Consensus nomenclature for CD8+ T cell phenotypes in cancer

OncoImmunology

Volumn 4, Issue 4, 2015, Pages

  Apetoh, Lionel ^a,b,c   Smyth, Mark J ^d   Drake, Charles G ^e   Abastado, Jean Pierre ^f   Apte, Ron N ^g   Ayyoub, Maha ^h   Blay, Jean Yves ^i,j   Bonneville, Marc ^k,l   Butterfield, Lisa H ^m   Caignard, Anne ⁿ   Castelli, Chiara ^o   Cavallo, Federica ^p   Celis, Esteban ^q   Chen, Lieping ^r   Colombo, Mario P ^o   Comin Anduix, Begoña ^s   Coukos, Georges ^t   Dhodapkar, Madhav V ^r   Dranoff, Glenn ^u   Frazer, Ian H ^v   Fridman, Wolf Hervé ^w   Gabrilovich, Dmitry I ^x   Gilboa, Eli ^y   Gnjatic, Sacha ^z   Jäger, Dirk ^aa   Kalinski, Pawel ^ab   Kaufman, Howard L ^ac   Kiessling, Rolf ^ad   Kirkwood, John ^ae   Knuth, Alexander ^af   Liblau, Roland ^ag,ah,ai,aj   Lotze, Michael T ^m   Lugli, Enrico ^ak   Marincola, Francesco ^al   Melero, Ignacio ^am   Melief, Cornelis J ^an   Mempel, Thorsten R ^ao   Mittendorf, Elizabeth A ^ap   Odun, Kunle ^aq   Overwijk, Willem W ^ap   Palucka, Anna Karolina ^ar   Parmiani, Giorgio ^as   Ribas, Antoni ^s   Romero, Pedro ^t   Schreiber, Robert D ^at   Schuler, Gerold ^au   Srivastava, Pramod K ^av   Tartour, Eric ^aw   Valmori, Danila ^h,ax   van der Burg, Sjoerd H ^ay   van der Bruggen, Pierre ^az   van den Eynde, Benoît J ^az   Wang, Ena ^al   Zou, Weiping ^ba   Whiteside, Theresa L ^m   Speiser, Daniel E ^t   Pardoll, Drew M ^e   Restifo, Nicholas P ^bb   Anderson, Ana C ^u   more..

^a Chu   (France)

^b CENTRE GEORGES FRANÇOIS LECLERC   (France)

^c UNIVERSITÉ DE BOURGOGNE   (France)

^d QIMR BERGHOFER MEDICAL RESEARCH INSTITUTE   (Australia)

^e JOHNS HOPKINS UNIVERSITY   (United States)

^f IRIS Institut de Recherches Internationales Servier   (France)

^g BEN GURION UNIVERSITY OF THE NEGEV   (Israel)

^h Institut de Cancérologie de l’Ouest ^*  (France)

ⁱ CENTRE LÉON BÉRARD   (France)

^j Departments of Gynecologic Oncology   (France)

^k Team 12   (France)

^l Institut Merieux   (France)

^m UNIVERSITY OF PITTSBURGH CANCER INSTITUTE   (United States)

ⁿ INSERM   (France)

^o NATIONAL CANCER INSTITUTE   (Italy)

^p UNIVERSITY OF TURIN   (Italy)

^q MEDICAL COLLEGE OF GEORGIA   (United States)

^r YALE CANCER CENTER   (United States)

^s UNIVERSITY OF CALIFORNIA   (United States)

^t UNIVERSITY OF LAUSANNE   (Switzerland)

^u BRIGHAM AND WOMEN S HOSPITAL   (United States)

^v UNIVERSITY OF QUEENSLAND   (Australia)

^w CENTRE DE RECHERCHE DES CORDELIERS   (France)

^x WISTAR INSTITUTE   (United States)

^y UNIVERSITY OF MIAMI   (United States)

^z MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^aa UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

^ab UNIVERSITY OF PITTSBURGH MEDICAL CENTER   (United States)

