BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Cancer immunotherapy with T-cell targeting cytokines: IL-2 and IL-7

  • Kim, Ji-Hae (Department of Life Sciences, Pohang University of Science and Technology (POSTECH)) ;
  • Lee, Kun-Joo (Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH)) ;
  • Lee, Seung-Woo (Department of Life Sciences, Pohang University of Science and Technology (POSTECH))
  • Received : 2020.11.02
  • Accepted : 2020.12.28
  • Published : 2021.01.31
Download PDF
⟨ Previous Next ⟩

Abstract

Clinical trials have demonstrated that an increased number of effector cells, especially tumor-specific T cells, is positively linked with patients' prognosis. Although the discovery of checkpoint inhibitors (CPIs) has led to encouraging progress in cancer immunotherapy, the lack of either T cells or targets for CPIs is a limitation for patients with poor prognosis. Since interleukin (IL)-2 and IL-7 are cytokines that target many aspects of T-cell responses, they have been used to treat cancers. In this review, we focus on the basic biology of how these cytokines regulate T-cell response and on the clinical trials using the cytokines against cancer. Further, we introduce several recent studies that aim to improve cytokines' biological activities and find the strategy for combination with other therapeutics.

Keywords

References

  1. Chen DS and Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1-10 https://doi.org/10.1016/j.immuni.2013.07.012
  2. Fridman WH, Pages F, Sautes-Fridman C and Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12, 298-306 https://doi.org/10.1038/nrc3245
  3. Menetrier-Caux C, Ray-Coquard I, Blay JY and Caux C (2019) Lymphopenia in cancer patients and its effects on response to immunotherapy: an opportunity for combination with cytokines? J Immunother Cancer 7, 85 https://doi.org/10.1186/s40425-019-0549-5
  4. Leonard WJ, Lin JX and O'Shea JJ (2019) The gammac family of cytokines: basic biology to therapeutic ramifications. Immunity 50, 832-850 https://doi.org/10.1016/j.immuni.2019.03.028
  5. Morgan DA, Ruscetti FW and Gallo R (1976) Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 193, 1007-1008 https://doi.org/10.1126/science.181845
  6. Boyman O and Sprent J (2012) The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol 12, 180-190 https://doi.org/10.1038/nri3156
  7. Wang X, Rickert M and Garcia KC (2005) Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors. Science 310, 1159-1163 https://doi.org/10.1126/science.1117893
  8. Zhang X, Sun S, Hwang I, Tough DF and Sprent J (1998) Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity 8, 591-599 https://doi.org/10.1016/S1074-7613(00)80564-6
  9. Boyman O, Kovar M, Rubinstein MP, Surh CD and Sprent J (2006) Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311, 1924-1927 https://doi.org/10.1126/science.1122927
  10. Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22, 531-562 https://doi.org/10.1146/annurev.immunol.21.120601.141122
  11. Liao W, Lin JX, Wang L, Li P and Leonard WJ (2011) Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat Immunol 12, 551-559 https://doi.org/10.1038/ni.2030
  12. Yang XP, Ghoreschi K, Steward-Tharp SM et al (2011) Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol 12, 247-254 https://doi.org/10.1038/ni.1995
  13. Liao W, Spolski R, Li P et al (2014) Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression. Proc Natl Acad Sci U S A 111, 3508-3513 https://doi.org/10.1073/pnas.1301138111
  14. Laurence A, Tato CM, Davidson TS et al (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371-381 https://doi.org/10.1016/j.immuni.2007.02.009
  15. Ballesteros-Tato A, Leon B, Graf BA et al (2012) Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36, 847-856 https://doi.org/10.1016/j.immuni.2012.02.012
  16. Sadlack B, Lohler J, Schorle H et al (1995) Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur J Immunol 25, 3053-3059 https://doi.org/10.1002/eji.1830251111
  17. Willerford DM, Chen J, Ferry JA, Davidson L, Ma A and Alt FW (1995) Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521-530 https://doi.org/10.1016/1074-7613(95)90180-9
