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• W2056006136 abstract "ImmunotherapyVol. 3, No. 5 EditorialFree AccessStat3-driven cancer-related inflammation as a key therapeutic target for cancer immunotherapyTakuma KatoTakuma KatoDepartment of Molecular & Cellular Immunology, Mie University Graduate School of Medicine, 2–174 Edobashi, Tsu, Mie, 514–8507, Japan. Search for more papers by this authorEmail the corresponding author at katotaku@doc.medic.mie-u.ac.jpPublished Online:9 May 2011https://doi.org/10.2217/imt.11.26AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: cancer immunotherapycancer-related inflammationNF-κBSTAT3tumor microenvironmentDespite advances in therapeutics and early detection, cancer remains a leading cause of death in developed countries. For decades, cancer therapies have concentrated on low-molecular-weight cytotoxic reagents aimed at killing tumor cells directly. The discovery that human tumor antigens can be recognized by cytotoxic T lymphocytes in autologous human hosts pioneered the development of immunotherapeutic strategies such as cancer vaccine and adoptive tumor immunotherapy targeting these antigens. However, antitumor immunity elicited by the host and introduced by immunotherapeutic strategies are dominantly attenuated by the regulatory barriers that limit the strength and/or duration of tumor-eliminating immune responses, including a number of immunoregulatory cells and the immunosuppressive factors. During tumorigenesis, the host-mediated anti-tumor immune responses mediated by innate and adaptive immune cells are suppressed and replaced by tumor-promoting inflammation that prevails in the tumor microenvironment to support tumor growth, angiogenesis, invasion and metastasis. Therefore, a better understanding of the cellular and molecular changes that occur in the tumor microenvironment and their roles in tumor development can pave the way for successful cancer immunotherapeutic strategies.There has been substantial data supporting a protective role for immunity in detecting and eliminating nascent tumors. This process, termed ‘cancer immunosurveillance’, originally proposed in the 1900s by Paul Ehrlich, has undergone a renaissance with elegant studies of cancer development in genetically engineered (targeting and/or transgenic) animals, and turned into the refined hypothesis known as ‘cancer immunoediting’ [1]. Cancer immunoediting controls tumor development and growth by three phases either independently or in sequence: the host immune system recognizes and eliminates primary developing tumors (cancer immunosurveillance), restrains the growth of established tumors to keep them clinically unapparent (equilibrium), and loses control of tumor cell variants that dampen immunogenicity and/or gain the capacity to subvert immune system (escape). Several recent studies in human cancer also provide circumstantial evidence to indicate that immunoediting might be operative in diverse human malignancies. It appears that any immunotherapeutic strategies aimed at eliminating clinically apparent tumors might be unsuccessful on the surface, because the tumors have been edited so that they are highly resistant to immune attack. However, intensifying immunity to tumors by cancer vaccines and/or adoptive immunotherapy in combination with blocking immunosuppressive mechanisms would be expected to have therapeutic efficacies.Notwithstanding these evidences supporting a suppressive role of immunity to tumor development, epidemiological and experimental evidence also indicates that inflammation driven by innate and adaptive immune responses play a supportive role in tumorigenesis, which was first postulated in the 19th Century by Virchow [2]. Approximately 20% of the human global cancer burden is caused by unresolved infection and/or inflammation, such as colorectal carcinoma and inflammatory bowel disease, gastric carcinoma and Helicobacter pylori infection, and cervical cancer and human papilloma virus infection. Moreover, an inflammatory environment is also evident even in tumors, where a direct causal relationship with inflammation has not yet been proven. Mutations of the various types of oncogenes irrespective of those encoding protein tyrosine kinases, transcription factors or tumor-suppressor proteins, all resulted in the initiation of inflammatory transcriptional programs [3]. These oncogene-initiated inflammatory responses (intrinsic pathway) also educate stromal cells and immune cells surrounding malignant cells to initiate and/or maintain inflammation (extrinsic pathway) that have common aspects, that is, support survival of malignant cells, promote angiogenesis and metastasis, subvert adaptive immune responses and alter responses to chemotherapeutic reagents. The importance of the inflammatory component in cancer development has been supported by clinical data showing that use of NSAIDs significantly reduces the risk of colorectal carcinoma in patients with inflammatory bowl disease and also decreases in the incidence of sporadic colon cancer [4]. Thus, the inflammatory microenvironment created by an intrinsic pathway (mediated by tumor cells) and extrinsic pathway (mediated by stromal cells and immune cells) contributes to tumor progression, and has now been