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IL-22 Gets to the Stem of Colorectal Cancer

2014; Cell Press; Volume: 40; Issue: 5 Linguagem: Inglês

10.1016/j.immuni.2014.04.014

1097-4180

Ekaterina K. Koltsova, Sergei I. Grivennikov,

Whipple's Disease and Interleukins

Cytokines can provide survival and proliferation signals to cancer cells, thus promoting tumor progression. In this issue of Immunity, Kryczek et al., 2014Kryczek I. Lin Y. Nagarsheth N. Peng D. Zhao L. Zhao E. Vatan L. Szeliga W. Dou Y. Owens S. et al.Immunity. 2014; 40 (this issue): 772-784Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar reveal that interleukin-22 can also promote "stemness" in human colorectal cancer via transcription factor STAT3-mediated epigenetic regulation of stem cell genes. Cytokines can provide survival and proliferation signals to cancer cells, thus promoting tumor progression. In this issue of Immunity, Kryczek et al., 2014Kryczek I. Lin Y. Nagarsheth N. Peng D. Zhao L. Zhao E. Vatan L. Szeliga W. Dou Y. Owens S. et al.Immunity. 2014; 40 (this issue): 772-784Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar reveal that interleukin-22 can also promote "stemness" in human colorectal cancer via transcription factor STAT3-mediated epigenetic regulation of stem cell genes. Chronic inflammation facilitates cancer development, as illustrated by the increased incidence of colitis-associated colon cancers (CAC) in patients with inflammatory bowel diseases (IBD) or liver cancer in patients with hepatitis. Many other cancers, including sporadic colorectal cancer (CRC), do not initially arise in an inflammatory context but later on induce "tumor-elicited inflammation." This inflammatory reaction acquired by tumors is important, because nonspecific inhibition of inflammation with aspirin reduces cancer-related deaths, and high interleukin-17 (IL-17) expression marks CRC with poor prognosis (Tosolini et al., 2011Tosolini M. Kirilovsky A. Mlecnik B. Fredriksen T. Mauger S. Bindea G. Berger A. Bruneval P. Fridman W.H. Pagès F. Galon J. Cancer Res. 2011; 71: 1263-1271Crossref PubMed Scopus (835) Google Scholar). Proinflammatory cytokines, whose expression is elevated in tumors, mediate crosstalk between immune and cancer cells. Receptors for such cytokines are often expressed by epithelial cells and are able to activate key transcription factors, such as NF-κB and signal transducer and activator of transcription 3 (STAT3), that normally maintain tissue homeostasis, but when deregulated can contribute to malignant transformation. The ability of cytokines to activate key oncogenic signaling hubs has focused research toward understanding their role in promoting cell proliferation and survival during tumorigenesis. In this issue of Immunity, Kryczek et al., 2014Kryczek I. Lin Y. Nagarsheth N. Peng D. Zhao L. Zhao E. Vatan L. Szeliga W. Dou Y. Owens S. et al.Immunity. 2014; 40 (this issue): 772-784Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar demonstrate that IL-22 promotes human CRC relying on STAT3-dependent pathway of epigenetic activation of genes responsible for maintenance of CRC cancer stem cells, thus adding a new dimension to what we know about how cytokines promote cancer through other, potentially diverse, mechanisms. IL-22 has recently emerged as a key regulator of epithelial homeostasis at multiple organ sites, including skin, liver, lung, and gastrointestinal tract. IL-22 triggers phosphorylation and activation of STAT3 to mediate its protective effects on the intestinal epithelium during colitis (Pickert et al., 2009Pickert G. Neufert C. Leppkes M. Zheng Y. Wittkopf N. Warntjen M. Lehr H.A. Hirth S. Weigmann B. Wirtz S. et al.J. Exp. Med. 2009; 206: 1465-1472Crossref PubMed Scopus (749) Google Scholar), and IL-22-driven STAT3 activation is detected in several models of intestinal tumorigenesis and is essential for tumor growth (Huber et al., 2012Huber S. Gagliani N. Zenewicz L.A. Huber F.J. Bosurgi L. Hu B. Hedl M. Zhang W. O'Connor Jr., W. Murphy A.J. et al.Nature. 