^ac RUTGERS CANCER INSTITUTE OF NEW JERSEY   (United States)

^ad KAROLINSKA INSTITUTE   (Sweden)

^ae UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^af National Center of Cancer Care and Research   (Qatar)

^ag INSER M UMR1043   (France)

^ah CNRS   (France)

^ai UNIVERSITÉ PAUL SABATIER   (France)

^aj CHU PURPAN   (France)

^ak HUMANITAS CLINICAL AND RESEARCH CENTER   (Italy)

^al SIDRA MEDICAL AND RESEARCH CENTER   (Qatar)

^am UNIVERSITY CLINIC OF NAVARRA   (Spain)

^an LEIDEN UNIVERSITY   (Netherlands)

^ao HARVARD MEDICAL SCHOOL   (United States)

^ap UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^aq ROSWELL PARK CANCER INSTITUTE   (United States)

^ar JACKSON LABORATORY   (United States)

^as UNIVERSITY HOSPITAL OF SIENA   (Italy)

^at WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^au UNIVERSITY HOSPITAL ERLANGEN   (Germany)

^av UNIVERSITY OF CONNECTICUT HEALTH CENTER   (United States)

^aw PARIS CARDIOVASCULAR RESEARCH CENTER   (France)

^ax UNIVERSITÉ DE NANTES   (France)

^ay LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

^az DE DUVE INSTITUTE   (Belgium)

^ba UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^bb NATIONAL CANCER INSTITUTE   (United States)

more..

Author keywords

Anergy; Anticancer immunity; CD8+ T cells; Cytotoxicity; Effector; Exhaustion; IFN ; Senescence; Stemness

Indexed keywords

CD8+ T LYMPHOCYTE; CONSENSUS; NOMENCLATURE; PHENOTYPE; PRACTICE GUIDELINE;

EID: 84954349779     PISSN: 21624011     EISSN: 2162402X     Source Type: Journal    
DOI: 10.1080/2162402X.2014.998538     Document Type: Article

References (98)