recognized as cancer-related inflammation that defines the seventh hallmark of cancer [5].Although numerous experimental and clinical data provide evidence for the role of inflammation in tumor development and progression, this is not always the case and the inflammation is also viewed as an attempt by the host immunity to eliminate tumors. Psoriasis, a chronic skin disease with marked chronic inflammation, may even reduce the risk for skin cancer [6]. In certain cases of colon, breast and pancreatic cancers, the presence of inflammatory cells and mediators positively correlates with better prognosis [7]. It is likely that, under a limited circumstance, inflammation creates unfavorable conditions for tumor development and progression, and can even eliminate tumor cells. Indeed, it has been shown that inflammatory reactions led to the shrinkage or even the disappearance of tumors. The apparent contradictory roles of inflammation in cancer might reflect distinct types of inflammation that occur in the tumor microenvironment that determines whether tumors grow or shrink. Given that cancer-related inflammation dominantly suppress immune responses to tumors, resolving cancer-related inflammation potentiates immunotherapies against cancer. Furthermore, reprogramming of inflammatory programs in the tumor microenvironment that supports tumor development/progression and subverts immunity to tumors into those that oppose tumor development/progression and stimulates immunity to tumors might represent a more attractive strategy.The major inflammatory cytokines involved in cancer-related inflammation are IL-1β, IL-6, IL-23, TNF-α and microphage migration inhibitory factor (MIF), which support tumor growth, angiogenesis, invasion and metastasis, and suppress antitumor functions of immune cells. The expressions of these cytokines are under the control of transcription factors, NF-κB and Stat3, which are activated constitutively in most tumors. An important common feature of these cytokines that are positively regulated by Stat3 is their ability to activate Stat3 upon binding of cognate receptors expressed on tumor cells and surrounding stromal cells and immune cells [8]. In addition, activation of Stat3 in immune cells resulted in the suppression of antitumor function and the stimulation of immunoregulatory function [9]. It also appears that Stat3 prolongs nuclear retention of NF-κB to ensure its constitutive activation [10]. This explains, at least in part, why Stat3 and NF-κB are constitutively activated in tumor cells and how they create a vicious circle between tumor cells and immune cells in inflammatory tumor microenvironment [11]. Although Stat3 stimulates specifically inflammatory cytokines that support tumor development and suppress antitumor immune responses, NF-κB is involved not only in the activation of cytokines that mediate protumor inflammation but also the activation of those that mediate antitumor inflammation [12]. Accumulating evidence indicates that NF-κB and Stat3 play a decisive role in determining the type of inflammation that can either promote or inhibit tumor development. Tumor-associated macrophages abundant in the tumor stroma of many tumor types can produce either anti- or pro-tumorigenic inflammatory cytokines, IL-12 or IL-23, respectively. Importantly, it has recently been demonstrated that inducible myeloid-specific Stat3 gene ablation resulted in the abrogation of IL-23 production of tumor-associated macrophages and induced IL-12 production of tumor-infiltrating dendritic cells [13]. Stat3 is shown to inhibit NF-κB binding to the IL-12p35 promoter leading to the suppression of dependent IL-12 production. Therefore, Stat3 appears to predominate the expression of NF-κB target genes involved in antitumor inflammation.Due to extensive redundancy among cytokines that activate Stat3 and the fact that Stat3 is central to determining the type of inflammation that can either promote or inhibit tumor development, direct inhibition of Stat3 may represent a promising therapeutic target to reprogram tumor-promoting inflammation into tumor-suppressing inflammation. Although low-molecular-weight compounds and oligonucleotides including antisense RNA and siRNA that inhibit Stat3 have been developed and show some efficacies [14,15], there are potential pitfalls to be avoided in the general suppression of Stat3. It has been shown that Stat3 activation in T cells is critically important for their migration [16] and confer resistance to regulatory T-cell-mediated suppression [17], and therefore its inhibition could have undesirable effects to the antitumor immune responses. A recent study in a mouse intestinal tumor model has also uncovered the negative regulatory role of Stat3 activation in tumor cells in their invasiveness [18]. Given that tumor cells quickly acquire drug resistance and their survival and growth are highly dependent on the inflammatory microenvironment created by surrounding stromal cells and immune cells, therapeutic intervention aimed at inflammatory components of tumor stroma rather than tumor cells seems a more attractive strategy. In this regard, a series of recent studies has demonstrated that silencing of Stat3 in immune cells including myeloid, dendritic and B cells, using a