Effects of radiation on T regulatory cells in normal states and cancer: Mechanisms and clinical implications

American Journal of Cancer Research

Volumn 5, Issue 11, 2015, Pages 3276-3285

  Liu, Shu ^a   Sun, Xiangdong ^b   Luo, Jinhua ^a   Zhu, Hongcheng ^a   Yang, Xi ^a   Guo, Qing ^c   Song, Yaqi ^d   Sun, Xinchen ^a  

^a THE FIRST AFFILIATED HOSPITAL OF NANJING MEDICAL UNIVERSITY   (China)

^b PLA Cancer Center   (China)

^c TAIZHOU PEOPLE S HOSPITAL   (China)

^d NANJING MEDICAL UNIVERSITY   (China)

Author keywords

Cancer; Immune response; Radiation; Radiotherapy; Regulatory T cell; T regulatory cells; Tregs

Indexed keywords

CD4 ANTIGEN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; INTERLEUKIN 2 RECEPTOR ALPHA; MACROPHAGE DERIVED CHEMOKINE; T LYMPHOCYTE RECEPTOR; TRANSCRIPTION FACTOR FOXP3;

CANCER GROWTH; CANCER IMMUNOTHERAPY; CANCER PROGNOSIS; CANCER RADIOTHERAPY; CELL FATE; CELL MIGRATION; CELLULAR IMMUNITY; CYTOKINE PRODUCTION; HUMAN; IMMUNOMODULATION; LYMPHOCYTE FUNCTION; LYMPHOCYTE SUBPOPULATION; MACROPHAGE; MALIGNANT NEOPLASTIC DISEASE; NONHUMAN; PATHOPHYSIOLOGY; PHENOTYPE; PROTEIN EXPRESSION; RADIATION EXPOSURE; REGULATORY T LYMPHOCYTE; REVIEW; TH17 CELL; TUMOR LOCALIZATION; TUMOR MICROENVIRONMENT;

EID: 85006210748     PISSN: None     EISSN: 21566976     Source Type: Journal    
DOI: None     Document Type: Review

References (69)

1. Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L and Formenti SC. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 2004; 58: 862-870.
2. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, Ritter E, Sedrak C, Jungbluth AA, Chua R, Yang AS, Roman RA, Rosner S, Benson B, Allison JP, Lesokhin AM, Gnjatic S and Wolchok JD. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 2012; 366: 925-931.
3. Nishioka A, Ogawa Y, Kubonishi I, Kataoka S, Hamada N, Terashima M, Inomata T and Yoshida S. An augmentation of Fas (CD95/APO-1) antigen induced by radiation: flow cytometry analysis of lymphoma and leukemia cell lines. Int J Mol Med 1999; 3: 275-278.
4. Gasser S, Orsulic S, Brown EJ and Raulet DH. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 2005; 436: 1186-1190.
5. Gonzalez S, Lopez-Soto A, Suarez-Alvarez B, Lopez-Vazquez A and Lopez-Larrea C. NKG2D ligands: key targets of the immune response. Trends Immunol 2008; 29: 397-403.
6. Champsaur M and Lanier LL. Effect of NKG2D ligand expression on host immune responses. Immunol Rev 2010; 235: 267-285.
7. Kershaw MH, Devaud C, John LB, Westwood JA and Darcy PK. Enhancing immunotherapy using chemotherapy and radiation to modify the tumor microenvironment. Oncoimmunology 2013; 2: e25962.
8. Dieckmann D, Plottner H, Berchtold S, Berger T and Schuler G. Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med 2001; 193: 1303-1310.
9. Persa E, Balogh A, Safrany G and Lumniczky K. The effect of ionizing radiation on regulatory T cells in health and disease. Cancer Lett 2015; S0304-3835: 00170-6.
10. Vignali DA, Collison LW and Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008; 8: 523-532.
11. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF and Ochs HD. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27: 20-21.
12. Dejaco C, Duftner C, Grubeck-Loebenstein B and Schirmer M. Imbalance of regulatory T cells in human autoimmune diseases. Immunology 2006; 117: 289-300.
13. Williams LM and Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 2007; 8: 277-284.
14. Bettini ML and Vignali DA. Development of thymically derived natural regulatory T cells. Ann N Y Acad Sci 2010; 1183: 1-12.
15. Ohkura N, Kitagawa Y and Sakaguchi S. Development and maintenance of regulatory T cells. Immunity 2013; 38: 414-423.
16. Raimondi G, Turner MS, Thomson AW and Morel PA. Naturally occurring regulatory T cells: recent insights in health and disease. Crit Rev Immunol 2007; 27: 61-95.
17. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J and Enk AH. Identification and functional characterization of human CD4(+) CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med 2001; 193: 1285-1294.
18. Bilate AM and Lafaille JJ. Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol 2012; 30: 733-758.
19. Curotto de Lafaille MA and Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 2009; 30: 626-635.
20. Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K and Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 2006; 212: 28-50.
21. Nishikawa H and Sakaguchi S. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol 2014; 27: 1-7.
22. Strauss L, Bergmann C, Gooding W, Johnson JT and Whiteside TL. The frequency and suppressor function of CD4+CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck. Clin Cancer Res 2007; 13: 6301-6311.
23. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L and Zou W. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10: 942-949.
24. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ and Odunsi K. 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: 18538-18543.
25. Leffers N, Gooden MJ, de Jong RA, Hoogeboom BN, ten Hoor KA, Hollema H, Boezen HM, van der Zee AG, Daemen T and Nijman HW. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 2009; 58: 449-459.
26. Correale P, Rotundo MS, Del Vecchio MT, Remondo C, Migali C, Ginanneschi C, Tsang KY, Licchetta A, Mannucci S, Loiacono L, Tassone P, Francini G and Tagliaferri P. Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J Immunother 2010; 33: 435-441.
27. Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C and Iacopetta B. Tumorinfiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009; 27: 186-192.
28. Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pages F and Galon J. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 2011; 71: 1263-1271.
29. Haas M, Dimmler A, Hohenberger W, Grabenbauer GG, Niedobitek G and Distel LV. Stromal regulatory T-cells are associated with a favourable prognosis in gastric cancer of the cardia. BMC Gastroenterol 2009; 9: 65.
30. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T and Nakayama E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 1999; 59: 3128-3133.
31. Attia P, Maker AV, Haworth LR, Rogers-Freezer L and Rosenberg SA. Inability of a fusion pro Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma. J Immunother 2005; 28: 582-592.
32. Litzinger MT, Fernando R, Curiel TJ, Grosenbach DW, Schlom J and Palena C. IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. Blood 2007; 110: 3192-3201.
33. Nishikawa H, Kato T, Tanida K, Hiasa A, Tawara I, Ikeda H, Ikarashi Y, Wakasugi H, Kronenberg M, Nakayama T, Taniguchi M, Kuribayashi K, Old LJ and Shiku H. CD4+ CD25+ T cells responding to serologically defined autoantigens suppress antitumor immune responses. Proc Natl Acad Sci U S A 2003; 100: 10902-10906.
34. Wei S, Kryczek I, Edwards RP, Zou L, Szeliga W, Banerjee M, Cost M, Cheng P, Chang A, Redman B, Herberman RB and Zou W. Interleukin-2 administration alters the CD4+FOXP3+ T-cell pool and tumor trafficking in patients with ovarian carcinoma. Cancer Res 2007; 67: 7487-7494.
35. Mailloux AW and Young MR. Regulatory T-cell trafficking: from thymic development to tumor-induced immune suppression. Crit Rev Immunol 2010; 30: 435-447.
36. Yu P, Lee Y, Liu W, Krausz T, Chong A, Schreiber H and Fu YX. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 2005; 201: 779-791.
37. Chen ML, Pittet MJ, Gorelik L, Flavell RA, Weissleder R, von Boehmer H and Khazaie K. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci U S A 2005; 102: 419-424.