1. Harty JT, Tvinnereim AR, White DW. CD8+ T cell effector mechanisms in resistance to infection. Ann Rev Immunol 2000; 18:275-308; PMID:10837060; http:// dx. doi. org/10. 1146/annurev. immunol. 18. 1. 275
2. Uyttenhove C, Maryanski J, Boon T. Escape of mouse mastocytoma P815 after nearly complete rejection is due to antigen-loss variants rather than immunosuppression. J Exp Med 1983; 157:1040-52; PMID:6187879; http://dx. doi. org/10. 1084/jem. 157. 3. 1040
3. Nakayama E, Uenaka A. Effect of in vivo administration of Lyt antibodies. Lyt phenotype of T cells in lymphoid tissues and blocking of tumor rejection. J Exp Med 1985; 161:345-55; PMID:3871834; http://dx. doi. org/10. 1084/jem. 161. 2. 345
4. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001; 410:1107-11; PMID:11323675; http://dx. doi. org/10. 1038/35074122
5. Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med 2000; 192:755-60; PMID:10974040; http://dx. doi. org/10. 1084/jem. 192. 5. 755
6. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3:991-8; PMID: 12407406; http://dx. doi. org/10. 1038/ni1102-991
7. Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 2007; 450:903-7; PMID:18026089; http://dx. doi. org/ 10. 1038/nature06309
8. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, Vermaelen K, Panaretakis T, Mignot G, Ullrich E, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 2009; 15:1170-8; PMID:19767732; http://dx. doi. org/ 10. 1038/nm. 2028
9. Mattarollo SR, Loi S, Duret H, Ma Y, Zitvogel L, Smyth MJ. Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors. Cancer Res 2011; 71:4809-20; PMID: 21646474; http://dx. doi. org/10. 1158/0008-5472. CAN-11-0753
10. Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma R, Chin R, Tu T, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 2009; 114:589-95; PMID:19349616; http://dx. doi. org/10. 1182/blood-2009-02-206870
11. Ratliff TL, Ritchey JK, Yuan JJ, Andriole GL, Catalona WJ. T-cell subsets required for intravesical BCG immunotherapy for bladder cancer. J Urol 1993; 150:1018-23; PMID:8102183
12. Gresser I, Maury C, Carnaud C, DeMaeyer E, Maunoury MT, Belardelli F. Anti-tumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend erythroleukemia cells. VIII. Role of the immune system in the inhibition of visceralmetastases. Int J Cancer 1990; 46:468-74; PMID:2394514; http://dx. doi. org/ 10. 1002/ijc. 2910460324
13. Remark R, Alifano M, Cremer I, Lupo A, Dieu-Nosjean MC, Riquet M, Crozet L, Ouakrim H, Goc J, Cazes A, et al. Characteristics and clinical impacts of the immune environments in colorectal and renal cell carcinoma lung metastases: influence of tumor origin. Clin Cancer Res 2013; 19:4079-91; PMID:23785047; http://dx. doi. org/10. 1158/1078-0432. CCR-12-3847
14. Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, Suzuki Y, Shintaku I, Nagura H, Ohtani H. Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 2001; 61:5132-6; PMID: 11431351
15. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003; 348:203-13; PMID:12529460; http://dx. doi. org/10. 1056/NEJMoa020177
16. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005; 353:2654-66; PMID:16371631; http://dx. doi. org/10. 1056/NEJMoa051424
17. Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, Lugli A, Zlobec I, Hartmann A, Bifulco C, et al. Towards the introduction of the 'Immunoscore' in the classification of malignant tumours. J Pathol 2014; 232:199-209; PMID:24122236; http://dx. doi. org/10. 1002/path. 4287
18. Koelzer VH, Lugli A, Dawson H, Hadrich M, Berger MD, Borner M, Mallaev M, Galván JA, Amsler J, Schnüriger B, et al. CD8/CD45RO T-cell infiltration in endoscopic biopsies of colorectal cancer predicts nodal metastasis and survival. J Transl Med 2014; 12:81; PMID:24679169; http://dx. doi. org/10. 1186/ 1479-5876-12-81
19. Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, Ellis IO, Green AR. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol 2011; 29:1949-55; PMID:21483002; http://dx. doi. org/10. 1200/JCO. 2010. 30. 5037
20. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 2005; 102:18538-43; PMID:16344461; http://dx. doi. org/10. 1073/pnas. 0509182102
21. Ladoire S, Mignot G, Dabakuyo S, Arnould L, Apetoh L, Rebe C, Coudert B, Martin F, Bizollon MH, Vanoli A, et al. In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pathol 2011; 224:389-400; PMID:21437909; http://dx. doi. org/10. 1002/path. 2866
22. Seo AN, Lee HJ, Kim EJ, Kim HJ, Jang MH, Lee HE, Kim YJ, Kim JH, Park SY. Tumour-infiltrating CD8+ lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. Br J Cancer 2013; 109:2705-13; PMID:24129232; http://dx. doi. org/10. 1038/ bjc. 2013. 634
23. Barry M, Bleackley RC. Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2002; 2:401-9; PMID:12093006; http://dx. doi. org/10. 1038/nri819
24. Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 1998; 393:480-3; PMID:9624005; http://dx. doi. org/ 10. 1038/31002
25. Masson D, Tschopp J. A family of serine esterases in lytic granules of cytolytic T lymphocytes. Cell 1987; 49:679-85; PMID:3555842; http://dx. doi. org/ 10. 1016/0092-8674(87)90544-7
26. Pasternack MS, Verret CR, Liu MA, Eisen HN. Serine esterase in cytolytic T lymphocytes. Nature 1986; 322:740-3; PMID:3489187; http://dx. doi. org/10. 1038/ 322740a0
27. Podack ER, Konigsberg PJ. Cytolytic T cell granules. Isolation, structural, biochemical, and functional characterization. J Exp Med 1984; 160:695-710; PMID:6332169; http://dx. doi. org/10. 1084/jem. 160. 3. 695
28. Brunner KT, Mauel J, Cerottini JC, Chapuis B. Quantitative assay of the lytic action of immune lymphoid cells on 51-Cr-labelled allogeneic target cells in vitro; inhibition by isoantibody and by drugs. Immunology 1968; 14:181-96; PMID:4966657
29. Griffiths GM, Isaaz S. Granzymes A and B are targeted to the lytic granules of lymphocytes by the mannose-6-phosphate receptor. J Cell Biol 1993; 120:885-96; PMID:8432729; http://dx. doi. org/10. 1083/jcb. 120. 4. 885
30. Wever PC, Van Der Vliet HJ, Spaeny LH, Wolbink AM, Van Diepen FN, Froelich CJ, Hack CE, ten Berge IJ. The CD8+ granzyme B+ T-cell subset in peripheral blood from healthy individuals contains activated and apoptosis-prone cells. Immunology 1998; 93:383-9; PMID:9640249; http://dx. doi. org/10. 1046/j. 1365-2567. 1998. 00448. x
31. Rubio V, Stuge TB, Singh N, Betts MR, Weber JS, Roederer M, Lee PP. Ex vivo identification, isolation and analysis of tumor-cytolytic T cells. Nat Med 2003; 9:1377-82; PMID:14528297; http://dx. doi. org/ 10. 1038/nm942
32. Takeshima T, Chamoto K, Wakita D, Ohkuri T, Togashi Y, Shirato H, Kitamura H, Nishimura T. Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: its potentiation by combination with Th1 cell therapy. Cancer Res 2010; 70:2697-706; PMID:20215523; http://dx. doi. org/ 10. 1158/0008-5472. CAN-09-2982
33. Caldwell SA, Ryan MH, McDuffie E, Abrams SI. The Fas/Fas ligand pathway is important for optimal tumor regression in a mouse model of CTL adoptive immunotherapy of experimental CMS4 lung metastases. J Immunol 2003; 171:2402-12; PMID:12928387; http://dx. doi. org/10. 4049/jimmunol. 171. 5. 2402
34. Seki N, Brooks AD, Carter CR, Back TC, Parsoneault EM, Smyth MJ, Wiltrout RH, Sayers TJ. Tumor-specific CTL kill murine renal cancer cells using both perforin and Fas ligand-mediated lysis in vitro, but cause tumor regression in vivo in the absence of perforin. J Immunol 2002; 168:3484-92; PMID:11907109; http://dx. doi. org/10. 4049/jimmunol. 168. 7. 3484
