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`Author manuscript
`Cytokine Growth Factor Rev. Author manuscript; available in PMC 2019 June 01.
`Published in final edited form as:
`Cytokine Growth Factor Rev. 2018 June ; 41: 10–17. doi:10.1016/j.cytogfr.2018.04.004.
`IL-6 Family Cytokines: Key inflammatory mediators as
`biomarkers and potential therapeutic targets
`Nese Unver1,* and Florencia McAllister1
`1Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center,
`Houston, TX 77030, USA
`Abstract
`IL-6 is a critical cytokine in acute phase response and involved in the pathogenesis of several
`chronic inflammatory diseases including cancer. Studies have highlighted that levels of IL-6 and
`its family members can be useful for diagnosis, prognosis of relapse-free survival and recurrence.
`IL-6 family cytokines have been identified as cancer biomarkers through screening of
`inflammatory mediators in different fluids including saliva, serum, and bronchoalveolar lavage
`fluid (BALF). IL-6 can be modulated by chemopreventive drugs, small molecules, monoclonal
`antibodies and immune checkpoint inhibitors. Unveiling the different sources of IL-6, the
`interaction between IL-6 and its cellular targets, the IL-6-dependent tumor resistance mechanisms,
`and the identification of novel regulators of IL-6 are some of the highly complex topics included in
`this review and their understanding could aid cancer biomarkers and therapy development.
`Graphical abstract
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`*Corresponding author at: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston,
`TX 77030, USA, nunver@mdanderson.org (Nese Unver).
`Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
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`Conflicts of interest statement
`None.
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`Keywords
`IL-6; IL-6 family; cytokine; cancer biomarker; immunoprevention
`1. IntroductionInflammation, one of the hallmarks of cancer, is a known contributor to cancer initiation and
`progression [1]. The role of IL-6 in the development and progression of inflammation-
`associated cancers has been widely described. Several cells in the tumor microenvironment
`are capable of secreting IL-6, including epithelial oncogenic cells as well as stromal cells
`including immune cells [2]. Besides its direct effect on tumor cell proliferation, IL-6 is also
`a major immunomodulatory agent, playing active roles in the regulation of acute phase
`reactions, activation of T helper cells, inhibition of T regulatory (Tregs) cells and
`differentiation of B cells by orchestrating innate and adaptive immune responses [3]. Dual
`roles for IL-6 have been described in some specific tumors as it is the example of lung
`cancer in which IL-6 has a preventive role in the tumor initiation but it is also capable of
`enhancing cancer progression [4] [5].
`IL-6 monoclonal antibody (Siltuximab) has been tested in mouse xenografts models of lung
`cancer and it has tumor inhibitory effect particularly potent when cancer-associated
`fibroblasts were coadministered, suggesting that IL-6 secreted by the stroma might be more
`susceptible to the antibody effect [6]. Cancer associated fibroblasts (CAF) in hepatocellular
`carcinoma (HCC) also secrete high levels of IL-6 which contributes to tumor progression via
`recruitment of immune cells with immunosuppressive phenotype. This data suggests that
`IL-6 blockade in addition to immune checkpoint inhibitors may potentially overcome the
`immune-checkpoint inhibitor resistance in some types of cancer [7]. The gp130 f/f (IL6st)
`knock-in mouse model exhibits hyper activation of the STAT3 arm of IL6. When this
`transgenic mouse is crossed with Kras(G12D) mice to study lung tumorigenesis, an increase
`in atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma
`throughout the lung are observed, suggesting that IL-6 trans-signaling can be a target for the
`treatment of KRAS-driven lung adenocarcinoma [8].
