CD4+ T-helpers in TCR-dependent tumor immunosurveillance and T-cell based adoptive transfer immunotherapy: are they really that helpful?

Home/2015, Vol. 3, No. 1/CD4+ T-helpers in TCR-dependent tumor immunosurveillance and T-cell based adoptive transfer immunotherapy: are they really that helpful?

Cell and Organ Transplantology. 2015; 3(1):87-91.
DOI: 10.22494/COT.V3I1.20

CD4+ T-helpers in TCR-dependent tumor immunosurveillance and T-cell based adoptive transfer immunotherapy: are they really that helpful?

Plachynta M. S.
V. N. Karazin Kharkiv National University, Kharkiv, Ukraine

In this brief review the advances and hurdles of the modern-day ACT (adoptive cell transfer) immunotherapy of cancer are discussed, with the focus on the positive or negative role of CD4+ T helper lymphocytes as one of major constituents of oncologic patient-administered CIK (cytokine-induced killers) lymphocyte culture. The beneficial role of CD4+ T helpers in adoptively-transferred lymphocyte culture is considered, questioned and being put under doubt. “Infectious tolerance” and tumor “immune avoidance” phenomena are described, emphasizing on their dramatic implications for cancer ACT therapy. The ways to circumvent apparent undesired effects of CD4+ T helpers elevated presence in CIK bulk mass are discussed, such as complete removal of CD4 -positive cells, along with a less radical measure, which is depletion of CD4+CD25+FoxP3+ T regulatory lymphocytes from bulk CIK culture.

Keywords: cancer immunotherapy; adoptive cell transfer; cytokine-induced killers; CD4+ Т-regulatory lymphocytes

