx.doi.org/10.1016/S1470-2045(14)70263-3
13. Haruki K, Shiba H, Shirai Y, Horiuchi T, Iwase R, Fujiwara Y, Furukawa K, Misawa T, Yanaga K. The C-reactive protein to albumin ratio predicts long-term outcomes in patients with pancreatic cancer after pancreatic resection. World J Surg 2016; 40(9):2254-2260; PMID:26956901; http://dx.doi.org/10.1007/s00268-016-3491-4
14. Jamieson NB, Denley SM, Logue J, MacKenzie DJ, Foulis AK, Dickson EJ, Imrie CW, Carter R, McKay CJ, McMillan DC. A prospective comparison of the prognostic value of tumor- and patient-related factors in patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma. Ann Surg Oncol 2011; 18:2318-2328; PMID:21267785; http://dx.doi.org/10.1245/s10434-011-1560-3
15. Villarino AV, Kanno Y, Ferdinand JR, O'Shea JJ. Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol 2015; 194:21-27; PMID:25527793; http://dx.doi.org/10.4049/jimmunol.1401867
16. Hirahara K, Onodera A, Villarino AV, Bonelli M, Sciume G, Laurence A, Sun HW, Brooks SR, Vahedi G, Shih HY, et al. Asymmetric action of STAT transcription factors drives transcriptional outputs and cytokine specificity. Immunity 2015; 42:877-889; PMID:25992861; http://dx.doi.org/10.1016/j.immuni.2015.04.014
17. Schwartz DM, Bonelli M, Gadina M, O'Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol 2016; 12:25-36; PMID:26633291; http://dx.doi.org/10.1038/nrrheum.2015.167
18. Wan CK, Andraski AB, Spolski R, Li P, Kazemian M, Oh J, Samsel L, Swanson PA, 2nd, McGavern DB, Sampaio EP, et al. Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells. Proc Natl Acad Sci U S A 2015; 112:9394-9399; PMID:26170288; http://dx.doi.org/10.1073/pnas.1511711112
19. Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G. Type I interferons in anticancer immunity. Nat Rev Immunol 2015; 15:405-414; PMID:26027717; http://dx.doi.org/10.1038/nri3845
20. gamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001; 410:1107-1111; PMID:11323675; http://dx.doi.org/10.1038/35074122
21. gamma induces DNA methylation-silenced GPR109A expression via pSTAT1/p300 and H3K18 acetylation in colon cancer. Cancer Immunol Res 2015; 3(7):795-805; PMID:25735954; http://dx.doi.org/10.1158/2326-6066.CIR-14-0164
22. Parker BS, Rautela J, Hertzog PJ. Antitumour actions of interferons:Implications for cancer therapy. Nat Rev Cancer 2016; 16:131-144; PMID:26911188; http://dx.doi.org/10.1038/nrc.2016.14
23. Cheon H, Borden EC, Stark GR. Interferons and their stimulated genes in the tumor microenvironment. Semin Oncol 2014; 41:156-173; PMID:24787290; http://dx.doi.org/10.1053/j.seminoncol.2014.02.002
24. Gracias DT, Stelekati E, Hope JL, Boesteanu AC, Doering TA, Norton J, Mueller YM, Fraietta JA, Wherry EJ, Turner M, et al. The microRNA miR-155 controls CD8(+) T cell responses by regulating interferon signaling. Nat Immunol 2013; 14:593-602; PMID:23603793; http://dx.doi.org/10.1038/ni.2576
25. Andraos R, Qian Z, Bonenfant D, Rubert J, Vangrevelinghe E, Scheufler C, Marque F, Régnier CH, De Pover A, Ryckelynck H, et al. Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent. Cancer Discov 2012; 2:512-523; PMID:22684457; http://dx.doi.org/10.1158/2159-8290.CD-11-0324
26. Crescenzo R, Abate F, Lasorsa E, Tabbo F, Gaudiano M, Chiesa N, Di Giacomo F, Spaccarotella E, Barbarossa L, Ercole E, et al. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell 2015; 27:516-532; PMID:25873174; http://dx.doi.org/10.1016/j.ccell.2015.03.006