2012; 491: 259-263Crossref PubMed Scopus (545) Google Scholar, Kirchberger et al., 2013Kirchberger S. Royston D.J. Boulard O. Thornton E. Franchini F. Szabady R.L. Harrison O. Powrie F. J. Exp. Med. 2013; 210: 917-931Crossref PubMed Scopus (409) Google Scholar). The ability of the IL-22-STAT3 pathway to induce the expression of tissue protective genes, such as antiapoptotic molecules, antimicrobial peptides, and chemokines, fits seemingly well into the accepted dogma that IL-22, just like many other cytokines, might directly regulate normal and malignant cell survival and proliferation (Figure 1). Kryczek et al. found that human CRC tumors contained elevated amounts of IL-22 compared with matching normal tissue and that expression was also high in tumor-infiltrating immune cells, a many times seen "smoking gun" for the potential involvement of a cytokine in tumorigenesis. Indeed, in a model where single cell suspensions of human CRC tumors (containing both cancer and immune cells) were injected into immunodeficient mice, IL-22 enhanced tumorigenic potential of CRC cells and IL-22 neutralization blocked tumor growth. Treatment of CRC cells with IL-22 predictably activated STAT3 but surprisingly induced the expression of bona fide stem cell markers, such as SOX2, NANOG, and POU5F1 and also promoted sphere formation in an in vitro surrogate assay for stemness. STAT3 is important regulator of the stem cell compartment in a normal mouse intestine (Matthews et al., 2011Matthews J.R. Sansom O.J. Clarke A.R. Cell Death Differ. 2011; 18: 1934-1943Crossref PubMed Scopus (48) Google Scholar). Indeed, STAT3 was required for the IL-22 driven increase in CRC stem cell numbers. Surprisingly, IL-22 treatment of cells increased histone 3 lysine 79 dimethylation (H3K79me2) and STAT3 was found to regulate the expression of disruptor of telomeric silencing-1 (DOT1L), the only H3K79 methyltransferase discovered so far, and its histone binding cofactor AFF4. DOT1L associated with the promoter regions of "stemness" genes such as Nanog, Sox2, and Pou5f and increased their expression, therefore contributing to enhancement of stem cell properties of cancer cells. Previous work suggested that DOT1L deficiency abrogates cell proliferation and indeed, knocking down DOT1L blocked the IL-22-dependent increase in CRC cancer stem cell numbers. Finally, studies in CRC patients demonstrated that IL-22, DOT1L, and SOX2 expression correlate with each other and with poor survival (Kryczek et al., 2014Kryczek I. Lin Y. Nagarsheth N. Peng D. Zhao L. Zhao E. Vatan L. Szeliga W. Dou Y. Owens S. et al.Immunity. 2014; 40 (this issue): 772-784Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). Previous studies did not single out IL-22 as a prognostic factor in CRC, but indeed demonstrated that an increase in expression of RORγt (required for IL-22 expression) and IL-17A (often coexpressed with IL-22) correlates with bad prognosis in human CRC (Tosolini et al., 2011Tosolini M. Kirilovsky A. Mlecnik B. Fredriksen T. Mauger S. Bindea G. Berger A. Bruneval P. Fridman W.H. Pagès F. Galon J. Cancer Res. 2011; 71: 1263-1271Crossref PubMed Scopus (835) Google Scholar). What is the source of IL-22 in human CRC? IL-22 can be produced by innate lymphoid cells (ILC) in IBD and in CAC tumors of Rag2−/− infected with H. hepaticus and injected with AOM (Kirchberger et al., 2013Kirchberger S. Royston D.J. Boulard O. Thornton E. Franchini F. Szabady R.L. Harrison O. Powrie F. J. Exp. Med. 2013; 210: 917-931Crossref PubMed Scopus (409) Google Scholar). Here, authors found preferential accumulation of CD3+CD4+IL-22+ cells, also expressing CCR6, and RORγt, a phenotype