Editors' ChoiceCancer Immunology

Unhelpful T Helper Cells

Sci. Signal.  27 May 2014:
Vol. 7, Issue 327, pp. ec141
DOI: 10.1126/scisignal.2005514

Chronic inflammation is associated with cancer, and the immune system is rapidly emerging as a critical factor in determining tumor progression. McAllister et al. (see coverage by Vonderheide) and Kryczek et al. (see coverage by Koltsova and Grivennikov) identified key cytokines released by infiltrating T helper (TH) cells that stimulated cancer progression in pancreatic neoplasia and colorectal tumors, respectively. In tissue from patients with pancreatic cancer, the abundance of interleukin 17 receptor A (IL-17RA) and infiltration of IL-17–producing TH17 and γδ T cells increased with the stage of the disease in the sample from chronic pancreatitis to acinar-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Infiltration of IL-17–producing T cells in mice with chronic pancreatitis and the abundance of IL-17RA on PanIN epithelial cells were increased by pancreas-specific mutation of the GTPase Kras, a frequent mutation in human pancreatic cancer. Injecting the pancreas with an adenovirus encoding IL-17 accelerated ADM and PanIN formation and early signs of epithelial-mesenchymal transition after conditional pancreatic expression of mutant Kras, whereas lesion formation was reduced or prevented by either treatment with a cocktail of IL-17 and IL-17RA antibodies or genetic ablation of hematopoietic IL-17 production through bone marrow transplantation. In colorectal cancer (CRC) patients, another cytokine, IL-22, was identified as a protumor culprit. IL22 expression was increased in the tumor compared with adjacent normal tissue or peripheral blood cells and was restricted to CD4+ memory TH cells in the tumor microenvironment. The initiation and growth of patient-derived xenografts was delayed and reduced, respectively, in mice treated with a function-blocking IL-22 antibody, whereas exogenous administration of IL-22 accelerated and increased tumor formation and growth in mice and increased the expression of stem cell–associated genes in various CRC cell lines in culture. The addition of IL-22 to CRC cells in culture induced sphere formation and activated the transcription factor STAT3, which bound directly to the promoters of stem cell–associated gene SOX2 and methyltransferase-encoding DOT1L. DOT1L di-methylated histone H3 Lys79 (H3K79) in the promoters of SOX2 and other core stem cell genes. In patients, the expression of IL22, DOT1L, and SOX2 were positively correlated with each other, with the abundance of H3K79me2, and with poor survival. The two studies show that paracrine cytokine signaling from infiltrating TH cells exacerbate cancer progression.

F. McAllister, J. M. Bailey, J. Alsina, C. J. Nirschl, R. Sharma, H. Fan, Y. Rattigan, J. C. Roeser, R. H. Lankapalli, H. Zhang, E. M. Jaffee, C. G. Drake, F. Housseau, A. Maitra, J. K. Kolls, C. L. Sears, D. M. Pardoll, S. D. Leach, Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell 25, 621–637 (2014). [PubMed]

I. Kryczek, Y. Lin, N. Nagarsheth, D. Peng, L. Zhao, E. Zhao, L. Vatan, W. Szeliga, Y. Dou, S. Owens, W. Zgodzinski, M. Majewski, G. Wallner, J. Fang, E. Huang, W. Zou, IL-22+CD4+ T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. Immunity 40, 772–784 (2014). [PubMed]

R. H. Vonderheide, Tumor-promoting inflammatory networks in pancreatic neoplasia: Another reason to loathe Kras. Cancer Cell 25, 553–554 (2014). [PubMed]

E. K. Koltsova, S. I. Grivennikov, IL-22 gets to the stem of colorectal cancer. Immunity 40, 639–641 (2014). [PubMed]