27. Losdyck E, Hornakova T, Springuel L, Degryse S, Gielen O, Cools J, Constantinescu SN, Flex E, Tartaglia M, Renauld JC, et al. Distinct acute lymphoblastic leukemia (ALL)-associated Janus kinase 3 (JAK3) mutants exhibit different cytokine-receptor requirements and JAK inhibitor specificities. J Biol Chem 2015; 290:29022-29034; PMID:26446793; http://dx.doi.org/10.1074/jbc.M115.670224
28. Quintas-Cardama A, Verstovsek S. Molecular pathways:Jak/STAT pathway:Mutations, inhibitors, and resistance. Clin Cancer Res 2013; 19:1933-1940; PMID:23406773; http://dx.doi.org/10.1158/1078-0432.CCR-12-0284
29. Gadina M, Schwartz DM, O'Shea JJ. Editorial:decernotinib:A next-generation jakinib. Arthritis Rheumatol 2016; 68:31-34; PMID:26479275; http://dx.doi.org/10.1002/art.39463
30. Ju W, Zhang M, Wilson KM, Petrus MN, Bamford RN, Zhang X, Guha R, Ferrer M, Thomas CJ, Waldmann TA. Augmented efficacy of brentuximab vedotin combined with ruxolitinib and/or Navitoclax in a murine model of human Hodgkin's lymphoma. Proc Natl Acad Sci U S A 2016; 113:1624-1629; PMID:26811457; http://dx.doi.org/10.1073/pnas.1524668113
31. Maude SL, Dolai S, Delgado-Martin C, Vincent T, Robbins A, Selvanathan A, Ryan T, Hall J, Wood AC, Tasian SK, et al. Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia. Blood 2015; 125:1759-1767; PMID:25645356; http://dx.doi.org/10.1182/blood-2014-06-580480
32. Silvennoinen O, Hubbard SR. Targeting the inactive conformation of JAK2 in hematological malignancies. Cancer Cell 2015; 28:1-2; PMID:26175407; http://dx.doi.org/10.1016/j.ccell.2015.06.010
33. Zhang M, Mathews Griner LA, Ju W, Duveau DY, Guha R, Petrus MN, Wen B, Maeda M, Shinn P, Ferrer M, et al. Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2-dependent adult T-cell leukemia. Proc Natl Acad Sci U S A 2015; 112:12480-12485; PMID:26396258; http://dx.doi.org/10.1073/pnas.1516208112
34. Britschgi A, Andraos R, Brinkhaus H, Klebba I, Romanet V, Muller U, Murakami M, Radimerski T, Bentires-Alj M. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade:A rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell 2012; 22:796-811; PMID:23238015; http://dx.doi.org/10.1016/j.ccr.2012.10.023
35. gamma R signaling mediates alloreactive T-cell trafficking and GVHD. Blood 2012; 120:4093-4103; PMID:22972985; http://dx.doi.org/10.1182/blood-2012-01-403196
36. gamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. J Exp Med 2006; 203:1391-1397; PMID:16717119; http://dx.doi.org/10.1084/jem.20060436
37. Wormann SM, Diakopoulos KN, Lesina M, Algul H. The immune network in pancreatic cancer development and progression. Oncogene 2014; 33:2956-2967; PMID:23851493; http://dx.doi.org/10.1038/onc.2013.257
38. Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Kloppel G, Yoshimura A, Reindl W, Sipos B, Akira S, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 2011; 19:456-469; PMID:21481788; http://dx.doi.org/10.1016/j.ccr.2011.03.009
39. Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells:role of STAT3 in the tumour microenvironment. Nat Rev Immunol 2007; 7:41-51; PMID:17186030; http://dx.doi.org/10.1038/nri1995
40. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity:A leading role for STAT3. Nat Rev Cancer 2009; 9:798-809; PMID:19851315; http://dx.doi.org/10.1038/nrc2734
41. Corcoran RB, Contino G, Deshpande V, Tzatsos A, Conrad C, Benes CH, Levy DE, Settleman J, Engelman JA, Bardeesy N. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res 2011; 71:5020-5029; PMID:21586612; http://dx.doi.org/10.1158/0008-5472.CAN-11-0908
