Th17 and Th17-stimulated CD8+ T cells play a distinct role in Th17-induced preventive and therapeutic antitumor immunity

  • Manjunatha Ankathatti Munegowda
  • Yulin Deng
  • Sean J. Mulligan
  • Jim Xiang
Original article

Abstract

CD4+ Th17 cells induce antitumor immunity leading to the eradication of established tumors. However, the mechanism of antitumour immunity and CTL activation by Th17 cells and the distinct role of Th17 and Th17-activated CTLs in antitumor immunity are still elusive. In this study, we generated ovalbumin (OVA)-specific Th17 cells by cultivating OVA-pulsed dendritic cells with CD4+ T cells derived from transgenic OTII mice in the presence of IL-6, IL-23, TGF-β, and anti-IFN-γ antibody. We demonstrated that Th17 cells acquired major histocompatibility complex/peptide (pMHC)-I and expressed RORγt, IL-17, and IL-2. Th17 cells did not have any direct in vitro tumor cell–killing activity. However, Th17 cells were able to stimulate CD8+ CTL responses via IL-2 and pMHC I, but not IL-17 signaling, which play a major role in Th17-induced preventive immunity against OVA-expressing B16 melanoma. Th17 cells stimulated the expression of CCL2 and CCL20 in lung tumor microenvironments promoting the recruitment of various inflammatory leukocytes (DCs, CD4+, and CD8+ T cells) stimulating more pronounced therapeutic immunity for early-stage (5-day lung metastases or 3 mm, s.c.) tumor than for well-established (6 mm, s.c.) tumor. The therapeutic effect of Th17 cells is associated with IL-17 and is mediated by Th17-stimulated CD8+ CTLs and other inflammatory leukocytes recruited into B16 melanoma via Th17-stimulated CCL20 chemoattraction. Taken together, our data elucidate a distinct role of Th17 and Th17-stimulated CD8+ CTLs in the induction of preventive and therapeutic antitumor immunity, which may greatly impact the development of Th17-based cancer immunotherapy.

