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Blood, 15 July 2008, Vol. 112, No. 2, pp. 214. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bronte, V. Search for Related Content PubMed PubMed Citation Articles by Bronte, V. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Comment on Muranski et al, page 362 Th17 and cancer: friends or foes? Vincenzo Bronte ISTITUTO ONCOLOGICO VENETO Adoptive transfer of tumor-reactive CD8+ T lymphocytes is one of the most effective immunotherapy approaches for the treatment of solid tumors.1 Muranski and colleagues show that a recently identified population of CD4+ T lymphocytes called Th17 cells possesses unexpected antimyeloma therapeutic properties. In mammals, CD4+ T lymphocytes are central elements of cell-mediated immunity, recruiting and directing other cells of both the innate and the acquired immune system toward antigens. Humans must cope with exposure to many different pathogens, which require diversified effector mechanisms in order to be properly eliminated. Evolution has addressed this environmental complexity by increasing the complexity of effector CD4+ T cells, and at least 4 main subsets have been described to date: Th1, Th2, Th17, and T regulatory cells (Tregs).2 Through the activation of peculiar transcription factors, cytokines mediate the transition from naive CD4+ T cells into one of these subsets, often simultaneously inhibiting other differentiation pathways.2 Th17 cells represent the latest addition to this group. Their differentiation is driven primarily by TGF-β and IL-6 cytokines, whereas IL-23, originally thought to be the master regulator, seems to be important for maintenance of Th17 responses. Th17 cells release IL-17 and IL-22, and are implicated in the induction of numerous autoimmune and inflammatory responses.2 The information about the relevance of this cell subset in cancer biology is scant and contradictory. IL-23 has been shown to promote tumor growth and impair antitumor CD8+ T cells3 but, on the other hand, dendritic cells transduced with IL-23 have been described as triggering powerful antitumor activity.4 These discrepancies might result from the oft-described dichotomous nature of the effects of endogenous production as compared with unregulated engineered release of the same cytokine. However, the effects of IL-23 alone cannot be taken as a bona fide demonstration of Th17 cell involvement. Indeed, few reports have addressed the presence of Th17 cells in experimental and human tumors,5 and none provide a clear indication about either a protumoral or antitumoral activity. Muranski and colleagues used transgenic mice expressing a high-affinity T-cell receptor (TCR) specific for an epitope of the melanoma antigen known as tyrosinase-related protein 1 (TRP-1). Exploiting different polarizing culture conditions in vitro, the authors drove TRP-1–specific CD4+ T cells toward either Th0, Th1, or Th17 cells. Upon adoptive transfer in mice bearing established cutaneous melanomas, Th17 cells were shown to be superior in mediating both rejection of established melanoma and autoimmune vitiligo. Interestingly, therapeutic activity depended on Th17-cell release of IFN-, rather than IL-17 and IL-23 production, even though Th1-polarized cells produced more IFN- than Th17 effectors. Muranski and colleagues do not clarify whether the polarizing regimen promoted differentiation of multiple cell subsets; nonetheless, they provide relevant perspectives for adoptive immunotherapy of cancer. Optimization of culture conditions to polarize human CD4+ T cells to Th17 cells with heightened antitumor activity (possibly dependent on high affinity of the TCR) and tumor specificity will require further efforts. It would certainly help to identify the tumor antigens recognized by tumor-infiltrating Th17 cells. The findings of Muranski and coworkers raise some interesting questions. If Th17 cells are so effective in destroying tissues, what limits their armamentarium during tumor development? Do Tregs play a role, as suggested by some studies5? For clinical translation, it will also be extremely important to understand whether concomitant autoimmunity can be controlled or mitigated, if this approach is to be extended to tumors other than melanomas. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8:299–308.[CrossRef][Medline] [Order article via Infotrieve] Reiner SL. Development in motion: helper T cells at work. Cell. 2007;129:33–36.[CrossRef][Medline] [Order article via Infotrieve] Langowski JL, Zhang X, Wu L, et al. IL-23 promotes tumour incidence and growth. Nature. 2006;442:461–465.[CrossRef][Medline] [Order article via Infotrieve] Hu J, Yuan X, Belladonna ML, et al. Induction of potent antitumor immunity by intratumoral injection of interleukin 23-transduced dendritic cells. Cancer Res. 2006;66:8887–8896.[Abstract/Free Full Text] Kryczek I, Wei S, Zou L, et al. Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol. 2007;178:6730–6733.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Tumor-specific Th17-polarized cells eradicate large established melanoma Pawel Muranski, Andrea Boni, Paul A. Antony, Lydie Cassard, Kari R. Irvine, Andrew Kaiser, Chrystal M. Paulos, Douglas C. Palmer, Christopher E. Touloukian, Krzysztof Ptak, Luca Gattinoni, Claudia Wrzesinski, Christian S. Hinrichs, Keith W. Kerstann, Lionel Feigenbaum, Chi-Chao Chan, and Nicholas P. Restifo Blood 2008 112: 362-373. [Abstract] [Full Text] [PDF] This article has been cited by other articles: C. S. Hinrichs, A. Kaiser, C. M. Paulos, L. Cassard, L. Sanchez-Perez, B. Heemskerk, C. Wrzesinski, Z. A. Borman, P. Muranski, and N. P. Restifo Type 17 CD8+ T cells display enhanced antitumor immunity Blood, July 16, 2009; 114(3): 596 - 599. [Abstract] [Full Text] [PDF] S. Guo, D. Cobb, and R. B. Smeltz T-bet Inhibits the In Vivo Differentiation of Parasite-Specific CD4+ Th17 Cells in a T Cell-Intrinsic Manner J. Immunol., May 15, 2009; 182(10): 6179 - 6186. [Abstract] [Full Text] [PDF] T. H. Schreiber, V. V. Deyev, J. D. Rosenblatt, and E. R. Podack Tumor-Induced Suppression of CTL Expansion and Subjugation by gp96-Ig Vaccination Cancer Res., March 1, 2009; 69(5): 2026 - 2033. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bronte, V. Search for Related Content PubMed PubMed Citation Articles by Bronte, V. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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