35. Afshar-Sterle S, Zotos D, Bernard NJ, Scherger AK, Rodling L, Alsop AE, Walker J, Masson F, Belz GT, Corcoran LM, et al. Fas ligand-mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas. Nat Med 2014; 20:283-90; PMID:24487434; http://dx. doi. org/10. 1038/nm. 3442
36. Jazirehi AR, Economou JS. Proteasome inhibition blocks NF-kappaB and ERK1/2 pathways, restores antigen expression, and sensitizes resistant human melanoma to TCR-engineered CTLs. Mol Cancer Ther 2012; 11:1332-41; PMID:22532603; http://dx. doi. org/10. 1158/1535-7163. MCT-11-0814
37. Abouzahr S, Bismuth G, Gaudin C, Caroll O, Van Endert P, Jalil A, Dausset J, Vergnon I, Richon C, Kauffmann A, et al. Identification of target actin content and polymerization status as a mechanism of tumor resistance after cytolytic T lymphocyte pressure. Proc Natl Acad Sci U S A 2006; 103:1428-33; PMID: 16432193; http://dx. doi. org/10. 1073/pnas. 0510454103
38. Durward M, Harms J, Splitter G. Antigen specific killing assay using CFSE labeled target cells. J Vis Exp 2010; 45:pii. 2250; PMID:21085108; http://dx. doi. org/10. 3791/2250
39. Boissonnas A, Fetler L, Zeelenberg IS, Hugues S, Amigorena S. In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor. J Exp Med 2007; 204:345-56; PMID:17261634; http://dx. doi. org/ 10. 1084/jem. 20061890
40. Breart B, Lemaitre F, Celli S, Bousso P. Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice. J Clin Invest 2008; 118:1390-7; PMID:18357341; http://dx. doi. org/10. 1172/JCI34388
41. Spiotto MT, Rowley DA, Schreiber H. Bystander elimination of antigen loss variants in established tumors. Nat Med 2004; 10:294-8; PMID:14981514; http://dx. doi. org/10. 1038/nm999
42. Schietinger A, Arina A, Liu RB, Wells S, Huang J, Engels B, Bindokas V, Bartkowiak T, Lee D, Herrmann A, et al. Longitudinal confocal microscopy imaging of solid tumor destruction following adoptive T cell transfer. Oncoimmunology 2013; 2:e26677; PMID:24482750; http://dx. doi. org/10. 4161/onci. 26677
43. Braumuller H, Wieder T, Brenner E, Assmann S, Hahn M, Alkhaled M, Schilbach K, Essmann F, Kneilling M, Griessinger C, et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 2013; 494:361-5; PMID: 23376950; http://dx. doi. org/10. 1038/nature11824
44. Street SE, Cretney E, Smyth MJ. Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. Blood 2001; 97:192-7; PMID:11133760; http://dx. doi. org/10. 1182/blood. V97. 1. 192
45. Street SE, Trapani JA, MacGregor D, Smyth MJ. Suppression of lymphoma and epithelial malignancies effected by interferon gamma. J Exp Med 2002; 196:129-34; PMID:12093877; http://dx. doi. org/ 10. 1084/jem. 20020063
46. Sato N, Nariuchi H, Tsuruoka N, Nishihara T, Beitz JG, Calabresi P, Frackelton AR Jr. Actions of TNF and IFN-gamma on angiogenesis in vitro. J Invest Dermatol 1990; 95:85S-9S; PMID:1701814; http://dx. doi. org/ 10. 1111/1523-1747. ep12874809
47. Qin Z, Schwartzkopff J, Pradera F, Kammertoens T, Seliger B, Pircher H, Blankenstein T. A critical requirement of interferon gamma-mediated angiostasis for tumor rejection by CD8+ T cells. Cancer Res 2003; 63:4095-100; PMID:12874012
48. Schwartz RH. T cell anergy. Ann Rev Immunol 2003; 21:305-34;PMID:12471050; http://dx. doi. org/10. 1146/ annurev. immunol. 21. 120601. 141110
49. Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, Krzysiek R, Knutson KL, Daniel B, Zimmermann MC, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 2003; 9:562-7; PMID:12704383; http://dx. doi. org/ 10. 1038/nm863
50. Melief CJ. Cancer immunotherapy by dendritic cells. Immunity 2008; 29:372-83; PMID:18799145; http:// dx. doi. org/10. 1016/j. immuni. 2008. 08. 004
51. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9:162-74; PMID:19197294; http://dx. doi. org/10. 1038/nri2506
52. Wherry EJ. T cell exhaustion. Nat Immunol 2011; 12:492-9; PMID:21739672; http://dx. doi. org/ 10. 1038/ni. 2035
53. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006; 439:682-7; PMID:16382236; http://dx. doi. org/10. 1038/nature04444
54. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DA, Wherry EJ. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 2009; 10:29-37; PMID:19043418; http://dx. doi. org/10. 1038/ni. 1679
55. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 2010; 207:2187-94; PMID:20819927; http://dx. doi. org/10. 1084/jem. 20100643
56. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, Kirkwood JM, Kuchroo V, Zarour HM. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med 2010; 207:2175-86; PMID:20819923; http://dx. doi. org/ 10. 1084/jem. 20100637
57. Baitsch L, Baumgaertner P, Devevre E, Raghav SK, Legat A, Barba L, Wieckowski S, Bouzourene H, Deplancke B, Romero P, et al. Exhaustion of tumorspecific CD8(+) T cells in metastases from melanoma patients. J Clin Invest 2011; 121:2350-60; PMID:21555851; http://dx. doi. org/10. 1172/JCI46102
58. Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, Murphy WJ, Azuma M, Anderson AC, Kuchroo VK, et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood 2011; 117:4501-10; PMID:21385853; http://dx. doi. org/10. 1182/blood-2010-10-310425
59. Yang ZZ, Grote DM, Ziesmer SC, Niki T, Hirashima M, Novak AJ, Witzig TE, Ansell SM. IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J Clin Invest 2012; 122:1271-82; PMID:22426209; http://dx. doi. org/10. 1172/JCI59806
60. Utzschneider DT, Legat A, Fuertes Marraco SA, Carrie L, Luescher I, Speiser DE, Zehn D. T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Nat Immunol 2013; 14:603-10; PMID:23644506; http://dx. doi. org/10. 1038/ni. 2606
61. Hailemichael Y, Dai Z, Jaffarzad N, Ye Y, Medina MA, Huang XF, Dorta-Estremera SM, Greeley NR, Nitti G, Peng W, et al. Persistent antigen at vaccination sites induces tumor-specific CD8(+) T cell sequestration, dysfunction and deletion. Nat Med 2013; 19:465-72; PMID:23455713; http://dx. doi. org/10. 1038/nm. 3105
62. Legat A, Speiser DE, Pircher H, Zehn D, Fuertes Marraco SA. Inhibitory receptor expression depends more dominantly on differentiation and activation than "exhaustion" of human CD8 T cells. Front Immunol 2013; 4:455; PMID:24391639; http://dx. doi. org/ 10. 3389/fimmu. 2013. 00455
63. Gros A, Robbins PF, Yao X, Li YF, Turcotte S, Tran E, Wunderlich JR, Mixon A, Farid S, Dudley ME, et al. PD-1 identifies the patient-specific CD8(+) tumorreactive repertoire infiltrating human tumors. J Clin Invest 2014; 124:2246-59; PMID:24667641; http:// dx. doi. org/10. 1172/JCI73639
64. Badoual C, Hans S, Merillon N, Van Ryswick C, Ravel P, Benhamouda N, Levionnois E, Nizard M, Si-Mohamed A, Besnier N, et al. PD-1-expressing tumorinfiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res 2013; 73:128-38; PMID:23135914; http://dx. doi. org/ 10. 1158/0008-5472. CAN-12-2606
65. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12:252-64; PMID:22437870; http://dx. doi. org/10. 1038/ nrc3239
66. Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol 2011; 192:547-56; PMID:21321098; http:// dx. doi. org/10. 1083/jcb. 201009094
67. Montes CL, Chapoval AI, Nelson J, Orhue V, Zhang X, Schulze DH, Strome SE, Gastman BR. Tumorinduced senescent T cells with suppressor function: a potential form of tumor immune evasion. Cancer Res 2008; 68:870-9; PMID:18245489; http://dx. doi. org/ 10. 1158/0008-5472. CAN-07-2282