Keywords

Th17 pMHC I complexes CD8+ CTL CCL2/20 Antitumor immunity 

References

  1. 1.
    Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25:821–852PubMedCrossRefGoogle Scholar
  2. 2.
    Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141PubMedCrossRefGoogle Scholar
  3. 3.
    Ye P, Garvey PB, Zhang P, Nelson S, Bagby G, Summer WR, Schwarzenberger P, Shellito JE, Kolls JK (2001) Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am J Respir Cell Mol Biol 25:335–340PubMedGoogle Scholar
  4. 4.
    Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240PubMedCrossRefGoogle Scholar
  5. 5.
    Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, Shah B, Chang SH, Schluns KS, Watowich SS, Feng XH, Jetten AM, Dong C (2008) Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29:44–56PubMedCrossRefGoogle Scholar
  6. 6.
    Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA, Oft M (2006) IL-23 promotes tumour incidence and growth. Nature 442:461–465PubMedCrossRefGoogle Scholar
  7. 7.
    Kryczek I, Wei S, Zou L, Altuwaijri S, Szeliga W, Kolls J, Chang A, Zou W (2007) Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol 178:6730–6733PubMedGoogle Scholar
  8. 8.
    Miyahara Y, Odunsi K, Chen W, Peng G, Matsuzaki J, Wang RF (2008) Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer. Proc Natl Acad Sci USA 105:15505–15510PubMedCrossRefGoogle Scholar
  9. 9.
    Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, DeMarzo AM, Meeker AK, Isaacs WB, Drake CG (2008) Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res 14:3254–3261PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang B, Rong G, Wei H, Zhang M, Bi J, Ma L, Xue X, Wei G, Liu X, Fang G (2008) The prevalence of Th17 cells in patients with gastric cancer. Biochem Biophys Res Commun 374:533–537PubMedCrossRefGoogle Scholar
  11. 11.
    Benchetrit F, Ciree A, Vives V, Warnier G, Gey A, Sautes-Fridman C, Fossiez F, Haicheur N, Fridman WH, Tartour E (2002) Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood 99:2114–2121PubMedCrossRefGoogle Scholar
  12. 12.
    Hirahara N, Nio Y, Sasaki S, Minari Y, Takamura M, Iguchi C, Dong M, Yamasawa K, Tamura K (2001) Inoculation of human interleukin-17 gene-transfected Meth-A fibrosarcoma cells induces T cell-dependent tumor-specific immunity in mice. Oncology 61:79–89PubMedCrossRefGoogle Scholar
  13. 13.
    Numasaki M, Watanabe M, Suzuki T, Takahashi H, Nakamura A, McAllister F, Hishinuma T, Goto J, Lotze MT, Kolls JK, Sasaki H (2005) IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. J Immunol 175:6177–6189PubMedGoogle Scholar
  14. 14.
    Spolski R, Leonard WJ (2008) Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol 26:57–79PubMedCrossRefGoogle Scholar
  15. 15.
    Muranski P, Boni A, Antony PA, Cassard L, Irvine KR, Kaiser A, Paulos CM, Palmer DC, Touloukian CE, Ptak K, Gattinoni L, Wrzesinski C, Hinrichs CS, Kerstann KW, Feigenbaum L, Chan CC, Restifo NP (2008) Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 112:362–373PubMedCrossRefGoogle Scholar
  16. 16.
    Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, Hwu P, Restifo NP, Overwijk WW, Dong C (2009) T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 31:787–798PubMedCrossRefGoogle Scholar
  17. 17.
    Ahmed KA, Munegowda MA, Xie Y, Xiang J (2008) Intercellular trogocytosis plays an important role in modulation of immune responses. Cell Mol Immunol 5:261–269PubMedCrossRefGoogle Scholar
  18. 18.
    Xiang J, Huang H, Liu Y (2005) A new dynamic model of CD8+ T effector cell responses via CD4+ T helper-antigen-presenting cells. J Immunol 174:7497–7505PubMedGoogle Scholar
  19. 19.
    Umeshappa CS, Huang H, Xie Y, Wei Y, Mulligan SJ, Deng Y, Xiang J (2009) CD4+ Th-APC with acquired peptide/MHC class I and II complexes stimulate type 1 helper CD4+ and central memory CD8+ T cell responses. J Immunol 182:193–206PubMedGoogle Scholar
  20. 20.
    Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, Huang E, Finlayson E, Simeone D, Welling TH, Chang A, Coukos G, Liu R, Zou W (2009) Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114:1141–1149PubMedCrossRefGoogle Scholar
  21. 21.
    Huang H, Bi XG, Yuan JY, Xu SL, Guo XL, Xiang J (2005) Combined CD4+ Th1 effect and lymphotactin transgene expression enhance CD8+ Tc1 tumor localization and therapy. Gene Ther 12:999–1010PubMedCrossRefGoogle Scholar
  22. 22.
    Sutton C, Brereton C, Keogh B, Mills KH, Lavelle EC (2006) A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med 203:1685–1691PubMedCrossRefGoogle Scholar
  23. 23.
    Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y (2006) IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177:566–573PubMedGoogle Scholar
  24. 24.
    Zou W, Restifo NP (2010) T(H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol 10:248–256Google Scholar
  25. 25.
    Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L, Shevach EM, O’Shea JJ (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26:371–381PubMedCrossRefGoogle Scholar
  26. 26.
    Bolitho P, Voskoboinik I, Trapani JA, Smyth MJ (2007) Apoptosis induced by the lymphocyte effector molecule perforin. Curr Opin Immunol 19:339–347PubMedCrossRefGoogle Scholar
  27. 27.
    Rosenberg SA, Dudley ME (2004) Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes. Proc Natl Acad Sci USA 101(Suppl 2):14639–14645PubMedCrossRefGoogle Scholar
  28. 28.
