Interleukin-11 (IL11), a stromal-cell derived pleiotropic cytokine with profibrotic and cellular remodeling properties, as a potential biomarker in non-small cell lung cancer (NSCLC). IL11 is an important tumor-promoting cytokine that that has both diagnostic and prognostic value in patients with NSCLC. Multiple in vitro studies confirm that IL11 activates known tumor-promoting signaling pathways and clinical studies link increased IL11 expression to poorer prognosis.
Cytokine | Receptors | References | |
---|---|---|---|
IL6 | IL6R, gp130/IL6ST | [7][8][9][10][11][12][13][14] | [15,16,17,18,19,20,21,22] |
IL-31 | IL31Rα, OSMR | [15] | [23] |
LIF | LIFR/LIFRα, gp130/IL6ST | [16] | [24] |
OSM | OSMR/OSMRβ, gp130/IL6ST, LIFR | [17][18] | [25,26] |
CLCF1 | CNTFR, LIFR, gp130/IL6ST | [14][19] | [22,27] |
To the best of theour knowledge, there are two studies that describe the utility of IL11 as a diagnostic biomarker (Table 2). Pastor et al. recruited a prospective cohort of 369 patients for which use of diagnostic biomarkers in bronchoalveolar lavage fluid (BALF) can potentially facilitate early detection of lung cancer [52][90]. Among 80 cytokines and growth factors, inflammation-related protein array analyses identified IL11 expression to be differentially increased in LUAD BALF samples in an initial discovery cohort, and subsequently validated in two separate exploratory and diagnostic cohorts. This study demonstrated that BALF IL11 expression was largely restricted to patients with LUAD, with or without chronic obstructive pulmonary disease (COPD). Despite the eventual diagnosis at stage III or IV in the majority of the LUAD cohort, the diagnostic performance of BALF IL11 remains similar between the subgroups even for the early stages. Interestingly, BALF IL11 expression was not increased in squamous cell carcinoma (SCC), a type of NSCLC of epithelial origin, which may suggest cell type-selective IL11 expression in NSCLC. In another study, Wu et al. measured IL11 protein concentration in serum and exhaled breath condensate in NSCLC cases compared to healthy donors and found increased IL11 expression in NSCLC patients even at early-stage disease [53][91].
Study | Recruited Population | Comparison | Sample Type | Diagnostic Biomarker | Assay | Receiver Operator Curve and Test Metrics | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
AUC (95% CI) |
Cutoff (pg/mL) | Sensitivity (95% CI) |
Specificity (95% CI) | PPV (95% CI) |
NPV (95% CI) |
||||||
Pastor et al. [52] | Pastor et al. [90] | Age > 40 yrs, current or ex-smokers of 30 pack-years, evaluated for hemoptysis or pulmonary nodule or mass, excluding those with prior diagnosis of malignancy, active tuberculosis, history of drug abuse or other inflammatory disease apart from COPD | LUAD vs. non-LUAD—First validation cohort (n = 149) | BALF | IL11 protein | ELISA | 0.93 (0.90–0.97) | 42.0 | |||
78.1 | |||||||||||
79.4 | NR | NR |
Accurate prognostication is important for identifying patients who may benefit from adjuvant or neoadjuvant therapy. Using molecular biomarkers in addition to clinical data can potentially allow patients to be stratified into risk groups with greater accuracy [54][55][106,107]. Numerous studies have identified IL11 mRNA in NSCLC lung tissue taken at the time of surgical resection to be prognostic of overall survival, both by itself and among other genes as part of a prognostic signature (summarized in Table 34).
Study | Year | Training Cohort | Validation Cohort (s) | Cancer Type | Prognostic Signature | Findings | ||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
90.2 (79–95.7) | 88.7 (90.6–93.5) | |||||||||||||||||||||||||||
Kratz et al. [55] | Kratz et al. [107] | 2012 | Non-squamous NSCLC (n = 361) | Stage I non-squamous NSCLC (n = 433), and stage I-III non-squamous NSCLC (n = 1006) | Non-squamous NSCLC | 11 Target genes ( | BAG1 | , | BRCA1 | , | CDC6 | , 80.7 (68.7–88.9) | CDK2AP1 | , | ERBB3 | , | FUT3 | , | IL11 | , | LCK | ) and 3 reference genes ( | ESD | , | TBP | , 94.5 (87.8–97.6) | ||
YAP1 | ) |
|
| LUAD vs. non-LUAD—Second validation cohort (n = 160) | BALF | IL11 protein | ELISA | 0.95 (0.92–0.98) | 42.0 | 90.6 (79.7–95.9) | 83.0 (86.8–87.7) | 60.8 (49.7–70.8) | 96.8 (92.7–98.6) | |||||||||||||||
Watza et al. [56] | Watza et al. [108] | 2018 | NSCLC patients without history of bronchiectasis or cystic fibrosis (n = 280) | TCGA Lung SCC and TCGA LUAD datasets (n = 1026) | NSCLC | 23 genes involved in the interleukin signaling pathway, including | IL11 |
| Wu et al. [53] | Wu et al. [91] | NSCLC patients with no history of radiochemotherapy, immune-targeted therapy or surgery (n = 91 for serum, of which 63 have LUAD and 28 have SCC; 64 for EBC) | Healthy volunteers without acute or chronic infectious diseases, vital organ diseases, or genetic family tumor history (n = 72 for serum; 63 for EBC) | Serum | IL11 protein | ELISA | |||||||||||||
Wang et al. [57] | 0.93 (0.88–0.97) | Wang et al. [79] | 2020 | TCGA LUAD dataset (497 LUAD tissues, 54 normal lung tissues) | n/a | LUAD | 6 genes ( | CRABP1 | , | IGKV4-1 | , | IL11 | , | INHA | , | LGR4 | , | VIPR1 | ) |
| 126.1 | 75.0 | 100.0 | NR |
| NR | ||
|
|
| EBC | IL11 protein | ||||||||||||||||||||||||
Fan et al. [58] | Fan et al. [109] | 2021ELISA | TGCA LUAD dataset (n = 464)(majority stage I and II)0.78 (0.69–0.86) | GSE13213 (n = 117), GSE30219 (n = 85), GSE31210 (n = 226), GSE72094 (n = 420)(majority stage I and II)21.5 | LUAD | 5 genes ( | IL7R | , | IL5RA | , | IL20RB | , | IL11 | , | IL22RA1 | ) |
| |||||||||||
Chen et al. [59] | Chen et al. [110] | 2021 | TCGA LUAD (535 LUAD tissues, 59 normal lung tissues)GSE161116 (9 LUAD tissues, 9 LUAD brain metastasis tissues) | n/a | LUAD | 6 genes ( | TNFRSF11A | , | MS4A2 | , | IL11 | , | CAMP | , | MS4A1 | , | F2RL1 | ) |
| |||||||||
Peng et al. [60] | Peng et al. [111] | 2021 | GSE161116 (13 lung tumor tissues, 15 brain tissues), GSE747706 (18 lung tumor tissues, 18 normal tissues), GSE21933 (21 lung tumor tissues, 21 normal tissues) datasets | n/a | NSCLC andBrain tumor | n/a |
|