Immunological Aspects in Oncology –  Circulating γδ T Cells


Authors: M. Cibulka 1,2;  I. Selingerová 1;  L. Fědorová 1;  Zdražilová Dubská L. 1–3
Authors‘ workplace: Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno 1;  Advanced Cell Immunotherapy Unit, Farmakologický ústav, LF MU, Brno 2;  Oddělení laboratorní medicíny, Masarykův onkologický ústav, Brno 3
Published in: Klin Onkol 2015; 28(Supplementum 2): 60-68
doi: 10.14735/amko20152S60

Overview

γδ T cells present a minor population of the T cell family which basically differs in construction of their T cell receptor (TCR). Thanks to the features of γδ TCR, these cells can acquire unique effector functions and play a specific role (not only) in anti‑tumor immune response. In this article, we describe the basic characteristics of this cell population and their connection to cancer. In the experimental part we performed exploratory analysis of circulating γδ T cells in reference population and comparison with melanoma and breast carcinoma patients. The median percentage of γδ T cells from all lymphocytes was 2.9% (interquartile range – IQR 1.7–4%). The median absolute numbers of γδ cells per liter of blood was 5.05 × 107 (IQR 2.9–7.84 × 107). The median percentage of γδ cells between all CD3 T cells was 3.9% (IQR 2.3–5.6%). No correlation between γδ T cells levels and gender or age was observed in reference population. Detailed immunophenotyping was also conducted describing representation of memory subsets (using CD45RO and CD27 markers) and presence of surface markers HLA‑Dr, CD69, CD25, CD28, CCR7, CTLA‑4, ICOS, PD‑1L and PD‑1 between γδ T cells of the controls and breast carcinoma patients. From this analysis, it is evident that γδ T cells do not represent a uniform population but they differ in surface markers as well as in their effector functions.

Key words:
γδ T cells –cancer – immune system – peripheral blood – immunotherapy – T lymfocytes

This study was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101), by the projects MEYS – NPS I – LO1413, ACIU LM201117, and by MH CZ – DRO (MMCI, 00209805).

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Submitted:
4. 5. 2015

Accepted:
9. 7. 2015


Sources

1. Morita CT, Beckman EM, Bukowski JF et al. Direct presentation of nonpeptide prenyl pyrophosphate antigens to human gamma delta T cells. Immunity 1995; 3(4): 495– 507.

2. Kakimi K, Matsushita H, Murakawa T et al. Gammadelta T cell therapy for the treatment of non‑small cell lung cancer. Transl Lung Cancer Res 2014; 3(1): 23– 33. doi: 10.3978/ j.issn.2218‑ 6751.2013.11.01.

3. Groh V, Porcelli S, Fabbi M et al. Human lymphocytes bearing T cell receptor gamma/ delta are phenotypically diverse and evenly distributed throughout the lymphoid system. J Exp Med 1989; 169(4): 1277– 1294.

4. Guzman E, Hope J, Taylor G et al. Bovine gammadelta T cells are a major regulatory T cell subset. J Immunol 2014; 193(1): 208– 222. doi: 10.4049/ jimmunol.1303398.

5. Hinz T, Wesch D, Halary F et al. Identification of the complete expressed human TCR V gamma repertoire by flow cytometry. Int Immunol 1997; 9(8): 1065– 1072.

6. Holtmeier W, Pfänder M, Hennemann A et al. The TCR‑ delta repertoire in normal human skin is restricted and distinct from the TCR‑ delta repertoire in the peripheral blood. J Invest Dermatol 2001; 116(2): 275– 280.

7. Groh V, Steinle A, Bauer S et al. Recognition of stress‑induced MHC molecules by intestinal epithelial gammadelta T cells. Science 1998; 279(5357): 1737– 1740.

8. Rincon‑ Orozco B, Kunzmann V, Wrobel P et al. Activation of V gamma 9V delta 2 T cells by NKG2D. J Immunol 2005; 175(4): 2144– 2151.

9. Das H, Groh V, Kuijl C et al. MICA engagement by human Vgamma2Vdelta2 T cells enhances their antigen‑ dependent effector function. Immunity 2001; 15(1): 83– 93.

10. Kong Y, Cao W, Xi X et al. The NKG2D ligand ULBP4 binds to TCRgamma9/ delta2 and induces cytotoxicity to tumor cells through both TCRgammadelta and NKG2D. Blood 2009; 114(2): 310– 317. doi: 10.1182/ blood‑ 2008‑ 12‑ 196287.