    Dudley ME, Rosenberg SA (2007) Adoptive cell transfer therapy. Semin Oncol 34:524–531PubMedCrossRefGoogle Scholar
  29. 29.
    Ogawa M, Umehara K, Yu WG, Uekusa Y, Nakajima C, Tsujimura T, Kubo T, Fujiwara H, Hamaoka T (1999) A critical role for a peritumoral stromal reaction in the induction of T-cell migration responsible for interleukin-12-induced tumor regression. Cancer Res 59:1531–1538PubMedGoogle Scholar
  30. 30.
    Mukai S, Kjaergaard J, Shu S, Plautz GE (1999) Infiltration of tumors by systemically transferred tumor-reactive T lymphocytes is required for antitumor efficacy. Cancer Res 59:5245–5249PubMedGoogle Scholar
  31. 31.
    Kottke T, Sanchez-Perez L, Diaz RM, Thompson J, Chong H, Harrington K, Calderwood SK, Pulido J, Georgopoulos N, Selby P, Melcher A, Vile R (2007) Induction of hsp70-mediated Th17 autoimmunity can be exploited as immunotherapy for metastatic prostate cancer. Cancer Res 67:11970–11979PubMedCrossRefGoogle Scholar
  32. 32.
    Brown IE, Blank C, Kline J, Kacha AK, Gajewski TF (2006) Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection. J Immunol 177:4521–4529PubMedGoogle Scholar
  33. 33.
    Kline J, Brown IE, Zha YY, Blank C, Strickler J, Wouters H, Zhang L, Gajewski TF (2008) Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma. Clin Cancer Res 14:3156–3167PubMedCrossRefGoogle Scholar
  34. 34.
    Nurieva R, Yang XO, Chung Y, Dong C (2009) Cutting edge: in vitro generated Th17 cells maintain their cytokine expression program in normal but not lymphopenic hosts. J Immunol 182:2565–2568PubMedCrossRefGoogle Scholar
  35. 35.
    Martin-Orozco N, Chung Y, Chang SH, Wang YH, Dong C (2009) Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol 39:216–224PubMedCrossRefGoogle Scholar
  36. 36.
    Zhang S, Bernard D, Khan WI, Kaplan MH, Bramson JL, Wan Y (2009) CD4+ T-cell-mediated anti-tumor immunity can be uncoupled from autoimmunity via the STAT4/STAT6 signaling axis. Eur J Immunol 39:1252–1259PubMedCrossRefGoogle Scholar
  37. 37.
    Overwijk WW, Lee DS, Surman DR, Irvine KR, Touloukian CE, Chan CC, Carroll MW, Moss B, Rosenberg SA, Restifo NP (1999) Vaccination with a recombinant vaccinia virus encoding a “self” antigen induces autoimmune vitiligo and tumor cell destruction in mice: requirement for CD4(+) T lymphocytes. Proc Natl Acad Sci USA 96:2982–2987PubMedCrossRefGoogle Scholar
  38. 38.
    Kryczek I, Bruce AT, Gudjonsson JE, Johnston A, Aphale A, Vatan L, Szeliga W, Wang Y, Liu Y, Welling TH, Elder JT, Zou W (2008) Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis. J Immunol 181:4733–4741PubMedGoogle Scholar
  39. 39.
    Su X, Ye J, Hsueh EC, Zhang Y, Hoft DF, Peng G (2010) Tumor microenvironments direct the recruitment and expansion of human Th17 cells. J Immunol 184:1630–1641Google Scholar
  40. 40.
    He T, Zong S, Wu X, Wei Y, Xiang J (2007) CD4+ T cell acquisition of the bystander pMHC I colocalizing in the same immunological synapse comprising pMHC II and costimulatory CD40, CD54, CD80, OX40L, and 41BBL. Biochem Biophys Res Commun 362:822–828PubMedCrossRefGoogle Scholar
  41. 41.
    Jung S, Unutmaz D, Wong P, Sano G, De los Santos K, Sparwasser T, Wu S, Vuthoori S, Ko K, Zavala F, Pamer EG, Littman DR, Lang RA (2002) In vivo depletion of CD11c(+) dendritic cells abrogates priming of CD8(+) T cells by exogenous cell-associated antigens. Immunity 17:211–220PubMedCrossRefGoogle Scholar
  42. 42.
    Purvis HA, Stoop JN, Mann J, Woods S, Kozijn AE, Hambleton S, Robinson JH, Isaacs JD, Anderson AE, Hilkens CM (2010) Low-strength T-cell activation promotes Th17 responses. Blood 116:4829–37Google Scholar
  43. 43.
    Xia D, Hao S, Xiang J (2006) CD8+ cytotoxic T-APC stimulate central memory CD8+ T cell responses via acquired peptide-MHC class I complexes and CD80 costimulation, and IL-2 secretion. J Immunol 177:2976–2984PubMedGoogle Scholar
  44. 44.
    Vremec D, Pooley J, Hochrein H, Wu L, Shortman K (2000) CD4 and CD8 expression by dendritic cell subtypes in mouse thymus and spleen. J Immunol 164:2978–2986PubMedGoogle Scholar
  45. 45.
    Prlic M, Hernandez-Hoyos G, Bevan MJ (2006) Duration of the initial TCR stimulus controls the magnitude but not functionality of the CD8+ T cell response. J Exp Med 203:2135–2143PubMedCrossRefGoogle Scholar
  46. 46.
    Xiang J, Moyana T (1998) Cytotoxic CD4+ T cells associated with the expression of major histocompatibility complex class II antigen of mouse myeloma cells secreting interferon-gamma are cytolytic in vitro and tumoricidal in vivo. Cancer Gene Ther 5:313–320PubMedGoogle Scholar
  47. 47.
    Sas S, Chan T, Sami A, El-Gayed A, Xiang J (2008) Vaccination of fiber-modified adenovirus-transfected dendritic cells to express HER-2/neu stimulates efficient HER-2/neu-specific humoral and CTL responses and reduces breast carcinogenesis in transgenic mice. Cancer Gene Ther 15:655–666PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Manjunatha Ankathatti Munegowda
    • 1
    • 2
  • Yulin Deng
    • 1
    • 2
  • Sean J. Mulligan
    • 3
  • Jim Xiang
    • 1
    • 2
  1. 1.Research Unit, Saskatchewan Cancer Agency, Department of OncologyUniversity of SaskatchewanSaskatoonCanada
  2. 2.Research Unit, Saskatchewan Cancer Agency, Department of Immunology PathologyUniversity of SaskatchewanSaskatoonCanada
  3. 3.Research Unit, Saskatchewan Cancer Agency, Department of PhysiologyUniversity of SaskatchewanSaskatoonCanada

Personalised recommendations