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1. Märten A, Renoth S, von Lilienfeld-Toal M, Buttgereit P, Schakowski F, Glasmacher A, Sauerbruch T, Schmidt-Wolf IG. Enhanced lytic activity of cytokine-induced killer cells against multiple myeloma cells after co-culture with idiotype-pulsed dendritic cells. Haematologica. 2001; 86:1029-1037
2. Sangiolo D. Cytokine induced killer cells as promising immunotherapy for solid tumors. Journal of Cancer. 2011; 2:363–368.
PMid:21716717 PMCid:PMC3119405
3. Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nature Reviews. Clinical Oncology. 2013; 10:267-276. DOI: 10.1038/nrclinonc.2013.46.
4. Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma and Indolent B-Cell Malignancies Can Be Effectively Treated With Autologous T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor. Journal of Clinical Oncology. 2015; 33(6):202-208.
PMid:25154820 PMCid:PMC4322257
5. Robbins PF, Morgan RA, Feldman SA, et al. Tumor Regression in Patients With Metastatic Synovial Cell Sarcoma and Melanoma Using Genetically Engineered Lymphocytes Reactive With NY-ESO-1. Journal of Clinical Oncology. 2011; 29(7):1129-1134.
PMid:21282551 PMCid:PMC3068063
6. Igney FH, Krammer PH. Immune escape of tumors: apoptosis resistance and tumor counterattack. J Leukoc Biol. 2002; 71(6):907-20.
7. Campoli M, Ferrone S. Tumor escape mechanisms: Potential role of soluble HLA antigens and NK cells activating ligands. Tissue Antigens. 2008, 72(4): 321–334. Published online Aug 12, 2008. DOI: 10.1111/j.1399-0039.2008.01106.x. PMCID: PMC2729103. NIHMSID: NIHMS131324.
8. Dranoff G. The Therapeutic Implications of Intratumoral Regulatory T Cells. Clin Cancer Res. 2005; 11(23):8226-8229.
9. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer. 2012;12:252-264. DOI:10.1038/nrc3239.
10. Yang Zh-Zh, Novak AJ, Ziesmer SC, et al. CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25- T cells. Blood, 2007; 110:2537-2544.
PMid:17615291 PMCid:PMC1988926
11. Blankenstein T, Leisegang M, Uckert W, et al. Targeting cancer-specific mutations by T cell receptor gene therapy. Immunology. 2015, 33:112-119.
12. Wang X, Riviere I. Manufacture of tumor- and virus-specific T lymphocytes for adoptive cell therapies. Cancer Gene Therapy. 2015; 22:85–94.
PMid:25721207 PMCid:PMC4480367
13. Tao QSh, Wang HP, Zhai ZhM. Targeting regulatory T cells in cytokine induced killer cell cultures. Biomedical reports. 2014; 2(3):317-320. DOI: 10.3892/br.2014.234.
14. Li H, Yu JP, Cao S, et al. CD4+CD25+ regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients. J Clin Immunol. 2007; 27:317–326.
15. Rustichelli D, Castiglia S, Gunetti M, et al. Validation of analytical methods in compliance with good manufacturing practice: a practical approach. Journal of Translational Medicine. 2013; 11:197. DOI: 10.1186/1479-5876-11-197.
16. Turcotte S, Gros A, Hogan K, et al. Phenotype and Function of T Cells Infiltrating Visceral Metastases from Gastrointestinal Cancers and Melanoma: Implications for Adoptive Cell Transfer Therapy. Immunol. 2013; 191(5):2217–2225.
PMid:23904171 PMCid:PMC3748336
17. Yee C, Thompson JA, Byrd D, et al. Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: In vivo persistence, migration, and antitumor effect of transferred T cells. Immunology. 2002; 99(25):16168–16173.
18. Hinrichs ChS, Rosenberg SA. Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunological Reviews. 2014; 257: 56–71.
PMid:24329789 PMCid:PMC3920180
19. Chang AE, Li Q, Jiang GH, et al. Phase II Trial of Autologous Tumor Vaccination, Anti-CD3-Activated Vaccine-Primed Lymphocytes, and Interleukin-2 in Stage IV Renal Cell Cancer. Journal of Clinical Oncology. 2003; 21(5):884-890.
20. Finn L, Markovic SN and Joseph RW. Therapy for metastatic melanoma: the past, present, and future. BMC Medicine. 2012; 10:23 DOI: 10.1186/1741-7015-10-23.
21. Tao Q, Chen T, Tao L, et al. IL-15 improves the cytotoxicity of cytokine-induced killer cells against leukemia cells by upregulating CD3+CD56+ cells and downregulating regulatory T cells as well as IL-35. J Immunother. 2013; 36:462–467.
22. Amakata Y, Fujiyama Y, Andoh A, et al. Mechanism of NK cell activation induced by coculture with dendritic cells derived from peripheral blood monocytes. Clin Exp Immunol. 2001; 124(2):214–222. DOI: 10.1046/j.1365-2249.2001.01550.x PMCID: PMC1906048.
23. Childs RW and Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. Hematology Am Soc Hematol Educ Program. 2013; 2013: 234-46. DOI: 10.1182/asheducation-2013.1.234.
24. Miao L, Run-Ming J and Yi J. T-Bet mediated anti-neoplastic effects of dendritic cell-cytokine induced killer cells in vitro. Iran J Pediatr. 2012; 22:43–51.
PMid:23056858 PMCid:PMC3448214
25. Kershaw MH, Westwood JA, Parker LL, et al. A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer. Clin Cancer Res. 2006; 12:6106–6115. doi: 10.1158/1078-0432.CCR-06-1183. PMCID: PMC2154351. NIHMSID: NIHMS35281.
26. Huang JP, Khong HT, Dudley ME, et al. Survival, Persistence, and Progressive Differentiation of Adoptively Transferred Tumor-Reactive T Cells Associated with Tumor Regression. J Immunother. 2005; 28(3): 258–267. PMCID: PMC2174599, NIHMSID: NIHMS35948.
