The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment

Journal of Experimental Medicine

Volumn 214, Issue 2, 2017, Pages 381-400

  Williams, Jason B ^a   Horton, Brendan L ^a   Zheng, Yan ^a   Duan, Yukan ^b   Powell, Jonathan D ^c   Gajewski, Thomas F ^a  

^a UNIVERSITY OF CHICAGO   (United States)

^b JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c JOHNS HOPKINS UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD137 LIGAND; CD8 ANTIGEN; CELL SURFACE PROTEIN; EARLY GROWTH RESPONSE FACTOR 2; GAMMA INTERFERON; INTERLEUKIN 2; LAG 3 PROTEIN; TUMOR ANTIGEN; TUMOR NECROSIS FACTOR; UNCLASSIFIED DRUG; CD137 ANTIGEN; CD223 ANTIGEN; EGR2 PROTEIN, MOUSE; FINGOLIMOD; LEUKOCYTE ANTIGEN; MONOCLONAL ANTIBODY;

ANIMAL EXPERIMENT; ANTIGEN SPECIFICITY; ARTICLE; CD8+ T LYMPHOCYTE; CONTROLLED STUDY; CYTOKINE PRODUCTION; FEMALE; GENE EXPRESSION PROFILING; IN VITRO STUDY; IN VIVO STUDY; LYMPHOID ORGAN; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; T LYMPHOCYTE SUBPOPULATION; TARGET CELL; TUMOR ASSOCIATED LEUKOCYTE; TUMOR MICROENVIRONMENT; TUMOR REGRESSION; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOSYNTHESIS; C57BL MOUSE; IMMUNOLOGY; PHYSIOLOGY;

ANIMALS; ANTIBODIES, MONOCLONAL; ANTIGENS, CD; ANTIGENS, CD137; ANTIGENS, NEOPLASM; CD8-POSITIVE T-LYMPHOCYTES; EARLY GROWTH RESPONSE PROTEIN 2; FEMALE; FINGOLIMOD HYDROCHLORIDE; INTERFERON-GAMMA; INTERLEUKIN-2; LYMPHOCYTES, TUMOR-INFILTRATING; MICE; MICE, INBRED C57BL; TUMOR MICROENVIRONMENT;

EID: 85012248846     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20160485     Document Type: Article

References (69)