characteristic of memory helper T cells; in agreement that in human CRC IL-22 is mostly produced by CD3+ T cells with a fraction of it coming from ILC (Kirchberger et al., 2013Kirchberger S. Royston D.J. Boulard O. Thornton E. Franchini F. Szabady R.L. Harrison O. Powrie F. J. Exp. Med. 2013; 210: 917-931Crossref PubMed Scopus (409) Google Scholar). Although these cells might represent the T helper 22 (Th22) cell subset, up to 30% also expressed IL-17 (Kryczek et al., 2014Kryczek I. Lin Y. Nagarsheth N. Peng D. Zhao L. Zhao E. Vatan L. Szeliga W. Dou Y. Owens S. et al.Immunity. 2014; 40 (this issue): 772-784Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar) and therefore could be classified as "Th17 cells." Functionally, IL-22+ T cells were able to migrate into CRC tumors and increase CRC "stemness" in a coculture experiment, in a largely IL-22-dependent manner (Kryczek et al., 2014Kryczek I. Lin Y. Nagarsheth N. Peng D. Zhao L. Zhao E. Vatan L. Szeliga W. Dou Y. Owens S. et al.Immunity. 2014; 40 (this issue): 772-784Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar), confirming their protumorigenic role. In CRC, STAT3 was often shown to be hyperactivated at the invasive front of the tumor, a site where potential cancer stem cells might be located. It still remains to be demonstrated whether ILC and Th22 cells might have different patterns of distribution in the tumor (tumor-infiltrating versus peritumoral) and that topology might better define their respective roles in activation of STAT3-dependent "bulk" tumor growth versus STAT3-dependent promotion of "stemness" phenotype and tumor progression. Are other cytokines and transcription factors involved in the promotion of "stemness" in cancer? The answer is yes, because previous work demonstrated that deregulated activation of NF-κB rendered stem cells properties to transformed intestinal epithelial cells (Schwitalla et al., 2013Schwitalla S. Fingerle A.A. Cammareri P. Nebelsiek T. Göktuna S.I. Ziegler P.K. Canli O. Heijmans J. Huels D.J. Moreaux G. et al.Cell. 2013; 152: 25-38Abstract Full Text Full Text PDF PubMed Scopus (767) Google Scholar). Can other STAT3-activating cytokines drive the same pathway to "stemness" as IL-22 does? IL-6 and IL-11 were previously shown to be important for CRC, particularly through their ability to activate STAT3 (Putoczki et al., 2013Putoczki T.L. Thiem S. Loving A. Busuttil R.A. Wilson N.J. Ziegler P.K. Nguyen P.M. Preaudet A. Farid R. Edwards K.M. et al.Cancer Cell. 2013; 24: 257-271Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar). Although IL-11 was not analyzed in the current study, addition of IL-6 to CRC cell lines elicited much weaker effect than the one by IL-22 on sphere formation, although no sIL-6R (normally available in tumor microenvironment to mediate IL-6 trans-signaling) were added to ensure full sensitivity of CRC cells to IL-6. One important quality of IL-22R over IL-6R and IL-11R is that IL-22R signaling is not subject to negative-feedback-loop regulation by suppressor of cytokine signaling 3 (SOCS3), which is a direct STAT3 target. Indeed, this might give significant advantages to the sustained IL-22 dependent protumorigenic signaling, although SOCS3 is often mutated or downregulated by epigenetic mechanisms in CRC. Another possible divergence between IL-22 and IL-6 and IL-11 might lie in the identity of cytokine-producing cells and in intricacies of cytokine gene regulation. For example, production of IL-6 and IL-11 by myeloid cells even in the presence of abundant stimuli (i.e., Toll-like receptor ligands) can be halted with time due to the phenomenon of "LPS tolerance," whereas production of IL-22 by ILC and Th22 cells might be sustainable as long as tumor-specific stimuli are present. Previous studies pointed out a significant role of "cancer stem cells" in resistance of tumors