68. Mondal AM, Horikawa I, Pine SR, Fujita K, Morgan KM, Vera E, Mazur SJ, Appella E, Vojtesek B, Blasco MA, et al. p53 isoforms regulate aging-and tumorassociated replicative senescence in T lymphocytes. J Clin Invest 2013; 123:5247-57; PMID:24231352; http://dx. doi. org/10. 1172/JCI70355
69. Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003; 299:1033-6; PMID:12532024; http://dx. doi. org/10. 1126/science. 1078231
70. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441:235-8; PMID:16648838; http://dx. doi. org/ 10. 1038/nature04753
71. Martin F, Apetoh L, Ghiringhelli F. Controversies on the role of Th17 in cancer: a TGF-beta-dependent immunosuppressive activity? Trends Mol Med 2012; 18:742-9; PMID:23083809; http://dx. doi. org/ 10. 1016/j. molmed. 2012. 09. 007
72. Naugler WE, Karin M. The wolf in sheep's clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med 2008; 14:109-19; PMID:18261959; http://dx. doi. org/10. 1016/j. molmed. 2007. 12. 007
73. Apetoh L, Vegran F, Ladoire S, Ghiringhelli F. Restoration of antitumor immunity through selective inhibition of myeloid derived suppressor cells by anticancer therapies. CurrMol Med 2011; 11:365-72; PMID:21568934; http://dx. doi. org/10. 2174/156652411795976574
74. Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol 2013; 14:e218-28; PMID:23639322; http://dx. doi. org/10. 1016/S1470-2045(12)70582-X
75. Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res 2008; 14:6735-41; PMID:18980965; http://dx. doi. org/10. 1158/1078-0432. CCR-07-4843
76. van Duikeren S, Fransen MF, Redeker A, Wieles B, Platenburg G, Krebber WJ, Ossendorp F, Melief CJ, Arens R. Vaccine-induced effector-memory CD8+ T cell responses predict therapeutic efficacy against tumors. J Immunol 2012; 189:3397-403; PMID:22914049; http:// dx. doi. org/10. 4049/jimmunol. 1201540
77. Gattinoni L, Klebanoff CA, Restifo NP. Paths to stemness: building the ultimate antitumour T cell. Nat Rev Cancer 2012; 12:671-84; PMID:22996603; http://dx. doi. org/10. 1038/nrc3322
78. Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, Almeida JR, Gostick E, Yu Z, Carpenito C, et al. A human memory T cell subset with stem cell-like properties. Nat Med 2011; 17:1290-7; PMID: 21926977; http://dx. doi. org/10. 1038/nm. 2446
79. Cieri N, Camisa B, Cocchiarella F, Forcato M, Oliveira G, Provasi E, Bondanza A, Bordignon C, Peccatori J, Ciceri F, et al. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood 2013; 121:573-84; PMID:23160470; http://dx. doi. org/10. 1182/blood-2012-05-431718
80. Gattinoni L, Restifo NP. Moving T memory stem cells to the clinic. Blood 2013; 121:567-8; PMID:23349370; http://dx. doi. org/10. 1182/blood-2012-11-468660
81. Wang RF. CD8+ regulatory T cells, their suppressive mechanisms, and regulation in cancer. Hum Immunol 2008; 69:811-4; PMID:18817828; http://dx. doi. org/ 10. 1016/j. humimm. 2008. 08. 276
82. Wei S, Kryczek I, Zou L, Daniel B, Cheng P, Mottram P, Curiel T, Lange A, Zou W. Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res 2005; 65:5020-6; PMID:15958543; http://dx. doi. org/10. 1158/0008-5472. CAN-04-4043
83. Pearce EL, Mullen AC, Martins GA, Krawczyk CM, Hutchins AS, Zediak VP, Banica M, DiCioccio CB, Gross DA, Mao CA, et al. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science 2003; 302:1041-3; PMID:14605368; http:// dx. doi. org/10. 1126/science. 1090148
84. Ji Y, Pos Z, Rao M, Klebanoff CA, Yu Z, Sukumar M, Reger RN, Palmer DC, Borman ZA, Muranski P, et al. Repression of the DNA-binding inhibitor Id3 by Blimp-1 limits the formation of memory CD8+ T cells. Nat Immunol 2011; 12:1230-7; PMID:22057288; http://dx. doi. org/10. 1038/ni. 2153
85. Yang CY, Best JA, Knell J, Yang E, Sheridan AD, Jesionek AK, Li HS, Rivera RR, Lind KC, D'Cruz LM, et al. The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets. Nat Immunol 2011; 12:1221-9; PMID:22057289; http://dx. doi. org/10. 1038/ni. 2158