1. Ahmadzadeh, M., L.A. Johnson, B. Heemskerk, J.R. Wunderlich, M.E. Dudley, D.E. White, and S.A. Rosenberg. 2009. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 114:1537-1544. http://dx.doi.org/10.1182/blood-2008-12-195792
2. + T cells in metastases from melanoma patients. J. Clin. Invest. 121:2350-2360. http://dx.doi.org/10.1172/JCI46102
3. Baitsch, L., A. Legat, L. Barba, S.A. Fuertes Marraco, J.-P. Rivals, P. Baumgaertner, C. Christiansen-Jucht, H. Bouzourene, D. Rimoldi, H. Pircher, et al. 2012. Extended co-expression of inhibitory receptors by human CD8 T-cells depending on differentiation, antigen-specificity and anatomical localization. PLoS One. 7:e30852. http://dx.doi.org/10.1371/journal.pone.0030852
4. + T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10:29-37. http://dx.doi.org/10.1038/ni.1679
5. + T cell anergy and promotes tumor rejection. J. Immunol. 177:4521-4529. http://dx.doi.org/10.4049/jimmunol.177.7.4521
6. Clouthier, D.L., A.C. Zhou, and T.H. Watts. 2014. Anti-GITR agonist therapy intrinsically enhances CD8 T cell responses to chronic lymphocytic choriomeningitis virus (LCMV), thereby circumventing LCMV-induced downregulation of costimulatory GITR ligand on APC. J. Immunol. 193:5033-5043. http://dx.doi.org/10.4049/jimmunol.1401002
7. + T cell dysfunction during chronic infection. Immunity. 40:289-302. http://dx.doi.org/10.1016/j.immuni.2014.01.005
8. Cunningham, C.R., A. Champhekar, M.V. Tullius, B.J. Dillon, A. Zhen, J.R. de la Fuente, J. Herskovitz, H. Elsaesser, L.M. Snell, E.B. Wilson, et al. 2016. Type I and Type II interferon coordinately regulate suppressive dendritic cell fate and function during viral persistence. PLoS Pathog. 12:e1005356. http://dx.doi.org/10.1371/journal.ppat.1005356
9. Currier, J.R., and M.A. Robinson. 2001. Spectratype/Immunoscope Analysis of the Expressed TCR Repertoire. John Wiley & Sons, Inc., Hoboken, NJ. 92544 pp. http://dx.doi.org/10.1002/0471142735.im1028s38
10. Diamond, M.S., M. Kinder, H. Matsushita, M. Mashayekhi, G.P. Dunn, J.M. Archambault, H. Lee, C.D. Arthur, J.M. White, U. Kalinke, et al. 2011. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J. Exp. Med. 208:1989-2003. http://dx.doi.org/10.1084/jem.20101158
11. + T cell exhaustion versus memory. Immunity. 37:1130-1144. http://dx.doi.org/10.1016/j.immuni.2012.08.021
12. Evaristo, C., S. Spranger, S.E. Barnes, M.L. Miller, L.L. Molinero, F.L. Locke, T.F. Gajewski, and M.-L. Alegre. 2016. Cutting edge: engineering active IKKβ in T cells drives tumor rejection. J. Immunol. 196:2933-2938. http://dx.doi.org/10.4049/jimmunol.1501144
13. Fan, X., S.A. Quezada, M.A. Sepulveda, P. Sharma, and J.P. Allison. 2014. Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J. Exp. Med. 211:715-725. http://dx.doi.org/10.1084/jem.20130590
14. + T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res. 72:887-896. http://dx.doi.org/10.1158/0008-5472.CAN-11-2637
15. Fridman, W.H., F. Pagès, C. Sautès-Fridman, and J. Galon. 2012. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer. 12:298-306. http://dx.doi.org/10.1038/nrc3245
16. + dendritic cells. J. Exp. Med. 208:2005-2016. http://dx.doi.org/10.1084/jem.20101159
17. Gajewski, T.F. 2007a. The expanding universe of regulatory T cell subsets in cancer. Immunity. 27:185-187. http://dx.doi.org/10.1016/j.immuni.2007.08.001
18. Gajewski, T.F. 2007b. Failure at the effector phase: immune barriers at the level of the melanoma tumor microenvironment. Clin. Cancer Res. 13:5256-5261. http://dx.doi.org/10.1158/1078-0432.CCR-07-0892