42. Fukuda A, Wang SC, Morris, JPt, Folias AE, Liou A, Kim GE, Akira S, Boucher KM, Firpo MA, Mulvihill SJ, et al. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 2011; 19:441-455; PMID:21481787; http://dx.doi.org/10.1016/j.ccr.2011.03.002
43. Kroemer G, Galluzzi L, Zitvogel L. STAT3 inhibition for cancer therapy:Cell-autonomous effects only? Oncoimmunology 2016; 5:e1126063; PMID:27467938; http://dx.doi.org/10.1080/2162402X.2015.1126063
44. Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J, Fowler N, Zhou T, Schmidt J, Jo M, et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci Transl Med 2015; 7:314ra185; PMID:26582900; http://dx.doi.org/10.1126/scitranslmed.aac5272
45. Yang H, Yamazaki T, Pietrocola F, Zhou H, Zitvogel L, Ma Y, Kroemer G. STAT3 inhibition enhances the therapeutic efficacy of immunogenic chemotherapy by stimulating Type 1 interferon production by cancer cells. Cancer Res 2015; 75:3812-3822; PMID:26208907; http://dx.doi.org/10.1158/0008-5472.CAN-15-1122
46. Gore J, Craven KE, Wilson JL, Cote GA, Cheng M, Nguyen HV, Cramer HM, Sherman S, Korc M. TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis. Oncotarget 2015; 6:7504-7521; PMID:25762644; http://dx.doi.org/10.18632/oncotarget.3233
47. Craven KE, Gore J, Wilson JL, Korc M. Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes. Oncotarget 2016; 7:323-341; PMID:26586478; http://dx.doi.org/10.18632/oncotarget.6345
48. Patel MR, Jacobson BA, Ji Y, Drees J, Tang S, Xiong K, Wang H, Prigge JE, Dash AS, Kratzke AK, et al. Vesicular stomatitis virus expressing interferon-beta is oncolytic and promotes antitumor immune responses in a syngeneic murine model of non-small cell lung cancer. Oncotarget 2015; 6:33165-33177; PMID:26431376; http://dx.doi.org/10.18632/oncotarget.5320
49. Yang S, Luo C, Gu Q, Xu Q, Wang G, Sun H, Qian Z, Tan Y, Qin Y, Shen Y, et al. Activating JAK1 mutation may predict the sensitivity of JAK-STAT inhibition in hepatocellular carcinoma. Oncotarget 2015; 7(5):5461-5469; PMID:26701727; http://dx.doi.org/10.18632/oncotarget.6684
50. An HJ, Choi EK, Kim JS, Hong SW, Moon JH, Shin JS, Ha SH, Kim KP, Hong YS, Lee JL, et al. INCB018424 induces apoptotic cell death through the suppression of pJAK1 in human colon cancer cells. Neoplasma 2014; 61:56-62; PMID:24195509; http://dx.doi.org/10.4149/neo_2014_009
51. Hurwitz HI, Uppal N, Wagner SA, Bendell JC, Beck JT, Wade SM, 3rd, Nemunaitis JJ, Stella PJ, Pipas JM, Wainberg ZA, et al. Randomized, double-blind, phase II study of Ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed. J Clin Oncol 2015; 33:4039-4047; PMID:26351344; http://dx.doi.org/10.1200/JCO.2015.61.4578
52. Ghoreschi K, Laurence A, O'Shea JJ. Janus kinases in immune cell signaling. Immunol Rev 2009; 228:273-287; PMID:19290934; http://dx.doi.org/10.1111/j.1600-065X.2008.00754.x
53. Purwar R, Schlapbach C, Xiao S, Kang HS, Elyaman W, Jiang X, Jetten AM, Khoury SJ, Fuhlbrigge RC, Kuchroo VK, et al. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 2012; 18:1248-1253; PMID:22772464; http://dx.doi.org/10.1038/nm.2856
54. Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K, Yoshioka Y, Baba T, Konishi I, Mandai M. IFN-gamma from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br J Cancer 2015; 112:1501-1509; PMID:25867264; http://dx.doi.org/10.1038/bjc.2015.101
55. Yu CR, Dambuza IM, Lee YJ, Frank GM, Egwuagu CE. STAT3 regulates proliferation and survival of CD8+ T cells:Enhances effector responses to HSV-1 infection, and inhibits IL-10+ regulatory CD8+ T cells in autoimmune uveitis. Mediators Inflamm 2013; 2013:359674; PMID:24204098; http://dx.doi.org/10.1155/2013/359674