to conventional therapies. It will be exciting to find out whether the activation status of components of IL-22-STAT3-DOT1L pathway is anyhow predictive of poor response to therapy and, vice versa, whether their inhibition could provide significant improvements of current chemotherapeutic regimens. Similarly, as increased IL-22 production correlates with poor prognosis in CRC, it is also important to explore whether "IL-22 high" patients should get DOT1L inhibitors, selected for more sophisticated chemotherapies, or treated with IL-22 blockers prior or past surgery. An essential question is what are the host and environmental cues that determine "high" or "low" IL-22 expression profile? Likely, genetics will play some role, and indeed distinct polymorphisms in IL-22 promoter are linked with CRC risk (Kryczek et al., 2014Kryczek I. Lin Y. Nagarsheth N. Peng D. Zhao L. Zhao E. Vatan L. Szeliga W. Dou Y. Owens S. et al.Immunity. 2014; 40 (this issue): 772-784Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). However, it is also known that the expression of IL-22 and its upstream regulator IL-23 are driven by commensal and pathogenic microorganisms. In addition, dietary components such as cruciferous vegetables and a high-fat diet can modulate IL-22 expression and, therefore, the interplay between microbiome and dietary habits likely has a significant impact on IL-22-producing cells in CRC. Previous gastrointestinal infections leave long-lived memory T cells specific not only to the pathogen itself but also to microbiota (Hand et al., 2012Hand T.W. Dos Santos L.M. Bouladoux N. Molloy M.J. Pagán A.J. Pepper M. Maynard C.L. Elson 3rd, C.O. Belkaid Y. Science. 2012; 337: 1553-1556Crossref PubMed Scopus (284) Google Scholar). Presumably, such history of infections would not only influence IL-22 expression at any given time later but also would have a tremendous impact on whether the majority of helper T cells in the intestine and in CRC tumors are differentiated towards more protumorigenic Th22 (and Th17) or, for example, towards more anticancerous Th1 lineages. Overall, Kryczek et al. provide an additional STAT3-dependent mechanism of CRC tumor progression, whereby IL-22 drives the expression of the components of histone methylation machinery and activation of key cancer stem cell genes (Figure 1). Whether this phenomenon has its functional counterpart in the gut under homeostatic or inflamed conditions remains to be determined; deletion of DOT1L in intestinal stem or epithelial cells increased basal levels of apoptosis but otherwise had no phenotype (Ho et al., 2013Ho L.L. Sinha A. Verzi M. Bernt K.M. Armstrong S.A. Shivdasani R.A. Mol. Cell. Biol. 2013; 33: 1735-1745Crossref PubMed Scopus (29) Google Scholar), similarly to IL-22 deficiency in normal gut. However, in cancer, epigenetic regulation of CRC cell "stemness" now finds its place along with well-characterized features of IL-22-STAT3 pathway in protection of epithelial barriers and activation of genes responsible for the resistance to apoptosis and increased cell proliferation during inflammation and tumor development. IL-22+CD4+ T Cells Promote Colorectal Cancer Stemness via STAT3 Transcription Factor Activation and Induction of the Methyltransferase DOT1LKryczek et al.ImmunityMay 8, 2014In BriefLittle is known about how the immune system impacts human colorectal cancer invasiveness and stemness. Here we detected interleukin-22 (IL-22) in patient colorectal cancer tissues that was produced predominantly by CD4+ T cells. In a mouse model, migration of these cells into the colon cancer microenvironment required the chemokine receptor CCR6 and its ligand CCL20. IL-22 acted on cancer cells to promote activation of the transcription factor STAT3 and expression of the histone 3 lysine 79 (H3K79) methytransferase DOT1L. Full-Text PDF Open Archive