  18. Suzuki H, Kundig TM, Furlonger C et al (1995) Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science 268, 1472-1476 https://doi.org/10.1126/science.7770771
  19. Almeida AR, Legrand N, Papiernik M and Freitas AA (2002) Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J Immunol 169, 4850-4860 https://doi.org/10.4049/jimmunol.169.9.4850
  20. Malek TR, Yu A, Vincek V, Scibelli P and Kong L (2002) CD4 regulatory T cells prevent lethal autoimmunity in IL-2 Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167-178 https://doi.org/10.1016/S1074-7613(02)00367-9
  21. Fontenot JD, Rasmussen JP, Gavin MA and Rudensky AY (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6, 1142-1151 https://doi.org/10.1038/ni1263
  22. Kalia V, Sarkar S, Subramaniam S, Haining WN, Smith KA and Ahmed R (2010) Prolonged interleukin-2Ralpha expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. Immunity 32, 91-103 https://doi.org/10.1016/j.immuni.2009.11.010
  23. Pipkin ME, Sacks JA, Cruz-Guilloty F, Lichtenheld MG, Bevan MJ and Rao A (2010) Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32, 79-90 https://doi.org/10.1016/j.immuni.2009.11.012
  24. Lenardo M, Chan KM, Hornung F et al (1999) Mature T lymphocyte apoptosis--immune regulation in a dynamic and unpredictable antigenic environment. Annu Rev Immunol 17, 221-253 https://doi.org/10.1146/annurev.immunol.17.1.221
  25. Rosenberg SA, Lotze MT, Muul LM et al (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313, 1485-1492 https://doi.org/10.1056/NEJM198512053132327
  26. Rosenberg SA, Lotze MT, Aebersold PM, Linehan WM, Seipp CA and White DE (1989) Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 210, 474-485 https://doi.org/10.1097/00000658-198910000-00008
  27. Rosenberg SA, Yang JC, Topalian SL et al (1994) Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271, 907-913 https://doi.org/10.1001/jama.1994.03510360033032
  28. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR and Louie AC (1995) Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13, 688-696 https://doi.org/10.1200/JCO.1995.13.3.688
  29. Atkins MB, Lotze MT, Dutcher JP et al (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17, 2105-2116 https://doi.org/10.1200/JCO.1999.17.7.2105
  30. Caligiuri MA, Murray C, Robertson MJ et al (1993) Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin 2. J Clin Invest 91, 123-132 https://doi.org/10.1172/JCI116161
  31. Caligiuri MA, Murray C, Soiffer RJ et al (1991) Extended continuous infusion low-dose recombinant interleukin-2 in advanced cancer: prolonged immunomodulation without significant toxicity. J Clin Oncol 9, 2110-2119 https://doi.org/10.1200/JCO.1991.9.12.2110
  32. Soiffer RJ, Murray C, Shapiro C et al (1996) Expansion and manipulation of natural killer cells in patients with metastatic cancer by low-dose continuous infusion and intermittent bolus administration of interleukin 2. Clin Cancer Res 2, 493-499
  33. Fehniger TA, Bluman EM, Porter MM et al (2000) Potential mechanisms of human natural killer cell expansion in vivo during low-dose IL-2 therapy. J Clin Invest 106, 117-124 https://doi.org/10.1172/JCI6218
  34. Wrangle JM, Patterson A, Johnson CB et al (2018) IL-2 and beyond in cancer immunotherapy. J Interferon Cytokine Res 38, 45-68 https://doi.org/10.1089/jir.2017.0101
  35. Krieg C, Letourneau S, Pantaleo G and Boyman O (2010) Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells. Proc Natl Acad Sci U S A 107, 11906-11911 https://doi.org/10.1073/pnas.1002569107
  36. Sim GC, Martin-Orozco N, Jin L et al (2014) IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients. J Clin Invest 124, 99-110 https://doi.org/10.1172/JCI46266
  37. Levin AM, Bates DL, Ring AM et al (2012) Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'. Nature 484, 529-533 https://doi.org/10.1038/nature10975
  38. Ardolino M, Azimi CS, Iannello A et al (2014) Cytokine therapy reverses NK cell anergy in MHC-deficient tumors. J Clin Invest 124, 4781-4794 https://doi.org/10.1172/JCI74337