19. Gajewski, T.F., Y. Meng, C. Blank, I. Brown, A. Kacha, J. Kline, and H. Harlin. 2006. Immune resistance orchestrated by the tumor microenvironment. Immunol. Rev. 213:131-145. http://dx.doi.org/10.1111/j.1600-065X.2006.00442.x
20. Gajewski, T.F., H. Schreiber, and Y.-X. Fu. 2013. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14:1014-1022. http://dx.doi.org/10.1038/ni.2703
21. Goldszmid, R.S., A. Dzutsev, and G. Trinchieri. 2014. Host immune response to infection and cancer: unexpected commonalities. Cell Host Microbe. 15:295-305. http://dx.doi.org/10.1016/j.chom.2014.02.003
22. + tumor-reactive repertoire infiltrating human tumors. J. Clin. Invest. 124:2246-2259. http://dx.doi.org/10.1172/JCI73639
23. Halin, C., M.L. Scimone, R. Bonasio, J.-M. Gauguet, T.R. Mempel, E. Quackenbush, R.L. Proia, S. Mandala, and U.H. von Andrian. 2005. The S1P-analog FTY720 differentially modulates T-cell homing via HEV: T-cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches. Blood. 106:1314-1322. http://dx.doi.org/10.1182/blood-2004-09-3687
24. + T cells in a patient with malignant melanoma ascites. Cancer Immunol. Immunother. 55:1185-1197. http://dx.doi.org/10.1007/s00262-005-0118-2
25. + T-cell recruitment. Cancer Res. 69:3077-3085. http://dx.doi.org/10.1158/0008-5472.CAN-08-2281
26. Hoelzinger, D.B., S.E. Smith, N. Mirza, A.L. Dominguez, S.Z. Manrique, and J. Lustgarten. 2010. Blockade of CCL1 inhibits T regulatory cell suppressive function enhancing tumor immunity without affecting T effector responses. J. Immunol. 184:6833-6842. http://dx.doi.org/10.4049/jimmunol.0904084
27. Jenkins, M.K., D.M. Pardoll, J. Mizuguchi, T.M. Chused, and R.H. Schwartz. 1987. Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones. Proc. Natl. Acad. Sci. USA. 84:5409-5413. http://dx.doi.org/10.1073/pnas.84.15.5409
28. + T cell effector function. Cancer Cell. 26:923-937. http://dx.doi.org/10.1016/j.ccell.2014.10.018
29. + T cell fates via the graded expression of T-bet transcription factor. Immunity. 27:281-295. http://dx.doi.org/10.1016/j.immuni.2007.07.010
30. Kaech, S.M., J.T. Tan, E.J. Wherry, B.T. Konieczny, C.D. Surh, and R. Ahmed. 2003. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat. Immunol. 4:1191-1198. http://dx.doi.org/10.1038/ni1009
31. Kearse, M., R. Moir, A. Wilson, S. Stones-Havas, M. Cheung, S. Sturrock, S. Buxton, A. Cooper, S. Markowitz, C. Duran, et al. 2012. Geneious Basic: an integrated and extendable desktop software platform for the organization and analysis of sequence data. Bioinformatics. 28:1647-1649. http://dx.doi.org/10.1093/bioinformatics/bts199
32. Kim, J.-O., H.W. Kim, K.-M. Baek, and C.-Y. Kang. 2003. NF-κB and AP-1 regulate activation-dependent CD137 (4-1BB) expression in T cells. FEBS Lett. 541:163-170. http://dx.doi.org/10.1016/S0014-5793(03)00326-0
33. Kline, J., L. Zhang, L. Battaglia, K.S. Cohen, and T.F. Gajewski. 2012. Cellular and molecular requirements for rejection of B16 melanoma in the setting of regulatory T cell depletion and homeostatic proliferation. J. Immunol. 188:2630-2642. http://dx.doi.org/10.4049/jimmunol.1100845
34. Kuchroo, V.K., A.C. Anderson, and C. Petrovas. 2014. Coinhibitory receptors and CD8 T cell exhaustion in chronic infections. Curr. Opin. HIV AIDS. 9:439-445. http://dx.doi.org/10.1097/COH.0000000000000088