27. Xu S, Koski GK, Faries M, et al. Rapid high efficiency sensitization of CD8+ T cells to tumor antigens by dendritic cells leads to enhanced functional avidity and direct tumor recognition through an IL-12-dependent mechanism. J Immunol. 2003; 171(5):2251-61.
28. Ge Q, Palliser D, Eisen HN, et al. Homeostatic T cell proliferation in a T cell-dendritic cell coculture system. Proc Natl Acad Sci U S A. 2002; 99(5): 2983–2988. Published online Feb 19, 2002. doi: 10.1073/pnas.052714199. PMCID: PMC122459 Immunology.
29. Tran E, Turcotte S, Gros A, et al. Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer. Science. 2014; 344: 641-645. DOI:10.1126/science.1251102.
30. Dudley ME, Wunderlich JR, Shelton ThE, et al. Generation of Tumor-Infiltrating Lymphocyte Cultures for Use in Adoptive Transfer Therapy for Melanoma Patients. J Immunother. 2003; 26(4):332–342. PMCID: PMC2305721, NIHMSID: NIHMS43934.
31. Ho WY, Nguyen HN, Wolfl M, et al. In vitro methods for generating CD8+ T-cell clones for immunotherapy from the naïve repertoire. Journal of Immunological. 2006; 310:40-52.
32. Ibe S, Qin ZhH, Schüler Th, et al. Tumor Rejection by Disturbing Tumor Stroma Cell Interactions. J. Exp. Med. 2001; 194:1549–1559.
PMid:11733570 PMCid:PMC2193522
33. Ambrosino E, Spadaro M, Iezzi M, et al. Immunosurveillance of Erbb2 Carcinogenesis in Transgenic Mice Is Concealed by a Dominant Regulatory T-Cell Self-Tolerance. Cancer Res. 2006; 66:15.
34. Dorf ME, Kuchroo VK, Collins M. Suppressor T cells: some answers but more questions. Immunology Today. 2002; 13(7):241-247.
35. Holaday BJ, de Lima Pompeu MM, Jeronimo S, et al. Potential Role for Interleukin-10 in the Immunosuppression Associated with Kala Azar. J. Clin. Invest. 1993; 92:2626-2632.
PMid:8254019 PMCid:PMC288459
36. Hara M, Kingsley CI, Niimi M, et al. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J Immunol. 2001; 166:3789-3796.
37. Shevach EM. Mechanisms of Foxp3+ T Regulatory Cell-Mediated Suppression. Immunity. 2009; 30(5):636–645. DOI:10.1016/j.immuni.2009.04.010.
38. Schwartz RH. Natural regulatory T cells and self-tolerance. Nature Immunology. 2005; 6:327 – 330. DOI:10.1038/ni1184.
39. Roncador G, Brown PhJ, Maestre L, et al. Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur. J. Immunol. 2005; 35:1681–1691. DOI 10.1002/eji.200526189.
40. Levings MK, Sangregorio R, Roncarolo MG. Human CD25+CD4+ T regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med. 2001; 193:1295–302.
PMid:11390436 PMCid:PMC2193376
41. Duggleby RC, Shaw TNF, Jarvis LB, et al. CD27 expression discriminates between regulatory and non-regulatory cells after expansion of human peripheral blood CD4+CD25+ cells. Immunology. 2007; 121(1):129–139. DOI: 10.1111/j.1365-2567.2006.02550.x. PMCID: PMC2265918.
42. Dieckmann D, Plottner H, Berchtold S, et al. Ex vivo isolation and characterization of CD4+CD25+ T cells with regulatory properties from human blood. J Exp Med. 2001; 193:1303–10.
PMid:11390437 PMCid:PMC2193384
43. Wu H, Li P, Shao N, et al. Aberrant expression of Treg-associated cytokine IL-35 along with IL-10 and TGF-β in acute myeloid leukemia. Oncol Lett. 2012; 3(5):1119–1123. DOI: 10.3892/ol.2012.614 PMCID: PMC3389635.
44. Shevach EM, Davidson TS, Huter EN, et al. Role of TGF-β in the Induction of Foxp3 Expression and T Regulatory Cell Function. Journal of Clinical Immunology. 2008; 28(6):640-646.
45. Horwitz DA, Zheng SG, Gray JD. Natural and TGF-β–induced Foxp3+CD4+CD25+ regulatory T cells are not mirror images of each other. Trends in Immunology. 2008; 29(9):429–435.
46. Zheng SG, Wang JH, Gray JD, et al. Natural and Induced CD4+CD25+ Cells Educate CD4+CD25− Cells to Develop Suppressive Activity: The Role of IL-2, TGF-β, and IL-10. The Journal of Immunology. 2004; 172(9):5213-5221. DOI: 10.4049/jimmunol.172.9.5213.
47. Tang QZh, Bluestone JA. Plasmacytoid DCs and Treg cells: casual acquaintance or monogamous relationship? Nature Immunology. 2006; 7:551 – 553. DOI:10.1038/ni0606-551.
48. Bardel E, Larousserie F, Charlot-Rabiega P, et al. Human CD4+CD25+Foxp3+ Regulatory T Cells Do Not Constitutively Express IL-35. The Journal of Immunology. 2008; 181:6898-6905. DOI: 10.4049/jimmunol.181.10.6898.
49. Colombo MP, Piconese S. Regulatory T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nature Reviews Cancer, 2007; 7:880-887. DOI:10.1038/nrc2250.
50. Walker MR, Kasprowicz DJ, Gersuk VH. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25– T cells. J Clin Invest. 2003; 112(9): 1437–1443. DOI: 10.1172/JCI200319441 , PMCID: PMC228469.
51. Wu HY, Quintana FJ, da Cunha AP, et al. In Vivo Induction of Tr1 Cells via Mucosal Dendritic Cells and AHR Signaling. PLoS One. 2011; 6(8):e23618. PMCID: PMC3160310.
PMid:21886804 PMCid:PMC3160310
52. Shen L, Pili R. Class I histone deacetylase inhibition is a novel mechanism to target regulatory T cells in immunotherapy. Oncoimmunology. 2012; 1(6):948–950. DOI: 10.4161/onci.20306. PMCID: PMC3489755.

Plachynta MS. CD4+ T-helpers in TCR-dependent tumor immunosurveillance and t-cell based adoptive transfer immunotherapy: are they really that helpful? Cell and Organ Transplantology. 2015; 3(1):87-91. doi: 10.22494/COT.V3I1.20


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