  39. Mortara L, Balza E, Bruno A, Poggi A, Orecchia P and Carnemolla B (2018) Anti-cancer therapies employing IL-2 cytokine tumor targeting: contribution of innate, adaptive and immunosuppressive cells in the anti-tumor efficacy. Front Immunol 9, 2905 https://doi.org/10.3389/fimmu.2018.02905
  40. Ishihara J, Ishihara A, Sasaki K et al (2019) Targeted antibody and cytokine cancer immunotherapies through collagen affinity. Sci Transl Med 11, eaau3259 https://doi.org/10.1126/scitranslmed.aau3259
  41. Mostbock S (2009) Cytokine/Antibody complexes: an emerging class of immunostimulants. Curr Pharm Des 15, 809-825 https://doi.org/10.2174/138161209787582174
  42. Kamimura D, Sawa Y, Sato M, Agung E, Hirano T and Murakami M (2006) IL-2 in vivo activities and antitumor efficacy enhanced by an anti-IL-2 mAb. J Immunol 177, 306-314 https://doi.org/10.4049/jimmunol.177.1.306
  43. Jin GH, Hirano T and Murakami M (2008) Combination treatment with IL-2 and anti-IL-2 mAbs reduces tumor metastasis via NK cell activation. Int Immunol 20, 783-789 https://doi.org/10.1093/intimm/dxn036
  44. Roopenian DC and Akilesh S (2007) FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 7, 715-725 https://doi.org/10.1038/nri2155
  45. Zhu EF, Gai SA, Opel CF et al (2015) Synergistic innate and adaptive immune response to combination immunotherapy with anti-tumor antigen antibodies and extended serum half-life IL-2. Cancer Cell 27, 489-501 https://doi.org/10.1016/j.ccell.2015.03.004
  46. Sun Z, Ren Z, Yang K et al (2019) A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8(+) T-cell response and effective tumor control. Nat Commun 10, 3874 https://doi.org/10.1038/s41467-019-11782-w
  47. Yang JC, Topalian SL, Schwartzentruber DJ et al (1995) The use of polyehylene glycol-modified interleukin-2 (PEG-IL-2) in the treatment of patients with metastatic renal cell carcinoma and melanoma. Cancer 76, 687-694 https://doi.org/10.1002/1097-0142(19950815)76:4<687::AID-CNCR2820760424>3.0.CO;2-M
  48. Charych DH, Hoch U, Langowski JL et al (2016) NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor Models. Clin Cancer Res 22, 680-690 https://doi.org/10.1158/1078-0432.CCR-15-1631
  49. Sharma M, Khong H, Fa'ak F et al (2020) Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy. Nat Commun 11, 661 https://doi.org/10.1038/s41467-020-14471-1
  50. Mackall CL, Fry TJ and Gress RE (2011) Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol 11, 330-342 https://doi.org/10.1038/nri2970
  51. Link A, Vogt TK, Favre S et al (2007) Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat Immunol 8, 1255-1265 https://doi.org/10.1038/ni1513
  52. Kim GY, Hong C and Park JH (2011) Seeing is believing: illuminating the source of in vivo interleukin-7. Immune Netw 11, 1-10 https://doi.org/10.4110/in.2011.11.1.1
  53. Guimond M, Veenstra RG, Grindler DJ et al (2009) Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat Immunol 10, 149-157 https://doi.org/10.1038/ni.1695
  54. Al-Shami A, Spolski R, Kelly J et al (2004) A role for thymic stromal lymphopoietin in CD4(+) T cell development. J Exp Med 200, 159-168 https://doi.org/10.1084/jem.20031975
  55. Peschon JJ, Morrissey PJ, Grabstein KH et al (1994) Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med 180, 1955-1960 https://doi.org/10.1084/jem.180.5.1955
  56. von Freeden-Jeffry U, Vieira P, Lucian LA, McNeil T, Burdach SE and Murray R (1995) Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J Exp Med 181, 1519-1526 https://doi.org/10.1084/jem.181.4.1519
  57. Clark MR, Mandal M, Ochiai K and Singh H (2014) Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling. Nat Rev Immunol 14, 69-80 https://doi.org/10.1038/nri3570
  58. Puel A, Ziegler SF, Buckley RH and Leonard WJ (1998) Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nat Genet 20, 394-397 https://doi.org/10.1038/3877
  59. Mazzucchelli R and Durum SK (2007) Interleukin-7 receptor expression: intelligent design. Nat Rev Immunol 7, 144-154 https://doi.org/10.1038/nri2023