35. Larkin, J., F.S. Hodi, and J.D. Wolchok. 2015. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373:1270-1271. http://dx.doi.org/10.1056/NEJMoa1504030
36. Li, S., T. Miao, M. Sebastian, P. Bhullar, E. Ghaffari, M. Liu, A.L.J. Symonds, and P. Wang. 2012. The transcription factors Egr2 and Egr3 are essential for the control of inflammation and antigen-induced proliferation of B and T cells. Immunity. 37:685-696. http://dx.doi.org/10.1016/j.immuni.2012.08.001
37. + T cells. Immunity. 42:265-278. http://dx.doi.org/10.1016/j.immuni.2015.01.006
38. + T cells. J. Exp. Med. 212:1125-1137. http://dx.doi.org/10.1084/jem.20142237
39. Palazón, A., I. Martínez-Forero, A. Teijeira, A. Morales-Kastresana, C. Alfaro, M.F. Sanmamed, J.L. Perez-Gracia, I. Peñuelas, S. Hervás-Stubbs, A. Rouzaut, et al. 2012. The HIF-1α hypoxia response in tumor-infiltrating T lymphocytes induces functional CD137 (4-1BB) for immunotherapy. Cancer Discov. 2:608-623. http://dx.doi.org/10.1158/2159-8290.CD-11-0314
40. Pardoll, D.M. 2012. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer. 12:252-264. http://dx.doi.org/10.1038/nrc3239
41. Pauken, K.E., and E.J. Wherry. 2015. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 36:265-276. http://dx.doi.org/10.1016/j.it.2015.02.008
42. Pearce, E.L., M.C. Poffenberger, C.H. Chang, and R.G. Jones. 2013. Fueling immunity: insights into metabolism and lymphocyte function. Science. 342:1242454. http://dx.doi.org/10.1126/science.1242454
43. Plaisier, S.B., R. Taschereau, J.A. Wong, and T.G. Graeber. 2010. Rank-rank hypergeometric overlap: identification of statistically significant overlap between gene-expression signatures. Nucleic Acids Res. 38:e169-e169. http://dx.doi.org/10.1093/nar/gkq636
44. Rosenblatt, J.D., and J.L. Stein. 2014. RRHO: Test overlap using the Rank-Rank Hypergeometric test. R package. https://bioconductor.riken.jp/packages/3.1/bioc/html/RRHO.html.
45. Safford, M., S. Collins, M.A. Lutz, A. Allen, C.-T. Huang, J. Kowalski, A. Blackford, M.R. Horton, C. Drake, R.H. Schwartz, and J.D. Powell. 2005. Egr-2 and Egr-3 are negative regulators of T cell activation. Nat. Immunol. 6:472-480. http://dx.doi.org/10.1038/ni1193
46. Sarkar, S., V. Kalia, W.N. Haining, B.T. Konieczny, S. Subramaniam, and R. Ahmed. 2008. Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J. Exp. Med. 205:625-640. http://dx.doi.org/10.1084/jem.20071641
47. Sarris, M., K.G. Andersen, F. Randow, L. Mayr, and A.G. Betz. 2008. Neuropilin-1 expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition. Immunity. 28:402-413. http://dx.doi.org/10.1016/j.immuni.2008.01.012
48. Schietinger, A., and P.D. Greenberg. 2014. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol. 35:51-60. http://dx.doi.org/10.1016/j.it.2013.10.001
49. Schietinger, A., M. Philip, V.E. Krisnawan, E.Y. Chiu, J.J. Delrow, R.S. Basom, P. Lauer, D.G. Brockstedt, S.E. Knoblaugh, G.J. Hämmerling, et al. 2016. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity. 45:389-401. http://dx.doi.org/10.1016/j.immuni.2016.07.011
50. Schwartz, R.H. 2003. T cell anergy. Annu. Rev. Immunol. 21:305-334. http://dx.doi.org/10.1146/annurev.immunol.21.120601.141110
51. Schwartz, R.H., D.L. Mueller, M.K. Jenkins, and H. Quill. 1989. T-cell clonal anergy. Cold Spring Harb. Symp. Quant. Biol. 54:605-610. http://dx.doi.org/10.1101/SQB.1989.054.01.072
52. Shannon, P., A. Markiel, O. Ozier, N.S. Baliga, J.T. Wang, D. Ramage, N. Amin, B. Schwikowski, and T. Ideker. 2003. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13:2498-2504. http://dx.doi.org/10.1101/gr.1239303
