Interleukin-11 promotes lung adenocarcinoma tumourigenesis and immune evasion

Abstract

Rationale: Interleukin-11 (IL-11) has emerged as a significant player in tumourigenesis, with implications across various cancer types. However, its specific role in driving tumour progression in lung adenocarcinoma (LUAD) remains elusive. IL-11's multifaceted impact on both tumour cells and the tumour microenvironment underscores its potential as a therapeutic target in LUAD. This study aims to unravel the involvement of IL-11 in LUAD progression and its influence on the tumour microenvironment.

Methods: Here, we used transcriptomic and digital spatial profiling analyses together with clinic data from two retrospective LUAD patient cohorts. LUAD cell lines genetically engineered to overexpress or to silence IL-11 or its receptor (IL-11RA) were used for in vitro functional analysis and for in vivo experiments. Additionally, we used three different in vivo models: patient-derived xenografts (PDXs), tobacco-exposed mice and genetically engineered mouse models. A neutralising monoclonal antibody against IL-11RA was produced and tested.

Results: Our findings revealed a pivotal role for IL-11 in driving tumourigenesis across various mouse models, highlighting its capacity to modulate tumour immunity towards an immunosuppressive microenvironment. Moreover, we observed a correlation between IL-11 expression and poorer patient outcomes in LUAD. Notably, therapeutic targeting of IL-11RA with a neutralising antibody demonstrated significant anti-tumour efficacy in a PDX model.

Conclusion: The IL-11/IL-11RA axis emerges as a critical driver of LUAD tumourigenesis, exerting its effects through enhanced tumour cell proliferation and remodelling of the tumour microenvironment. Our study highlights the therapeutic potential of disrupting this axis, suggesting that patients exhibiting elevated IL-11 levels may benefit from therapies targeting the IL-11/IL-11RA pathway.

Keywords

lung adenocarcinoma / IL-11/IL-11RA axis / tobacco smoke / immunosuppressive tumour microenvironment / therapeutic target

References

[1] Brawley OW. Avoidable Cancer Deaths Globally. 2011; Available from: http://www.who.int/fctc/FCTC-

[2] Herbst RS, Heymach J v., Lippman SM. Lung cancer. N Engl J Med. 2008 [cited 2022 Mar 22]; 359(13): 1367-80. Available from: https://pubmed.ncbi.nlm.nih.gov/18815398/

[3] Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018; 29: iv192-237.

[4] Reck M, Wehler T, Orlandi F, et al. Safety and patient-reported outcomes of atezolizumab plus chemotherapy with or without bevacizumab versus bevacizumab plus chemotherapy in non-small-cell lung cancer. J Clin Oncol. 2020 [cited 2022 Jun 7]; 38(22): 2530. Available from: pmc/articles/PMC7392741/

[5] Tan J. Targeting Resistance. Cell. 2016 [cited 2022 Mar 22]; 166(3): 523. Available from: https://pubmed.ncbi.nlm.nih.gov/27471957/

[6] Berraondo P, Sanmamed MF, Ochoa MC, et al. Cytokines in clinical cancer immunotherapy. Br J Cancer. 2019; 120(1): 6-15 Available from: https://doi.org/10.1038/s41416-018-0328-y

[7] Garbers C, Hermanns HM, Schaper F, et al. Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine Growth Factor Rev. 2012 [cited 2022 Mar 22]; 23(3): 85-97. Available from: https://pubmed.ncbi.nlm.nih.gov/22595692/

[8] Ernst M, Putoczki TL. Molecular pathways: IL11 as a tumor-promoting cytokine-translational implications for cancers. Clin Cancer Res. 2014; 20(22): 5579-5588; Available from: www.aacrjournals.org

[9] Ren C, Chen Y, Han C, Fu D, Chen H. Plasma interleukin-11 (IL-11) levels have diagnostic and prognostic roles in patients with pancreatic cancer. Tumour Biol. 2014; 35(11): 11467-11472;

[10] Yu D, Zhong Y, Li X, et al. ILs-3, 6 and 11 increase, but ILs-10 and 24 decrease stemness of human prostate cancer cells in vitro. Oncotarget. 2015; 6(40): 42687-42703. Available from: www.impactjournals.com/oncotarget/

[11] Lay V, Yap J, Sonderegger S, Dimitriadis E. Interleukin 11 regulates endometrial cancer cell adhesion and migration via STAT3. Int J Oncol. 2012; 41(2): 759-64.