  60. Kondo M, Akashi K, Domen J, Sugamura K and Weissman IL (1997) Bcl-2 rescues T lymphopoiesis, but not B or NK cell development, in common gamma chain-deficient mice. Immunity 7, 155-162 https://doi.org/10.1016/S1074-7613(00)80518-X
  61. Akashi K, Kondo M, von Freeden-Jeffry U, Murray R and Weissman IL (1997) Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell 89, 1033-1041 https://doi.org/10.1016/S0092-8674(00)80291-3
  62. Maraskovsky E, O'Reilly LA, Teepe M, Corcoran LM, Peschon JJ and Strasser A (1997) Bcl-2 can rescue T lymphocyte development in interleukin-7 receptor-deficient mice but not in mutant rag-1(-/-) mice. Cell 89, 1011-1019 https://doi.org/10.1016/S0092-8674(00)80289-5
  63. Pellegrini M, Bouillet P, Robati M, Belz GT, Davey GM and Strasser A (2004) Loss of Bim increases T cell production and function in interleukin 7 receptor-deficient mice. J Exp Med 200, 1189-1195 https://doi.org/10.1084/jem.20041328
  64. Khaled AR, Li WQ, Huang J et al (2002) Bax deficiency partially corrects interleukin-7 receptor alpha deficiency. Immunity 17, 561-573 https://doi.org/10.1016/S1074-7613(02)00450-8
  65. Boudil A, Matei IR, Shih HY et al (2015) IL-7 coordinates proliferation, differentiation and Tcra recombination during thymocyte beta-selection. Nat Immunol 16, 397-405 https://doi.org/10.1038/ni.3122
  66. Moore TA, von Freeden-Jeffry U, Murray R and Zlotnik A (1996) Inhibition of gamma delta T cell development and early thymocyte maturation in IL-7 -/- mice. J Immunol 157, 2366-2373
  67. Shitara S, Hara T, Liang B et al (2013) IL-7 produced by thymic epithelial cells plays a major role in the development of thymocytes and TCRgammadelta+ intraepithelial lymphocytes. J Immunol 190, 6173-6179 https://doi.org/10.4049/jimmunol.1202573
  68. Vosshenrich CA, Garcia-Ojeda ME, Samson-Villeger SI et al (2006) A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127. Nat Immunol 7, 1217-1224 https://doi.org/10.1038/ni1395
  69. Vogt TK, Link A, Perrin J, Finke D and Luther SA (2009) Novel function for interleukin-7 in dendritic cell development. Blood 113, 3961-3968 https://doi.org/10.1182/blood-2008-08-176321
  70. Soares MV, Borthwick NJ, Maini MK, Janossy G, Salmon M and Akbar AN (1998) IL-7-dependent extrathymic expansion of CD45RA+ T cells enables preservation of a naive repertoire. J Immunol 161, 5909-5917
  71. Swainson L, Kinet S, Mongellaz C, Sourisseau M, Henriques T and Taylor N (2007) IL-7-induced proliferation of recent thymic emigrants requires activation of the PI3K pathway. Blood 109, 1034-1042 https://doi.org/10.1182/blood-2006-06-027912
  72. Ernst B, Lee DS, Chang JM, Sprent J and Surh CD (1999) The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11, 173-181 https://doi.org/10.1016/S1074-7613(00)80092-8
  73. Goldrath AW and Bevan MJ (1999) Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity 11, 183-190 https://doi.org/10.1016/S1074-7613(00)80093-X
  74. Surh CD and Sprent J (2008) Homeostasis of naive and memory T cells. Immunity 29, 848-862 https://doi.org/10.1016/j.immuni.2008.11.002
  75. Surh CD and Sprent J (2005) Regulation of mature T cell homeostasis. Semin Immunol 17, 183-191 https://doi.org/10.1016/j.smim.2005.02.007
  76. Hennion-Tscheltzoff O, Leboeuf D, Gauthier SD et al (2013) TCR triggering modulates the responsiveness and homeostatic proliferation of CD4+ thymic emigrants to IL-7 therapy. Blood 121, 4684-4693 https://doi.org/10.1182/blood-2012-09-458174
  77. Park JH, Adoro S, Lucas PJ et al (2007) 'Coreceptor tuning': cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specificity of the TCR. Nat Immunol 8, 1049-1059 https://doi.org/10.1038/ni1512
  78. Seddiki N, Santner-Nanan B, Martinson J et al (2006) Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 203, 1693-1700 https://doi.org/10.1084/jem.20060468
  79. Liu W, Putnam AL, Xu-Yu Z et al (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203, 1701-1711 https://doi.org/10.1084/jem.20060772
  80. Barata JT, Silva A, Brandao JG, Nadler LM, Cardoso AA and Boussiotis VA (2004) Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells. J Exp Med 200, 659-669 https://doi.org/10.1084/jem.20040789