`2. Identification of IL-6 family cytokines as cancer biomarkers
`2.1. IL-6
`The IL-6-type family cytokines are IL-6, IL-11, IL-31, Cardiotrophin-1, Ciliary neurotrophic
`factor (CNTF), Cardiotrophin-like cytokine (CLC), Granulocyte-colony stimulating factor
`(G-CSF), Leptin, Leukemia inhibitory factor (LIF), Neuropoietin and Oncostatin M. The
`main cellular source of IL-6 is monocytes and T cells but it can also be produced by other
`cells including epithelial cells [9]. IL-6 promotes Th17 cells development when combined
`with TGF-(cid:868)(cid:3)[10], inhibits TGF-(cid:868)-induced Treg differentiation [11], plays a role in
`neutrophil and macrophage recruitment and is also associated with the pathogenesis of
`chronic inflammatory disease [12]. IL-6 activates STAT3 through two pathways: classical
`and trans-signaling. Classical signaling of IL-6 occurs in cells expressing IL-6R(cid:867) and it
`induces anti-inflammatory molecules [12]. On the other hand, trans-signaling is possible in
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`all cells expressing gp130 and causes pro-inflammatory cytokines induction which drives
`chronic inflammation. IL-6 not only contributes to cancer related inflammation but also
`plays crucial roles in DNA damage repair, anti-oxidant defense system, proliferation,
`invasion, metastasis, angiogenesis and metabolic remodeling [12] (Figure 1).
`Screening of cytokines can serve to identify immunological response-related soluble factors
`which may be increased in cancer even at early stages. A study that included 224
`hepatocellular carcinoma (HCC) cases and 644 controls revealed that higher serum levels of
`IL-6 are predictive of increased HCC risk, independently of hepatitis virus infection,
`radiation exposure and lifestyle-associated factors [13]. IL-6 can also be involved in
`stemness and metastasis via its downstream target, Osteopontin, in HCC. Plasma levels of
`IL-6 and Osteopontin were found to be independent prognostic factors for HCC patients
`[14].Serum levels of IL-6 have been associated with tumor progression. In bladder cancer, IL-6
`serum levels were found to be remarkably higher in patients with recurrence compared to
`non-recurrent patients [15]. In pancreatic ductal adenocarcinoma (PDAC), serum levels of
`IL-6 can be useful as diagnostic biomarker and this cytokine has also been implicated in the
`progression of this type of tumor [16]. It has also been reported as a useful classifier for the
`identification of high-risk stage I lung adenocarcinoma patients [17]. In addition to serum
`based studies of inflammatory mediators, tissue microarray and immunohistochemistry
`analysis of IL-6 in human cervical cancer tissues suggest its usefulness as prognostic
`biomarker as well as potential therapeutic targets for treatment of cervical cancer [18].
`Advanced or metastatic colorectal cancer patients with high serum IL-6 levels had poorer
`overall survival (OS), progression-free survival (PFS) and anti-VEGF resistance [19] than
`patients with lower levels. In addition to solid tumors, elevated serum levels of IL-6 can
`serve as a biomarker in hematological malignancies like Hodgkin’s lymphoma [20]. IL-6
`and the JAK-STAT3 signaling pathway have also been found upregulated in
`myeloproliferative neoplasms (MPN). Interestingly, the recent JAK1/2 inhibitor trials in
`MPNs demonstrated that lessening inflammation can be even more helpful that targeting
`mutations [21].
`Besides serum levels, Il-6 detection in saliva has been proposed as a useful diagnostic
`biomarker of cancers like oral squamous cell carcinoma (OSCC) [22]. In OSCC, IL-6
`modulates resistance to radiation by inhibiting oxidative stress through the Nrf2-antioxidant
`pathway [23].
`2.2. IL-6 as a critical inflammatory marker in murine models
`IL-6 is the most highly elevated cytokine in COPD-like inflammatory mouse model and is
`required for lung cancer promoted by COPD-like inflammation [24]. IL-6 differently
`modulates both tumor initiation and progression via activating STAT3 in a mouse model of
`lung cancer induced by the Kras oncogene. It suppresses lung cancer initiation via sustaining
`lung homeostasis, modulating lung macrophages and activating cytotoxic CD8+ T cells
`under Kras oncogenic stress, and on the other hand it promotes lung cancer cell growth by
`promoting the cell proliferation regulator Cyclin D1 [4]. In a different lung cancer mouse
`model, CcspCre/+ KrasLSL-G12D/+ (CC-LR), IL-6 and IL-6 class cytokine LIF were highly
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`detected in BALF from mice with tumors. Chemopreventive treatment of mice with myo-
`inositol diminished IL-6 and phospho-STAT3 signaling, a process likely mediated by tumor
`associated macrophages [25].