[12] Sotiriou C, Lacroix M, Lespagnard L, Larsimont D, Paesmans M, Body JJ. Interleukins-6 and -11 expression in primary breast cancer and subsequent development of bone metastases. Cancer Lett. 2001 [cited 2022 Mar 22]; 169(1): 87-95. Available from: www.elsevier.com/locate/canlet

[13] Hassani M, Mahdevar M, Peymani M. Exploring the role of interleukin 11 in cancer progression, patient survival, and therapeutic insights. Mol Biol Rep. 2024 [cited 2024 May 3]; 51(1): 461. Available from: https://pubmed.ncbi.nlm.nih.gov/38551695/

[14] Cheng B, Li L, Luo T, et al. Single-cell deconvolution algorithms analysis unveils autocrine IL11-mediated resistance to docetaxel in prostate cancer via activation of the JAK1/STAT4 pathway. J Exp Clin Cancer Res. 2024 [cited 2024 May 3]; 43(1): 67. Available from: pmc/articles/PMC10905933/

[15] Pastor MD, Nogal A, Molina-Pinelo S, et al. IL-11 and CCL-1: novel protein diagnostic biomarkers of lung adenocarcinoma in bronchoalveolar lavage fluid (BALF). J Thorac Oncol. 2016 [cited 2022; 11(12): 2183-92. Available from: https://doi.org/10.1016/j.jtho.2016.07.026

[16] Morris R, Kershaw NJ, Babon JJ, Hall E. The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Sci. 2018; 27(12): 1984-2009

[17] Lim JH. Inhibition of the interleukin-11-STAT3 axis attenuates hypoxia-induced migration and invasion in MDA-MB-231 breast cancer cells. Korean J Physiol Pharmacol. 2014; 18: 391-6. Available from: https://doi.org/10.4196/kjpp.2014.18.5.391

[18] Onnis B, Fer N, Rapisarda A, Perez VS, Melillo G. Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells. J Clin Invest. 2013; 123(4): 1615-1629. Available from: http://www.jci.org

[19] Tao L, Huang G, Wang R, et al. Cancer-associated fibroblasts treated with cisplatin facilitates chemoresistance of lung adenocarcinoma through IL-11/IL-11R/STAT3 signaling pathway. Sci Rep. 2016; 6: 38408.

[20] Zhao M, Liu Y, Liu R, et al. Cellular physiology and biochemistry cellular physiology and biochemistry upregulation of IL-11, an IL-6 family cytokine, promotes tumor progression and correlates with poor prognosis in non-small cell lung cancer cellular physiology and biochemistry cellular physiology and biochemistry. Cell Physiol Biochem. 2018; 45: 2213-24. Available from: www.karger.com/cpbZhaoetal.:IL-11PromotesNSCLCProgressionwww.karger.com/cpb

[21] Roncador G, Brown PJ, Maestre L, et al. Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur J Immunol. 2005; 35(6): 1681-91.

[22] Guijarro M V, Leal JFM, Blanco-Aparicio C, et al. MAP17 enhances the malignant behavior of tumor cells through ROS increase. Carcinogenesis. 2007; 28(10): 2096-104. Available from: https://academic.oup.com/carcin/article/28/10/2096/2476306

[23] Quintanal-Villalonga A, Molina-Pinelo S, Cirauqui C, et al. FGFR1 cooperates with EGFR in lung cancer oncogenesis, and their combined inhibition shows improved efficacy. J Thorac Oncol. 2019; 14(4): 641-655. [cited 2023 Aug 2]; Available from: https://doi.org/10.1016/j.jtho.2018.12.021

[24] Ramos-Paradas J, Gómez-Sánchez D, Rosado A, et al. Comprehensive characterization of human lung large cell carcinoma identifies transcriptomic signatures with potential implications in response to immunotherapy. J Clin Med. 2022 [cited 2023 Aug 2]; 11(6): 1500. Available from: pmc/articles/PMC8953709/