11. Shojaei H, Oberg HH, Juricke M et al. Toll‑like receptors 3 and 7 agonists enhance tumor cell lysis by human gammadelta T cells. Cancer Res 2009; 69(22): 8710– 8717. doi: 10.1158/ 0008‑ 5472.CAN‑ 09‑ 1602.

12. Modlin RL, Pirmez C, Hofman FM et al. Lymphocytes bearing antigen‑ specific gamma delta T‑ cell receptors accumulate in human infectious disease lesions. Nature 1989; 339(6225): 544– 548.

13. Dunne MR, Mangan BA, Madrigal‑ Estebas L et al. Preferential Th1 cytokine profile of phosphoantigen‑ stimulated human Vgamma9Vdelta2 T cells. Mediators Inflamm 2010; 2010: 704941. doi: 10.1155/ 2010/ 704941.

14. Thedrez A, Sabourin C, Gerner J et al. Self/ non‑self discrimination by human gammadelta T cells: simple solutions for a complex issue? Immunol Rev 2007; 215: 123– 135.

15. Gibbons DL, Hague SF, Silberzahn T et al. Neonates harbour highly active gammadelta T cells with selective impairments in preterm infants. Eur J Immunol 2009; 39(7): 1794– 1806. doi: 10.1002/ eji.200939222.

16. Wesch D, Glatzel A, Kabelitz D. Differentiation of resting human peripheral blood gamma delta T cells toward Th1- or Th2- phenotype. Cell Immunol 2001; 212(2): 110– 117.

17. Casetti R, Agrati C, Wallace M et al. Cutting edge: TGF‑beta1 and IL‑15 Induce FOXP3+ gammadelta regulatory T cells in the presence of antigen stimulation. J Immunol 2009; 183(6): 3574– 3577. doi: 10.4049/ jimmunol.0901334.

18. Gober HJ, Kistowska M, Angman L et al. Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 2003; 197(2): 163– 168.

19. Lafont V, Sanchez F, Laprevotte E et al. Plasticity of gammadelta T cells: impact on the anti‑tumor response. Front Immunol 2014; 5: 622. doi: 10.3389/ fimmu.2014.00622.

20. Lu Y, Yang W, Qin C et al. Responsiveness of stromal fibroblasts to IFN‑ gamma blocks tumor growth via angiostasis. J Immunol 2009; 183(10): 6413– 6421. doi: 10.4049/ jimmunol.0901073.

21. Kuhl AA, Pawlowski NN, Grollich K et al. Human peripheral gammadelta T cells possess regulatory potential. Immunology 2009; 128(4): 580– 588. doi: 10.1111/ j.1365‑ 2567.2009.03162.x.

22. Drabsch Y, ten Dijke P. TGF‑beta signalling and its role in cancer progression and metastasis. Cancer Metastasis Rev 2012; 31(3– 4): 553– 568. doi: 10.1007/ s10555‑ 012‑ 9375‑ 7.

23. Dhar S, Chiplunkar SV. Lysis of aminobisphosphonate‑ sensitized MCF‑ 7 breast tumor cells by Vgamma9Vdelta2 T cells. Cancer Immun 2010; 10: 10.

24. Ferrarini M, Pupa SM, Zocchi MR et al. Distinct pattern of HSP72 and monomeric laminin receptor expression in human lung cancers infiltrated by gamma/ delta T lymphocytes. Int J Cancer 1994; 57(4): 486– 490.

25. Choudhary A, Davodeau F, Moreau A et al. Selective lysis of autologous tumor cells by recurrent gamma delta tumor‑ infiltrating lymphocytes from renal carcinoma. J Immunol 1995; 154(8): 3932– 3940.

26. Cordova A, Toia F, La Mendolona C et al. Characterization of human gammadelta T lymphocytes infiltrating primary malignant melanomas. PLoS One 2012; 7(11): e49878. doi: 10.1371/ journal.pone.0049878.

27. Liu Z, Guo BL, Gehrs BC et al. Ex vivo expanded human Vgamma9Vdelta2+ gammadelta‑ T cells mediate innate antitumor activity against human prostate cancer cells in vitro. J Urol 2005; 173(5): 1552– 1556.

28. Kobayashi H, Tanaka Y, Yagi J et al. Safety profile and anti‑tumor effects of adoptive immunotherapy using gamma‑ delta T cells against advanced renal cell carcinoma: a pilot study. Cancer Immunol Immunother 2007; 56(4): 469– 476.