`In the pancreas, KrasG12D activation induces premalignant lesions called pancreatic
`intraepithelial neoplasias (PanINs). IL-6 trans-signaling-dependent activation of Stat3/Socs3
`is required to promote murine PanIN progression to PDAC [26]. In a similar fashion, IL-6
`has been described as a critical tumor booster during early colitis-associated cancer (CAC).
`Its production by myeloid cells in the lamina propia has a protective role on normal and
`premalignant intestinal epithelial cells (IECs) against apoptosis [27].
`IL-6 has also been found increased during the development and malignant progression of
`astrocytomas [28]. Although suppression of IL-6 does not influence preneoplastic
`astrogliosis, it prevents tumor formation in a spontaneous GFAP-v-src+/− mouse astrocytoma
`model. In a murine model of osteosarcoma, tumor progression and recurrence are modulated
`by IL-6 via promoting tumor self-seeding by CTCs [29].
`In murine models of hematological malignancies such as CML, increased IL-6 levels were
`detected in BCR/ABL transgenic mice. IL-6 produced by myeloid CML cells inhibits
`lymphoid differentiation from multipotent progenitor cells [30] and shapes the CML
`pathogenesis.
`Apart from tumor cells derived IL-6 secretion, mesenchymal stem cells (OvMSC) can
`secrete IL-6 which contributes to tumor progression in models like ovarian cancer.
`Coinjection of OvMSC with ovarian cancer cells enhances ovarian tumor development in
`NOD-SCID mice [31]. In a murine model of hepatocellular carcinoma (HCC), IL-6 is
`predominantly expressed by CAFs creating an immunosuppressive environment via up-
`regulation of inhibitory immune checkpoints [7] (Figure 2).
`A study of gastric tumorigenesis in mice challenged with N-methyl-N-nitrosourea
`demonstrated the importance of IL-6 in driving tumor development through STAT3
`stimulation by using IL-6 knockout mice [32]. Inoculation of another chemical carcinogen,
`diethylnitrosamine (DEN), remarkably increased serum interleukin-6 (IL-6) concentration in
`males compared to females. Estrogen-mediated suppression of IL-6 production by Kupffer
`cells diminished liver cancer risk in females in the DEN-induced hepatocellular carcinoma
`mouse model [33], suggesting that suppression of IL-6 abrogates the gender differences in
`hepatic carcinogenesis.
`IL-11 was identified as a 19 kDa soluble factor belonging to the IL-6 cytokine family in the
`supernatant of bone-marrow derived stromal cell. The main cellular source of IL-11 are
`bone, connective tissue, and malignant cells [34]. Through transmembrane protein
`glycoprotein-130 beta subunit, IL-11 shows pro-tumorigenic activities such as proliferation,
`self-renewal, invasion and angiogenesis [34]. In a prospective cohort of 60 smokers
`including patients with lung cancer, COPD and both, IL-11 was found to be a specific
`biomarker for the diagnosis of lung adenocarcinoma in BALF specimens [35].
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`Although there is a limitation with cohort size and short follow-up time, IL-11 has been
`found to be a useful biomarker for diagnosis and prognosis in patients with pancreatic
`cancer [36]. Assessment of IL-11 expression by immunohistochemistry in clear-cell RCC
`(ccRCC) has demonstrated its association with increased risk of recurrence and poor
`survival for ccRCC patients with early-stage disease. As a result of immunohistochemical
`evaluation of tissue microarrays including paired tumor/peritumoral liver tissue from 290
`patients who had undergone hepatectomy for histologically proven HCC, intra-tumoral
`IL-11 is significantly concordant with higher tumor node metastasis (TNM) stage and has
`been found to be an independent prognostic factor for progression-free survival (PFS) [37],
`[38].