  81. Wofford JA, Wieman HL, Jacobs SR, Zhao Y and Rathmell JC (2008) IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood 111, 2101-2111 https://doi.org/10.1182/blood-2007-06-096297
  82. Cui GL, Staron MM, Gray SM et al (2015) IL-7-induced glycerol transport and TAG synthesis promotes memory CD8(+) T cell longevity. Cell 161, 750-761 https://doi.org/10.1016/j.cell.2015.03.021
  83. Kimura MY, Pobezinsky LA, Guinter TI et al (2013) IL-7 signaling must be intermittent, not continuous, during CD8 (+) T cell homeostasis to promote cell survival instead of cell death. Nat Immunol 14, 143-151 https://doi.org/10.1038/ni.2494
  84. Rosenberg SA, Sportes C, Ahmadzadeh M et al (2006) IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells. J Immunother 29, 313-319 https://doi.org/10.1097/01.cji.0000210386.55951.c2
  85. Sportes C, Hakim FT, Memon SA et al (2008) Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med 205, 1701-1714 https://doi.org/10.1084/jem.20071681
  86. Tredan O, Menetrier-Caux C, Ray-Coquard I et al (2015) ELYPSE-7: a randomized placebo-controlled phase IIa trial with CYT107 exploring the restoration of CD4+ lymphocyte count in lymphopenic metastatic breast cancer patients. Ann Oncol 26, 1353-1362 https://doi.org/10.1093/annonc/mdv173
  87. Merchant MS, Bernstein D, Amoako M et al (2016) Adjuvant immunotherapy to improve outcome in high-risk pediatric sarcomas. Clin Cancer Res 22, 3182-3191 https://doi.org/10.1158/1078-0432.CCR-15-2550
  88. Reimers MA, Slane KE and Pachynski RK (2019) Immunotherapy in metastatic castration-resistant prostate cancer: past and future strategies for optimization. Curr Urol Rep 20, 64 https://doi.org/10.1007/s11934-019-0931-3
  89. Sportes C, Babb RR, Krumlauf MC et al (2010) Phase I study of recombinant human interleukin-7 administration in subjects with refractory malignancy. Clin Cancer Res 16, 727-735 https://doi.org/10.1158/1078-0432.CCR-09-1303
  90. Miller PW, Sharma S, Stolina M et al (2000) Intratumoral administration of adenoviral interleukin 7 gene-modified dendritic cells augments specific antitumor immunity and achieves tumor eradication. Hum Gene Ther 11, 53-65 https://doi.org/10.1089/10430340050016157
  91. Li B, VanRoey MJ and Jooss K (2007) Recombinant IL-7 enhances the potency of GM-CSF-secreting tumor cell immunotherapy. Clin Immunol 123, 155-165 https://doi.org/10.1016/j.clim.2007.01.002
  92. Pellegrini M, Calzascia T, Elford AR et al (2009) Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat Med 15, 528-536 https://doi.org/10.1038/nm.1953
  93. Andersson A, Srivastava MK, Harris-White M et al (2011) Role of CXCR3 ligands in IL-7/IL-7R alpha-Fc-mediated antitumor activity in lung cancer. Clin Cancer Res 17, 3660-3672 https://doi.org/10.1158/1078-0432.CCR-10-3346
  94. Boyman O, Ramsey C, Kim DM, Sprent J and Surh CD (2008) IL-7/anti-IL-7 mAb complexes restore T cell development and induce homeostatic T cell expansion without lymphopenia. J Immunol 180, 7265-7275 https://doi.org/10.4049/jimmunol.180.11.7265
  95. Martin CE, van Leeuwen EM, Im SJ, Roopenian DC, Sung YC and Surh CD (2013) IL-7/anti-IL-7 mAb complexes augment cytokine potency in mice through association with IgG-Fc and by competition with IL-7R. Blood 121, 4484-4492 https://doi.org/10.1182/blood-2012-08-449215
  96. Nam HJ, Song MY, Choi DH, Yang SH, Jin HT and Sung YC (2010) Marked enhancement of antigen-specific T-cell responses by IL-7-fused nonlytic, but not lytic, Fc as a genetic adjuvant. Eur J Immunol 40, 351-358 https://doi.org/10.1002/eji.200939271
  97. Lee SW, Choi D, Heo M et al (2020) hIL-7-hyFc, a longacting IL-7, increased absolute lymphocyte count in healthy subjects. Clin Transl Sci 13, 1161-1169 https://doi.org/10.1111/cts.12800
  98. Choi YW, Kang MC, Seo YB et al (2016) Intravaginal administration of Fc-fused IL7 suppresses the cervicovaginal tumor by recruiting HPV DNA vaccine-induced CD8 T cells. Clin Cancer Res 22, 5898-5908 https://doi.org/10.1158/1078-0432.CCR-16-0423
  99. Kim JH, Kim YM, Choi D et al (2020) Hybrid Fc-fused interleukin-7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy. Clin Transl Immunology 9, e1168