siRNA linked to a CpG through both local and systemic delivery, exhibits a potent antitumor effect. This effect was associated with an increase in cells producing antitumorigenic cytokines and a decrease in immunosuppressive cells within the tumor [19]. Although oligonucleotide-based therapeutics need to be improved in terms of toxicity and stability [20], these studies provide a proof-of-concept for the feasibility of direct inhibition of Stat3 in reprogramming cancer-related inflammation that leads to tumor destruction.With an improved method to specifically inhibit Stat3 activity in tumor stroma, future antitumor immmunotherapeutic strategies will probably involve approaches designed to restore antitumor immune responses, overcome tumor induced immune subversion and maximize the host immune function to control tumor growth by the reprogramming of protumor inflammation into antitumor inflammation.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Bibliography1 Dunn GP, Bruce AT, Ikeda H et al.: Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol.3,991–998 (2002).Crossref, Medline, CAS, Google Scholar2 Balkwill F, Mantovani A: Inflammation and cancer: back to Virchow? Lancet357,539–545 (2001).Crossref, Medline, CAS, Google Scholar3 Allavena P, Garlanda C, Borrello MG et al.: Pathways connecting inflammation and cancer. Curr. Opin. Gene. Dev.18,3–10 (2008).Crossref, Medline, CAS, Google Scholar4 Jacobs EJ, Thun MJ, Bain EB et al.: A large cohort study of long-term daily use of adult-strength aspirin and cancer incidence. J. Natl Cancer Inst.99,608–615 (2007).Crossref, Medline, CAS, Google Scholar5 Mantovani A: Cancer: inflaming metastasis. Nature457,36–37 (2009).Crossref, Medline, CAS, Google Scholar6 Nickoloff BJ, Ben-Neriah Y, Pikarsky E: Inflammation and cancer: is the link as simple as we think? J. Invest. Dermatol.124,X–XIV (2005).Crossref, Medline, CAS, Google Scholar7 DeNardo DG, Andreu PCoussens LM: Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev.29,309–316 (2010).Crossref, Medline, Google Scholar8 Yu H, Pardoll DJove R: STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer9,798–809 (2009).Crossref, Medline, CAS, Google Scholar9 Kortylewski M, Yu H: Role of Stat3 in suppressing anti-tumor immunity. Curr. Opin. Immunol.20,228–233 (2008).Crossref, Medline, CAS, Google Scholar10 Lee H, Herrmann A, Deng JH et al.: Persistently activated Stat3 maintains constitutive NF-κB activity in tumors. Cancer Cell15,283–293 (2009).Crossref, Medline, CAS, Google Scholar11 Grivennikov SI, Karin M: Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev.21,11–19 (2010).Crossref, Medline, CAS, Google Scholar12 Kortylewski M, Kujawski M, Wang T et al.: Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat. Med.11,1314–1321 (2005).Crossref, Medline, CAS, Google Scholar13 Kortylewski M, Xin H, Kujawski M et al.: Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell15,114–123 (2009).Crossref, Medline, CAS, Google Scholar14 Chiarle R, Simmons WJ, Cai H et al.: Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nat. Med.11,623–629 (2005).Crossref, Medline, CAS, Google Scholar15 Ling X, Arlinghaus RB: Knockdown of STAT3 expression by RNA interference inhibits the induction of breast tumors in immunocompetent mice. Cancer Res.65,2532–2536 (2005).Crossref, Medline, CAS, Google Scholar16 Verma NK, Dourlat J, Davies AM et al.: STAT3-stathmin interactions control microtubule dynamics in migrating T-cells. J. Biol. Chem.284,12349–12362 (2009).Crossref, Medline, CAS, Google Scholar17 Goodman WA, Young AB, McCormick TS et al.: Stat3 Phosphorylation mediates resistance of primary human T cells to regulatory T cell suppression. J. Immunol.186(6),3336–3345 (2011).Crossref, Medline, CAS, Google Scholar18 Musteanu M, Blaas L, Mair M et al.: Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice. Gastroenterology138,1003–1011 E1–E5 (2010).Crossref, Medline, CAS, Google Scholar19 Herrmann A, Kortylewski M, Kujawski M et al.: Targeting Stat3 in the myeloid compartment drastically improves the in vivo antitumor functions of adoptively transferred T cells. Cancer Res.70,7455–7464 (2010).Crossref, Medline, CAS, Google Scholar20 Juliano R, Alam MR, Dixit V et al.: Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides. Nucleic Acids Res.36,4158–4171 (2008).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByBiomarkers of Cancer18 September 2017Butein and Its Role in Chronic Diseases25 September 2016Butein effects in colitis and interleukin-6/signal transducer and activator of transcription 3 expressionWorld Journal of Gastroenterology, Vol. 21, No. 2Biomarkers of Cancer29 October 2013Targeting the Interleukin-6/Jak/Stat Pathway in Human MalignanciesJournal of Clinical Oncology, Vol. 30, No. 9Analysis of the contribution of nasopharyngeal epithelial cancer cells to the induction of a local inflammatory response30 September 2011 | Journal of Cancer Research and Clinical Oncology, Vol. 138, No. 1 Vol. 3, No. 5 STAY CONNECTED Metrics History Published online 9 May 2011 Published in print May 2011 Information© Future Medicine LtdKeywordscancer immunotherapycancer-related inflammationNF-κBSTAT3tumor microenvironmentFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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