`2.4. Oncostatin MOncostatin M (OSM) is produced by monocytes, macrophages, T cells, neutrophils and
`dendritic cells. Oncostatin M plays fundamental roles in heart remodeling, inflammation,
`hematopoiesis, liver regeneration and cancer [39]. OSM levels are associated with
`inflammatory response-genes, epidermal growth factor (EGF) signaling and epithelial-to-
`mesenchymal transition (EMT) in human estrogen receptor (ER)-negative/human epidermal
`growth factor receptor 2 (HER2)-negative breast cancer [40]. High expression of OSM and
`OSM receptor (OSMR) mRNA have been associated with reduced ER and progesterone
`receptor (PR) protein levels in a cohort of 70 invasive breast cancers [41]. OSM stimulates
`the expression of ZEB1, Snail (SNAI1), and OSMR as well as the CSC phenotypes in
`pancreatic cancer, suggesting that therapeutic targeting of the OSM/OSMR axis could be
`useful for patients with PDAC [42]. Analysis of serum diagnostic biomarkers in PDAC
`showed that OSM was overexpressed in PDAC patients versus controls (AUC=0.744). OSM
`could also be a predictive biomarker for treatment of PDAC response to drugs like
`gemcitabine and erlotinib [43].
`IL-31 is mainly expressed by circulating Th2 lymphocytes and skin-homing CLA+ CD45RO
`+ T cells. IL-31 binds its heterodimeric receptor formed from IL-31RA and the OSMR
`chains and this leads to phosphorylation of Jak1/2, which in turn, triggers phosphorylation of
`STAT1/3/5 or PI3K/AKT. These pathways promote skin inflammation, development of T
`cell type-2 inflammation in asthma and allergic rhinitis as well as gut inflammation.
`Elevated serum levels of IL-31 contribute to the pathogenesis of different tumor types
`including endometrial, lung cancer, cutaneous T cell lymphoma, follicular B cell lymphoma
`[44] [45]. Expression of IL-31 was found to be increased in patients with mastocytosis
`compared with those seen in healthy control subjects (P < .0473) [46].
`3. Identification of IL-6 family cytokines as potential cancer treatment target
`3.1. IL-6
`Activation of IL-6/STAT3 pathway has been reported in various cancer types. Blockade of
`IL-6/STAT3 has been targeted by potent chemopreventive drugs. As an example, disulfiram,
`targets cancer stem cells [47] and STAT3 signaling in triple-negative breast cancer [48].
`Targeting STAT3 could cause elimination of cancer stem-like cells and contribute to
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`blockade of recurrence in breast cancer. Recently published papers have also focused on
`small molecules such as Tanshinone IIA (Tan-IIA) possessing anti-cancer and anti-
`inflammatory activities or proteins like repebody which binds IL-6 ligand with high affinity
`attenuating STAT3 signaling and inhibiting human breast cancer stem cells growth and
`NSCLC, respectively [49] [50]. In prostate cancer, elevation of IL-6 and loss of ESE3/EHF,
`required for differentiation of human prostate epithelial cells, were associated with STAT3
`activation. IL-6 upregulates cancer stem-like and metastatic spread-related gene expressions,
`indicating that identification of the novel regulator sites in IL-6 promoter could be beneficial
`for prostate cancer with loss of ESE3/EHF. Besides transcriptional modifiers, a long non-
`coding RNA identified as antisense IL6 stimulates IL-6 expression, which induces IL-6/
`STAT3 activation and increases invasive ability of glioblastoma cells [51].
`Interleukin-6 (IL-6) is a growth factor for estrogen receptor-(cid:867)(cid:3)(ER(cid:867))-positive breast cancer.
`Preclinical models have shown that breast cancer patients-derived xenografts respond to IL-6
`blocking antibody [52]. Siltuximab has been well tolerated in patients with solid tumors
`including ovarian and KRAS-mutant cancers [53]. Siltuximab inhibits the growth of human
`renal cell carcinoma (RCC) in nude mice and remarkably stabilizes disease in patients with
`progressive metastatic RCC [54]. Since IL-6 has been involved in resistance to anti-
`angiogenic treatment, combinational therapy targeting angiogenic factors could be useful to
`prevent or minimize side effects of the monoclonal antibody.