[25] Takahashi H, Ogata H, Nishigaki R, Broide DH, Karin M. Cancer Cell Article Tobacco smoke promotes lung tumorigenesis by triggering IKKb-and JNK1-dependent inflammation. Cancer Cell. 2010; 17(1): 89-97

[26] Zugazagoitia J, Gupta S, Liu Y, Fuhrman K, et al. Clinical Cancer Research | Translational Cancer Mechanisms and Therapy Biomarkers Associated with Beneficial PD-1 Checkpoint Blockade in Non-Small Cell Lung Cancer (NSCLC) Identified Using High-Plex Digital Spatial Profiling. Clin Cancer Res. 2020; 26(16): 4360-4368. Available from: http://clincancerres.aacrjournals.org/

[27] Leung JH, Ng B, Lim WW. Interleukin-11: a potential biomarker and molecular therapeutic target in non-small cell lung cancer. Cells. 2022; 11(14): 2257; Available from: https://doi.org/10.3390/cells11142257

[28] Ng B, Dong J, Viswanathan S, Widjaja AA, et al. Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. Sci. Transl. Med. 2019; 11(511): eaaw1237. Available from: https://www.science.org

[29] Ernst M, Najdovska M, Grail D, et al. STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J Clin Invest. 2008 [cited 2022 Jun 14]; 118(5): 1727. Available from: pmc/articles/PMC2323192/

[30] Ollila S, Domènech-Moreno E, Laajanen K, et al. Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11-JAK/STAT3 pathway. J Clin Invest. 2018; 128(1): 402-14. Available from: https://doi.org/10.1172/JCI93597DS1

[31] Calon A, Espinet E, Palomo-Ponce S, et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012 [cited 2022 Jun 14]; 22(5): 571-84. Available from: https://pubmed.ncbi.nlm.nih.gov/23153532/

[32] Sumida K, Ohno Y, Ohtake J, et al. IL-11 induces differentiation of myeloid-derived suppressor cells through activation of STAT3 signalling pathway. Nature Publishing Group. 2015; Available from: www.nature.com/scientificreports/

[33] Winship A, van Sinderen M, Rainczuk K, Dimitriadis E. Therapeutically blocking interleukin-11 receptor-α enhances doxorubicin cytotoxicity in high grade type I endometrioid tumours. Oncotarget. 2017; 8(14): 22716-22729. Available from: www.impactjournals.com/oncotarget

[34] Stuart SF, Bezawork-Geleta A, Areeb Z, et al. Citation: The interleukin-11/IL-11 receptor promotes glioblastoma survival and invasion under glucose-starved conditions through enhanced glutaminolysis. Int J Mol Sci. 2023; 24(4): 3356. Available from: https://doi.org/10.3390/ijms24043356

[35] Meissl K, Macho-Maschler S, Müller M, Strobl B. The good and the bad faces of STAT1 in solid tumours. Cytokine. 2017; 89: 12-20.

[36] Gavcovich TB, Walker KL, Bouchlaka MN, Capitini CM. Inhibition of the JAK/STAT and Bcl-2 pathways enhances anti-tumor effects in an in vitro model of T-cell acute lymphoblastic leukemia (T-ALL). Blood. 2015 [cited 2022 Jun 14]; 126(23): 2528-2528. Available from: https://ashpublications.org/blood/article/126/23/2528/113355/Inhibition-of-the-JAK-STAT-and-Bcl-2-Pathways

[37] Kim JW, Marquez CP, Kostyrko K, et al. Antitumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma. Nat Med. 2019; 25(11): 1783-95.

[38] Bremnes RM, Busund LT, Kilver TL, et al. The role of tumor-infiltrating lymphocytes in development, progression, and prognosis of non-small cell lung cancer. J Thorac Oncol. 2016; 11(6): 789-800.

[39] Leng SX EJA. Interleukin-11 inhibits macrophage interleukin-12 production. J Immunol. 1997; 1(159): 2161-8.