38. Loser K, Apelt J, Voskort M, Mohaupt M, Balkow S, Schwarz T, Grabbe S and Beissert S. IL-10 controls ultraviolet-induced carcinogenesis in mice. J Immunol 2007; 179: 365-371.
39. Strauss L, Bergmann C, Szczepanski M, Gooding W, Johnson JT and Whiteside TL. A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment. Clin Cancer Res 2007; 13: 4345-4354.
40. Anderson BE, McNiff JM, Matte C, Athanasiadis I, Shlomchik WD and Shlomchik MJ. Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease. Blood 2004; 104: 1565-1573.
41. Komatsu N and Hori S. Full restoration of peripheral Foxp3+ regulatory T cell pool by radioresistant host cells in scurfy bone marrow chimeras. Proc Natl Acad Sci U S A 2007; 104: 8959-8964.
42. Qu Y, Jin S, Zhang A, Zhang B, Shi X, Wang J and Zhao Y. Gamma-ray resistance of regulatory CD4+CD25+Foxp3+ T cells in mice. Radiat Res 2010; 173: 148-157.
43. Balogh A, Persa E, Bogdandi EN, Benedek A, Hegyesi H, Safrany G and Lumniczky K. The effect of ionizing radiation on the homeostasis and functional integrity of murine splenic regulatory T cells. Inflamm Res 2013; 62: 201-212.
44. McFarland HI, Puig M, Grajkowska LT, Tsuji K, Lee JP, Mason KP, Verthelyi D and Rosenberg AS. Regulatory T cells in gamma irradiation-induced immune suppression. PLoS One 2012; 7: e39092.
45. Cao M, Cabrera R, Xu Y, Liu C and Nelson D. Gamma irradiation alters the phenotype and function of CD4+CD25+ regulatory T cells. Cell Biol Int 2009; 33: 565-571.
46. Qu Y, Zhang B, Liu S, Zhang A, Wu T and Zhao Y. 2-Gy whole-body irradiation significantly alters the balance of CD4+ CD25- T effector cells and CD4+ CD25+ Foxp3+ T regulatory cells in mice. Cell Mol Immunol 2010; 7: 419-427.
47. Liu R, Xiong S, Zhang L and Chu Y. Enhancement of antitumor immunity by low-dose total body irradiationis associated with selectively decreasing the proportion and number of T regulatory cells. Cell Mol Immunol 2010; 7: 157-162.
48. Billiard F, Buard V, Benderitter M and Linard C. Abdominal gamma-radiation induces an accumulation of function-impaired regulatory T cells in the small intestine. Int J Radiat Oncol Biol Phys 2011; 80: 869-876.
49. Burnette B and Weichselbaum RR. Radiation as an immune modulator. Semin Radiat Oncol 2013; 23: 273-280.
50. Battaglia A, Buzzonetti A, Martinelli E, Fanelli M, Petrillo M, Ferrandina G, Scambia G and Fattorossi A. Selective changes in the immune profile of tumor-draining lymph nodes after different neoadjuvant chemoradiation regimens for locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 2010; 76: 1546-1553.
51. Wang M, Gou X and Wang L. Protein kinase B promotes radiation-induced regulatory T cell survival in bladder carcinoma. Scand J Immunol 2012; 76: 70-74.
52. Li CG, He MR, Wu FL, Li YJ and Sun AM. Akt promotes irradiation-induced regulatory T-cell survival in hepatocellular carcinoma. Am J Med Sci 2013; 346: 123-127.
53. Wu L, Wu MO, De la Maza L, Yun Z, Yu J, Zhao Y, Cho J and de Perrot M. Targeting the inhibitory receptor CTLA-4 on T cells increased apscopal effects in murine mesothelioma model. Oncotarget 2015; 6: 12468-12480.
54. Wu CT, Hsieh CC, Yen TC, Chen WC and Chen MF. TGF-beta1 mediates the radiation re sponse of prostate cancer. J Mol Med (Berl) 2015; 93: 73-82.
55. Park B, Yee C and Lee KM. The effect of radiation on the immune response to cancers. Int J Mol Sci 2014; 15: 927-943.
56. Wei S, Egenti MU, Teitz-Tennenbaum S, Zou W and Chang AE. Effects of tumor irradiation on host T-regulatory cells and systemic immunity in the context of adoptive T-cell therapy in mice. J Immunother 2013; 36: 124-132.
57. Li Q, Xu X, Zhong W, Du Q, Yu B and Xiong H. IL-17 induces radiation resistance of B lymphoma cells by suppressing p53 expression and thereby inhibiting irradiation-triggered apoptosis. Cell Mol Immunol 2015; 12: 366-72.
58. Kachikwu EL, Iwamoto KS, Liao YP, DeMarco JJ, Agazaryan N, Economou JS, McBride WH and Schaue D. Radiation enhances regulatory T cell representation. Int J Radiat Oncol Biol Phys 2011; 81: 1128-1135.
59. Smilowitz HM, Sasso D, Lee EW, Goh G, Micca PL and Dilmanian FA. Therapy model for advanced intracerebral B16 mouse melanoma using radiation therapy combined with immunotherapy. Cancer Immunol Immunother 2013; 62: 1187-1197.
60. Le DT and Jaffee EM. Regulatory T-cell modulation using cyclophosphamide in vaccine approaches: a current perspective. Cancer Res 2012; 72: 3439-3444.
61. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T and Sakaguchi S. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008; 322: 271-275.
62. Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, Vonderheide RH and Minn AJ. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015; 520: 373-377.
63. Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP and Formenti SC. Immunemediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 2005; 11: 728-734.
64. Silk AW, Bassetti MF, West BT, Tsien CI and Lao CD. Ipilimumab and radiation therapy for melanoma brain metastases. Cancer Med 2013; 2: 899-906.
65. Barker CA and Postow MA. Combinations of radiation therapy and immunotherapy for melanoma: a review of clinical outcomes. Int J Radiat Oncol Biol Phys 2014; 88: 986-997.
66. Grimaldi AM, Simeone E, Giannarelli D, Muto P, Falivene S, Borzillo V, Giugliano FM, Sandomenico F, Petrillo A, Curvietto M, Esposito A, Paone M, Palla M, Palmieri G, Caraco C, Ciliberto G, Mozzillo N and Ascierto PA. Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy. Oncoimmunology 2014; 3: e28780.
67. Golden EB, Demaria S, Schiff PB, Chachoua A and Formenti SC. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res 2013; 1: 365-372.
68. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, Scher HI, Chin K, Gagnier P, McHenry MB and Beer TM. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol 2013; 24: 1813-1821.
69. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengelov L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D and Gerritsen WR. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2014; 15: 700-712.