86. Henson SM, Franzese O, Macaulay R, Libri V, Azevedo RI, Kiani-Alikhan S, Plunkett FJ, Masters JE, Jackson S, Griffiths SJ, et al. KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells. Blood 2009; 113:6619-28; PMID:19406987; http://dx. doi. org/10. 1182/blood-2009-01-199588
87. Voehringer D, Koschella M, Pircher H. Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1). Blood 2002; 100:3698-702; PMID:12393723; http:// dx. doi. org/10. 1182/blood-2002-02-0657
88. Gothert JR, Eisele L, Klein-Hitpass L, Weber S, Zesewitz ML, Sellmann L, Röth A, Pircher H, Dührsen U, Dürig J. Expanded CD8+ T cells of murine and human CLL are driven into a senescent KLRG1+ effector memory phenotype. Cancer Immunol Immunother 2013; 62:1697-709; PMID:24022692; http://dx. doi. org/10. 1007/s00262-013-1473-z
89. Fourcade J, Kudela P, Sun Z, Shen H, Land SR, Lenzner D, Guillaume P, Luescher IF, Sander C, Ferrone S, et al. PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J Immunol 2009; 182:5240-9; PMID:19380770; http://dx. doi. org/10. 4049/jimmunol. 0803245
90. Gattinoni L, Klebanoff CA, Palmer DC, Wrzesinski C, Kerstann K, Yu Z, Finkelstein SE, Theoret MR, Rosenberg SA, Restifo NP. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. JClin Invest 2005; 115:1616-26; PMID:15931392; http://dx. doi. org/ 10. 1172/JCI24480
91. Lugli E, Dominguez MH, Gattinoni L, Chattopadhyay PK, Bolton DL, Song K, Klatt NR, Brenchley JM, Vaccari M, Gostick E, et al. Superior T memory stem cell persistence supports long-lived T cell memory. J Clin Invest 2013; 123:594-9; PMID:23281401
92. Fourcade J, Sun Z, Pagliano O, Guillaume P, Luescher IF, Sander C, Kirkwood JM, Olive D, Kuchroo V, Zarour HM. CD8(+) 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 2012; 72:887-96; PMID:22205715; http://dx. doi. org/ 10. 1158/0008-5472. CAN-11-2637
93. Mittal R, Wagener M, Breed ER, Liang Z, Yoseph BP, Burd EM, Farris AB 3rd, Coopersmith CM, Ford ML. Phenotypic T cell exhaustion in a murine model of bacterial infection in the setting of pre-existing malignancy. PLoS One 2014; 9:e93523; PMID:24796533; http:// dx. doi. org/10. 1371/journal. pone. 0093523
94. Fourcade J, Sun Z, Pagliano O, Chauvin JM, Sander C, Janjic B, Tarhini AA, Tawbi HA, Kirkwood JM, Moschos S, et al. PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8(+) T cells induced by melanoma vaccines. Cancer Res 2014; 74:1045-55; PMID:24343228; http://dx. doi. org/10. 1158/0008-5472. CAN-13-2908
95. Nunes C, Wong R, Mason M, Fegan C, Man S, Pepper C. Expansion of a CD8(+)PD-1(+) replicative senescence phenotype in early stage CLL patients is associated with inverted CD4:CD8 ratios and disease progression. Clin Cancer Res 2012; 18:678-87; PMID:22190592; http://dx. doi. org/10. 1158/1078-0432. CCR-11-2630
96. Beatty GL, Smith JS, Reshef R, Patel KP, Colligon TA, Vance BA, Frey NV, Johnson FB, Porter DL, Vonderheide RH. Functional unresponsiveness and replicative senescence of myeloid leukemia antigen-specific CD8+ T cells after allogeneic stem cell transplantation. Clin Cancer Res 2009; 15:4944-53; PMID:19602548; http://dx. doi. org/10. 1158/1078-0432. CCR-08-3332
97. Mahnke YD, Brodie TM, Sallusto F, Roederer M, Lugli E. The who's who of T-cell differentiation: human memory T-cell subsets. Eur J Immunol 2013; 43:2797-809; PMID:24258910; http://dx. doi. org/ 10. 1002/eji. 201343751
98. De Rosa SC, Herzenberg LA, Roederer M. 11-color, 13-parameter flow cytometry: identification of human naive T cells by phenotype, function, and T-cell receptor diversity. Nat Med 2001; 7:245-8; PMID:11175858; http://dx. doi. org/10. 1038/84701