53. Snell, L.M., and D.G. Brooks. 2015. New insights into type I interferon and the immunopathogenesis of persistent viral infections. Curr. Opin. Immunol. 34:91-98. http://dx.doi.org/10.1016/j.coi.2015.03.002
54. Spiotto, M.T., P. Yu, D.A. Rowley, M.I. Nishimura, S.C. Meredith, T.F. Gajewski, Y.-X. Fu, and H. Schreiber. 2002. Increasing tumor antigen expression overcomes "ignorance" to solid tumors via crosspresentation by bone marrow-derived stromal cells. Immunity. 17:737-747. http://dx.doi.org/10.1016/S1074-7613(02)00480-6
55. Spranger, S., R.M. Spaapen, Y. Zha, J. Williams, Y. Meng, T.T. Ha, and T.F. Gajewski. 2013. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci. Transl. Med. 5:200ra116.
56. + T cells directly within the tumor microenvironment. J. Immunother. Cancer. 2:3.
57. Sumitomo, S., K. Fujio, T. Okamura, and K. Yamamoto. 2013. Egr2 and Egr3 are the unique regulators for systemic autoimmunity. JAK-STAT. 2:e23952. http://dx.doi.org/10.4161/jkst.23952
58. Tumeh, P.C., C.L. Harview, J.H. Yearley, I.P. Shintaku, E.J.M. Taylor, L. Robert, B. Chmielowski, M. Spasic, G. Henry, V. Ciobanu, et al. 2014. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 515:568-571. http://dx.doi.org/10.1038/nature13954
59. Twyman-Saint Victor, C., A.J. Rech, A. Maity, R. Rengan, K.E. Pauken, E. Stelekati, J.L. Benci, B. Xu, H. Dada, P.M. Odorizzi, et al. 2015. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 520:373-377. http://dx.doi.org/10.1038/nature14292
60. Vesely, M.D., M.H. Kershaw, R.D. Schreiber, and M.J. Smyth. 2011. Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol. 29:235-271. http://dx.doi.org/10.1146/annurev-immunol-031210-101324
61. + T cell hypofunction in a transplantable murine cancer model. J. Immunol. 197:1477-1488. http://dx.doi.org/10.4049/jimmunol.1600589
62. Wherry, E.J., and M. Kurachi. 2015. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15:486-499. http://dx.doi.org/10.1038/nri3862
63. + T cell exhaustion during chronic viral infection. Immunity. 27:670-684. http://dx.doi.org/10.1016/j.immuni.2007.09.006
64. + T cells are exhausted in tumours and functional in draining lymph nodes of colorectal cancer patients. Br. J. Cancer. 111:1391-1399. http://dx.doi.org/10.1038/bjc.2014.416
65. Zajac, A.J., J.N. Blattman, K. Murali-Krishna, D.J. Sourdive, M. Suresh, J.D. Altman, and R. Ahmed. 1998. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188:2205-2213. http://dx.doi.org/10.1084/jem.188.12.2205
66. Zha, Y., R. Marks, A.W. Ho, A.C. Peterson, S. Janardhan, I. Brown, K. Praveen, S. Stang, J.C. Stone, and T.F. Gajewski. 2006. T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-alpha. Nat. Immunol. 7:1166-1173. http://dx.doi.org/10.1038/ni1394
67. Zhang, L., T.F. Gajewski, and J. Kline. 2009. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood. 114:1545-1552. http://dx.doi.org/10.1182/blood-2009-03-206672
68. Zheng, Y., Y. Zha, G. Driessens, F. Locke, and T.F. Gajewski. 2012. Transcriptional regulator early growth response gene 2 (Egr2) is required for T cell anergy in vitro and in vivo. J. Exp. Med. 209:2157-2163. http://dx.doi.org/10.1084/jem.20120342
69. Zheng, Y., Y. Zha, R.M. Spaapen, R. Mathew, K. Barr, A. Bendelac, and T.F. Gajewski. 2013. Egr2-dependent gene expression profiling and ChIPSeq reveal novel biologic targets in T cell anergy. Mol. Immunol. 55:283-291. http://dx.doi.org/10.1016/j.molimm.2013.03.006