56. Spoerl S, Mathew NR, Bscheider M, Schmitt-Graeff A, Chen S, Mueller T, Verbeek M, Fischer J, Otten V, Schmickl M, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 2014; 123:3832-3842; PMID:24711661; http://dx.doi.org/10.1182/blood-2013-12-543736
57. Heine A, Held SA, Daecke SN, Wallner S, Yajnanarayana SP, Kurts C, Wolf D, Brossart P. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 2013; 122:1192-1202; PMID:23770777; http://dx.doi.org/10.1182/blood-2013-03-484642
58. Spolski R, Leonard WJ. Interleukin-21:A double-edged sword with therapeutic potential. Nat Rev Drug Discov 2014; 13:379-395; PMID:24751819; http://dx.doi.org/10.1038/nrd4296
59. Phillips T, Simmons P, Inzunza HD, Cogswell J, Novotny J, Jr., Taylor C, Zhang X. Development of an automated PD-L1 immunohistochemistry (IHC) assay for non-small cell lung cancer. Appl Immunohistochem Mol Morphol 2015; 23:541-549; PMID:26317305; http://dx.doi.org/10.1097/PAI.0000000000000256
60. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, Rietz C, Flies DB, Lau JS, Zhu G, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 2005; 65:1089-1096; PMID:15705911
61. Fridman JS, Scherle PA, Collins R, Burn TC, Li Y, Li J, Covington MB, Thomas B, Collier P, Favata MF, et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis:preclinical characterization of INCB028050. J Immunol 2010; 184:5298-5307; PMID:20363976; http://dx.doi.org/10.4049/jimmunol.0902819
62. Stark GR, Darnell JE, Jr. The JAK-STAT pathway at twenty. Immunity 2012; 36:503-514; PMID:22520844; http://dx.doi.org/10.1016/j.immuni.2012.03.013
63. Sutherland AP, Joller N, Michaud M, Liu SM, Kuchroo VK, Grusby MJ. IL-21 promotes CD8+ CTL activity via the transcription factor T-bet. J Immunol 2013; 190:3977-3984; PMID:23479229; http://dx.doi.org/10.4049/jimmunol.1201730
64. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med 2013; 5:200ra116; PMID:23986400; http://dx.doi.org/10.1126/scitranslmed.3006504
65. Bellucci R, Martin A, Bommarito D, Wang K, Hansen SH, Freeman GJ, Ritz J. Interferon-gamma-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression. Oncoimmunology 2015; 4:e1008824; PMID:26155422; http://dx.doi.org/10.1080/2162402X.2015.1008824
66. Herbeuval JP, Lelievre E, Lambert C, Dy M, Genin C. Recruitment of STAT3 for production of IL-10 by colon carcinoma cells induced by macrophage-derived IL-6. J Immunol 2004; 172:4630-4636; PMID:15034082; http://dx.doi.org/10.4049/jimmunol.172.7.4630
67. Kida H, Ihara S, Kumanogoh A. Involvement of STAT3 in immune evasion during lung tumorigenesis. Oncoimmunology 2013; 2:e22653; PMID:23482587; http://dx.doi.org/10.4161/onci.22653
68. Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, Mikse OR, Cherniack AD, Beauchamp EM, Pugh TJ, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov 2013; 3:1355-1363; PMID:24078774; http://dx.doi.org/10.1158/2159-8290.CD-13-0310
69. Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, Gandhi L, Redig AJ, Rodig SJ, Asahina H, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun 2016; 7:10501; PMID:26883990; http://dx.doi.org/10.1038/ncomms10501
70. Wang Y, Zhang Y, Yang J, Ni X, Liu S, Li Z, Hodges SE, Fisher WE, Brunicardi FC, Gibbs RA, et al. Genomic sequencing of key genes in mouse pancreatic cancer cells. Curr Mol Med 2012; 12:331-341; PMID:22208613; http://dx.doi.org/10.2174/156652412799218868