29. Bennouna J, Bompas E, Neidhardt EM et al. Phase‑ I study of Innacell gammadelta, an autologous cell‑ therapy product highly enriched in gamma9delta2 T lymphocytes, in combination with IL‑2, in patients with metastatic renal cell carcinoma. Cancer Immunol Immunother 2008; 57(11): 1599– 1609. doi: 10.1007/ s00262‑ 008‑ 0491‑ 8.

30. Kobayashi H, Tanaka Y, Yagi J et al. Phase I/ II study of adoptive transfer of gammadelta T cells in combination with zoledronic acid and IL‑2 to patients with advanced renal cell carcinoma. Cancer Immunol Immunother 2011; 60(8): 1075– 1084.

31. Nicol AJ, Tokuyama H, Mattarollo SR et al. Clinical evaluation of autologous gamma delta T cell‑based immunotherapy for metastatic solid tumours. Br J Cancer 2011; 105(6): 778– 786. doi: 10.1038/ bjc.2011.293.

32. Abe Y, Muto M, Nieda M et al. Clinical and immunological evaluation of zoledronate‑activated Vgamma9gammadelta T‑ cell‑based immunotherapy for patients with multiple myeloma. Exp Hematol 2009; 37(8): 956– 968. doi: 10.1016/ j.exphem.2009.04.008.

33. Kunzmann V, Bauer E, Wilhelm M. Gamma/ delta T‑ cell stimulation by pamidronate. N Engl J Med 1999; 340(9): 737– 738.

34. Wilhelm M, Kunzmann V, Eckstein S et al. Gammadelta T cells for immune therapy of patients with lymphoid malignancies. Blood 2003; 102(1): 200– 206.

35. Dieli F, Vermijlen D, Fulfaro F et al. Targeting human (gamma)delta) T cells with zoledronate and interleukin‑2 for immunotherapy of hormone‑ refractory prostate cancer. Cancer Res 2007; 67(15): 7450– 7457.

36. Fowler DW, Copier J, Wilson N et al. Mycobacteria activate gammadelta T‑ cell anti‑tumour responses via cytokines from type 1 myeloid dendritic cells: a mechanism of action for cancer immunotherapy. Cancer Immunol Immunother 2012; 61(4): 535– 547. doi: 10.1007/ s00262‑ 011‑ 1121‑ 4.

37. Naoe M, Ogawa Y, Takeshita K et al. Bacillus Calmette‑ Guerin‑pulsed dendritic cells stimulate natural killer T cells and gammadeltaT cells. Int J Urol 2007; 14(6): 532– 538.

38. Dalgleish A. A Trial comparing gemcitabine with and without IMM‑ 101 in advanced pancreatic cancer. NCT01303172.

39. Mann ER, McCarthy NE, Peake ST et al. Skin‑ and gut‑ homing molecules on human circulating gammadelta T cells and their dysregulation in inflammatory bowel disease. Clin Exp Immunol 2012; 170(2): 122– 130. doi: 10.1111/ j.1365‑ 2249.2012.04649.x.

40. Su C, Jakobsen I, Nei M. Diversity and evolution of T‑ cell receptor variable region genes in mammals and birds. Immunogenetics 1999; 50(5– 6): 301– 308.

41. Petrini I, Scatena C, Naccarato AG et al. CD57 and gammadelta T‑ cell receptor expression in nodal metastatic spread of melanoma. Eur J Clin Invest 2012; 42(5): 575– 576. doi: 10.1111/ j.1365‑ 2362.2011.02612.x.

42. Campillo JA, Martínez‑ Escribano JA, Minguela A et al. Increased number of cytotoxic CD3+ CD28–  gammadelta T cells in peripheral blood of patients with cutaneous malignant melanoma. Dermatology 2007; 214(4): 283– 288.

43. Hu C, Qian L, Miao Y et al. Antigen‑ presenting effects of effector memory Vgamma9Vdelta2 T cells in rheumatoid arthritis. Cell Mol Immunol 2012; 9(3): 245– 254. doi: 10.1038/ cmi.2011.50.

44. Peters C, Oberg HH, Kabelitz D et al. Phenotype and regulation of immunosuppressive Vdelta2- expres-sing gammadelta T cells. Cell Mol Life Sci 2014; 71(10): 1943– 1960.

45. Shibuya K, Nakano N. Interleukin‑2 drives immature double negative thymocytes into gammadelta T cells expressing Foxp3 on a stromal cell line in vitro. Biochem Biophys Res Commun 2014; 452(4): 912– 919. doi: 10.1016/ j.bbrc.2014.08.155.

Labels
Paediatric clinical oncology Surgery Clinical oncology
Login
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account