`IL-11 is the dominant IL-6 family cytokine identified as an inducer of oncogenic STAT3
`activity in the gastrointestinal (GI) epithelium during tumorigenesis, which can be targeted
`pharmacologically. mIL-11 Mutein treatment remarkably diminished overall tumor burden,
`gastric epithelial hyperplasia and reduced expression of the inflammatory mediators in the
`gastrointestinal tumorigesis model [55]. IL-11/IL-11R(cid:867) axis modulates human
`osteosarcoma through STAT3 [56–58]. Bone metastasis-targeting peptidomimetic
`(BMTP-11) directed against IL-11R(cid:867) retards primary tumor growth and lung metastasis in
`preclinical models of human osteosarcoma. BMTP-11 in combination with gemcitabine
`shows better outcomes than BMTP-11 alone [59]. Similarly, targeting IL-11R(cid:867) in
`combination with doxorubicin therapeutically improves the effect of chemotherapy in high
`grade Type I endometrioid cancer [60].
`3.3. Oncostatin MThe role of Oncostatin M on tumor progression is controversial. A lung cancer study has
`shown that Oncostatin M inhibits metastasis of lung adenocarcinoma by suppressing SLUG
`expression via STAT1/STAT3 dependent signaling [61].
`Oncostatin M (OSM) was described as a robust inducer of mesenchymal/CSC. Eradication
`of OSM or suppression of STAT3 or SMAD3 causes a significant reversion to a non-
`invasive, epithelial phenotype [62]. OSMR has been described as an inducer of
`mesenchymal properties in glioblastoma. Analysis of TCGA data has showed that OSMR
`but not IL-6R or LIFR is upregulated in GBM [63]. In contrast to osteosarcomas and
`chondrosarcomas, OSM induces proliferation of Ewing carcinoma cells which are rare bone
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`malignant cells, suggesting its potential utility for therapeutic intervention [64]. In sum,
`OSM/OSMR could be potential cancer therapeutic targets besides their usefulness as
`diagnostic biomarkers [63].
`4. Promising Trials targeting IL-6/ IL-6R and IL-11/IL-11R(cid:867) in cancer
`Inhibition of IL-6 and IL-6R using specific monoclonal antibodies is being tested
`therapeutically for many different types of cancer [65]. Phase I and II studies assessed
`siltuximab in various solid tumors including ovarian, pancreatic, colorectal, head & neck and
`lung neoplasms [66]. In addition to solid tumors, siltuximab has also been evaluated for
`patients with multiple myeloma who are relapsed or refractory [67]. Phase I trials related to
`siltuximab are also undergoing in hematological tumors including non-Hodgkin’s
`lymphomas (NHL) and B cell Chronic Lymphocytic Leukemia [68]. In pancreatic cancer, a
`current phase II trial will evaluate the safety and efficacy of gemcitabine and nab-paclitaxel
`with or without tocilizumab (monoclonal antibody against IL-6 receptor) (Clinical trial
`identification: NCT02767557). IL-6R has been described as an independent prognostic
`factor and potential therapeutic target for ovarian cancer. Tocilizumab has been found to be
`well tolerated in clinical trials [69]. The on-going phase I trial will evaluate tolerability and
`safety of tocilizumab given with trastuzumab and pertuzumab in subject with metastatic
`HER2+ breast cancer (Clinical trial identification: NCT03135171).
`Recombinant IL-11 (Neumega) is also under clinical development for acceleration of
`platelet recovery and inhibition of inflammation in cancer patients to prevent chemotherapy-
`induced thrombocytopenia [70]. BMTP-1 for IL-11R(cid:867) has been shown as a promising drug
`candidate in metastatic prostate cancer [71]. A comprehensive list with the completed and
`ongoing clinical trials targeting IL-6 family cytokines as well as their receptors can be found
`in Table 1.
`5. IL-6/STAT3 pathway can be targeted for cancer prevention
`Chemoprevention targets many steps including tumor initiation, promotion and progression.
`Dietary derived products play a role in all steps of the carcinogenic process [72].