[40] Eissmann MF, Dijkstra C, Jarnicki A, et al. IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nat Commun. 2019 [cited 2022 Jun 14]; 10(1): 2735. Available from: https://pubmed.ncbi.nlm.nih.gov/31227713/

[41] Peng N, Lu M, Kang M, Liu X, Li B, Dong C. Recombinant human IL-11 promotes lung adenocarcinoma A549 cell growth and EMT through activating STAT3/HIF-1α/EMT signaling pathway. Anticancer Agents Med Chem. 2021 [cited 2022 Mar 22]; 21(15): 1996-2003. Available from: https://pubmed.ncbi.nlm.nih.gov/33292141/

[42] Nishina T, Deguchi Y, Ohshima D, et al. Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer. Nat Commun. 2021 [cited 2022 Mar 22]; 12(1): 2281. Available from: https://pubmed.ncbi.nlm.nih.gov/33863879/

[43] Heichler C, Scheibe K, Schmied A, et al. STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis. Gut. 2020 [cited 2022 Mar 22]; 69(7): 1269-82. Available from: https://pubmed.ncbi.nlm.nih.gov/31685519/

[44] Huynh J, Baloyan D, Chisanga D, et al. Host IL11 signaling suppresses CD4 + T cell-mediated antitumor responses to colon cancer in mice. Cancer Immunol Res. 2021 [cited 2022 Mar 22]; 9(7): 735-47. Available from: https://pubmed.ncbi.nlm.nih.gov/33906864/

[45] Araujo AM, Abaurrea A, Azcoaga P, et al. Stromal Oncostatin M cytokine promotes breast cancer progression by reprogramming the tumour microenvironment. J Clin Invest. 2022; 132(19): e165107 [cited 2022 Mar 15]; Available from: https://pubmed.ncbi.nlm.nih.gov/35192545/

[46] Ng B, Dong J, Viswanathan S, et al. Fibroblast-specific IL11 signaling drives chronic inflammation in murine fibrotic lung disease. FASEB J. 2020; 34(9): 11802-15.

[47] Kortekaas RK, Burgess JK, van Orsoy R, Lamb D, Webster M, Gosens R. Therapeutic targeting of IL-11 for chronic lung disease. Trends Pharmacol Sci. 2021; 42(5): 354-66.

[48] Wang H, Wang DH, Yang X, Sun Y, Yang CS. Colitis-induced IL11 promotes colon carcinogenesis. Carcinogenesis. 2021; 42(4): 557-69.

[49] Putoczki TL, Thiem S, Loving A, et al. Interleukin-11 is the dominant Il-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell. 2013; 24(2): 257-271. Available from: https://reader.elsevier.com/reader/sd/pii/S1535610813003164?token=F3468EDBBF0078616659587E7EBAED3BC8C2651E669098537ECF2EA425F25EC76653DA85F67AB6521C28F86F57895583&originRegion=eu-west-1&originCreation=20220130130921

[50] Winship AL, Van Sinderen M, Donoghue J, Rainczuk K, Dimitriadis E. Targeting interleukin-11 receptor- impairs human endometrial cancer cell proliferation and invasion in vitro and reduces tumour growth and metastasis in vivo. Mol Cancer Ther. 2016; 15(April): 720-30.

[51] Lewis VO, Devarajan E, Cardó-Vila M, et al. BMTP-11 is active in preclinical models of human osteosarcoma and a candidate targeted drug for clinical translation. Proc Natl Acad Sci. 2017; 114(30): 8065-70. Available from: www.pnas.org/cgi/doi/10.1073/pnas.1704173114

[52] Huang G, Yu L, Cooper LJN, Hollomon M, Huls H, Kleinerman ES. Genetically modified T cells targeting interleukin-11 receptor α-chain kill human osteosarcoma cells and induce the regression of established osteosarcoma lung metastases. Cancer Res. 2012 [cited 2022 Jun 14]; 72(1): 271-81. Available from: https://pubmed.ncbi.nlm.nih.gov/22075555/

[53] Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: A multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2004; 50(6): 1761-9.

[54] West NR. Coordination of immune-stroma crosstalk by IL-6 family cytokines. Front Immunol 2019; 10: 1093,. 2019 [cited 2022 Jun 14];10(MAY). Available from: https://pubmed.ncbi.nlm.nih.gov/31156640/

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