`Administration of (cid:867)-Tocopherol (vitamin E) in an inducible mouse model of non-Hodgkin's
`T-cell lymphoma diminishes IL-6 gene and protein expression [73]. In a similar manner,
`plant derived glycoprotein (UDN glycoprotein) inhibits the levels of IL-6 in 1,2-
`dimethylhydrazine-treated mice, suggesting that UDN glycoprotein may be an effective
`agent for colon cancer prevention [74]. Intragastric treatment with Isoliquiritigenin,
`originated from licorice root, downregulates IL-6 signaling in a chemically induced mouse
`model of colon carcinogenesis and it suppresses macrophage polarization into M2-like
`phenotype partially through IL-6/STAT3 pathway [75]. IL-6/STAT3 pathway can be also
`regulated by balsalazide (a 5-ASA prodrug) and probiotic agent VSL#3 in colorectal cancer
`chemoprevention [76]. The diet-derived polyphenols Apigenin and luteolin have an
`inhibitory effect on angiogenesis mediated by IL-6/STAT3 pathway in human endothelial
`cells [77]. Another example of IL-6 suppression is the mechanism of Quercetin, a compound
`found in many plant-based foods, which has been proposed for chemoprevention and
`treatment of glioblastoma [78]. Finally, the estrogen receptor modulator Evista (Raloxifene
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`HCl), found to also inhibit IL-6/GP130 protein interaction, represents a promising
`chemopreventive agent for breast, colon, multiple myeloma and liver cancer [79] [80].
`6. Conclusion & Perspectives
`IL-6 is a multi-functional cytokine and its abnormal expression levels are associated with
`cancer diagnosis, prognosis and disease progression. Recently, the new area of
`immunoprevention has gained major attention. Direct targeting of the IL-6 family members
`with some of the monoclonal antibodies currently described in clinical trials for treatment of
`various cancers could potentially be used for cancer prevention [81] [82].
`Development of monoclonal antibodies and small molecules in addition to defining de novo
`transcriptional regulators targeting trans-signaling of IL-6 would improve cancer therapeutic
`strategies. Defining the origin of IL-6 and IL-6 family cytokines in the tumor
`microenvironment and molecular stratification of cancer subtypes based on these key
`inflammatory mediators would open up novel insights for chemoresistance and
`immunotherapy in cancer therapy. Using in vivo models, application of combinational
`therapies including IL-6 blockade and conventional chemotherapeutic or immunotherapy
`drugs will provide basis for clinical research.
`Acknowledgments
`Dr. McAllister received support from the PanCAN/AACR Career Development Award (14-20-25 MCAL), National
`Pancreas Foundation and V Foundation (V Scholar). Dr McAllister is also a Paul Calabresi K12 clinical scholar
`(NCI grant awarded to MDACC K12CA088084-16A1).
`AbbreviationsBALF
`Bronchoalveolar lavage fluid
`Colitis-associated cancer
`CAC
`Cancer associated fibroblast
`CAF
`Clear cell renal cell carcinoma
`ccRCC
`Cardiotrophin-like cytokine
`CLC
`Chronic myeloid leukemia
`CML
`Ciliary neurotrophic factor
`CNTF
`Chronic obstructive pulmonary disease
`COPD
`Circulating tumor cells
`CTC
`Epidermal Growth Factor
`EGF
`Epithelial–mesenchymal transition
`EMT
`Granulocyte-colony stimulating factor
`GCSF
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`Glycoprotein 130
`Gp130
`Hepatocellular carcinoma
`HCC
`Intestinal epithelial cells
`IEC
`Interleukin 11
`IL-11
`Interleukin 31
`IL-31
`Interleukin 6
`IL-6
`Interleukin 6 receptor
`IL-6R
`Januse kinase 1/2
`Jak1/2
`Leukemia inhibitory factor
`LIF
`Leukemia inhibitory factor receptor
`LIFR
`Mitogen-activated protein kinase
`MAPK
`Myeloproliferative neoplasms
`MPN
`Nuclear factor (erythroid-derived 2)-like 2
`Nrf-2
`Non-Hodgkin’s lymphomas
`NHL
`Non-small cell lung cancer
`NSCLC
`Oral squamous cell carcinoma
`OSCC
`Pancreatic intraepithelial neoplasia
`PanIN
`Pancreatic ductal adenocarcinoma
`PDAC
`Progression-free survival
`PFS
`PI3K/AKT The phosphatidylinositol-3-kinase/Protein kinase B
`Renal cell carcinoma
`RCC
`Signal transducer and activator of transcription 1
`STAT1
`Signal transducer and activator of transcription 3
`STAT3
`Tumor node metastasis
`TNM
`Regulatory T cell
`Treg
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`Cytokine Growth Factor Rev. Author manuscript; available in PMC 2019 June 01.
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