Top

Published in:

Open Access 01-11-2020 | NSCLC | Original Article

ADRB3 expression in tumor cells is a poor prognostic factor and promotes proliferation in non-small cell lung carcinoma

Authors: Meng Zheng, Zhiling Zhou, Xiangting Tian, Dingzhang Xiao, Xinghua Hou, Zhi Xie, Haidan Liang, Shuguang Lin

Published in: Cancer Immunology, Immunotherapy | Issue 11/2020

Abstract

The cross-talk between cancer cells and monocyte-derived alveolar macrophages (Mo-AMs) promotes non-small cell lung carcinoma (NSCLC) progression. In this study, we report that both cancer cells and Mo-AMs robustly express beta 3-adrenergic receptor (ADRB3) in NSCLC. ADRB3 supports lung cancer cells proliferation and promotes chronic inflammation. Genetic and pharmacologic inhibition of ADRB3 reverses tumor growth and inflammation in mouse. Furthermore, we demonstrate that M5D1, a novel anti-ADRB3 monoclonal antibody, inhibits human lung cancer cells proliferation and inflammation via affecting the intracellular mTOR pathway and activating p53. In NSCLC patients, we confirmed that upregulation of ADRB3 expression correlates with tumor progression and poor prognosis. Altogether, these results shed light on the role of ADRB3 in NSCLC and suggest that M5D1 could become powerful antitumor weapons.

Available only for authorised users

Dela Cruz CS, Tanoue LT, Matthay RA (2011) Lung Cancer: epidemiology, etiology and prevention. Clin Chest Med 32(4):605–644CrossRef

Kanitkar AA, Schwartz AG, George J, Soubani AO (2018) Causes of death in long-term survivors of non-small cell lung cancer: a regional surveillance, epidemiology, and end results study. Ann Thorac Med 13(2):76–81CrossRef

Glatzel-Plucinska N, Piotrowska A, Grzegrzolka J, Olbromski M, Rzechonek A, Dziegiel P, Podhorska-Okolow M (2018) SATB1 level correlates with Ki-67 expression and is a positive prognostic factor in non-small cell lung carcinoma. Anticancer Res 38(2):723–736PubMed

Pawelczyk K, Piotrowska A, Ciesielska U, Jablonska K, Gletzel-Plucinska N, Grzegrzolka J, Podhorska-Okolow M, Dziegiel P, Nowinska K (2019) Role of PD-L1 expression in non-small cell lung cancer and their prognostic significance according to clinicopathological factors and diagnostic markers. Int J Mol Sci 20(4):824–839CrossRef

Zhang M, Li G, Wang Y, Wang Y, Zhao S, Haihong P, Zhao H, Wang Y (2017) PD-L1 expression in lung cancer and its correlation with driver mutations: a meta-analysis. Sci Rep 7(1):10255–10265CrossRef

Crawford S (2014) Anti-inflammatory/antioxidant use in long-term maintenance cancer therapy: a new therapeutic approach to disease progression and recurrence. Ther Adv Med Oncol 6(2):52–68CrossRef

Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, Zhao S, Das S, Beckermann KE, Ha L, Rathmell WK, Ancell KK, Balko JM, Bowman C, Davis EJ, Chism DD, Horn L, Long GV, Carlino MS, Lebrun-Vignes B, Eroglu Z, Hassel JC, Menzies AM, Sosman JA, Sullivan RJ, Moslehi JJ, Johnson DB (2018) Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 4(12):1721–1728CrossRef

Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, Wu X, Ma J, Zhou M, Li X, Li Y, Li G, Xiong W, Guo C, Zeng Z (2019) Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer 18(1):10–27CrossRef

Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899CrossRef

10.

Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124(2):263–266CrossRef

11.

Grujic D, Susulic VS, Harper ME, Himms-Hagen J, Cunningham BA, Corkey BE, Lowell BB (1997) Beta3-adrenergic receptors on white and brown adipocytes mediate beta3-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. A study using transgenic and gene knockout mice. J Biol Chem 272(28):17686–17693CrossRef

12.

McKean-Cowdin R, Li X, Bernstein L, McTiernan A, Ballard-Barbash R, Gauderman WJ, Gilliland F (2007) The ADRB3 Trp64Arg variant and obesity in African–American breast cancer cases. Int J Obes (Lond) 31(7):1110–1118CrossRef

13.

Rai R, Kim JJ, Misra S, Kumar A, Mittal B (2015) A multiple interaction analysis reveals ADRB3 as a potential candidate for gallbladder cancer predisposition via a complex interaction with other candidate gene variations. Int J Mol Sci 16(12):28038–28049CrossRef

14.

Perrone MG, Notarnicola M, Caruso MG, Tutino V, Scilimati A (2008) Upregulation of beta3-adrenergic receptor mRNA in human colon cancer: a preliminary study. Oncology 75(3–4):224–229CrossRef

15.

Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, Frenette PS (2013) Autonomic nerve development contributes to prostate cancer progression. Science 341(6142):1236361CrossRef

16.

Dal Monte M, Casini G, Filippi L, Nicchia GP, Svelto M, Bagnoli P (2013) Functional involvement of β3-adrenergic receptors in melanoma growth and vascularization. J Mol Med (Berl) 91(12):1407–1419CrossRef

17.

Calvani M, Pelon F, Comito G, Taddei ML, Moretti S, Innocenti S, Nassini R, Gerlini G, Borgognoni L, Bambi F, Giannoni E, Filippi L, Chiarugi P (2015) Norepinephrine promotes tumor microenvironment reactivity through β3-adrenoreceptors during melanoma progression. Oncotarget 6(7):4615–4632CrossRef

18.

Calvani M, Cavallini L, Tondo A, Spinelli V, Ricci L, Pasha A, Bruno G, Buonvicino D, Bigagli E, Vignoli M, Bianchini F, Sartiani L, Lodovici M, Semeraro R, Fontani F, De Logu F, Dal Monte M, Chiarugi P, Favre C, Filippi L (2018) β3-Adrenoreceptors control mitochondrial dormancy in melanoma and embryonic stem cells. Oxid Med Cell Longev 2018:6816508CrossRef

19.

Calvani M, Bruno G, Dal Monte M, Nassini R, Fontani F, Casini A, Cavallini L, Becatti M, Bianchini F, De Logu F, Forni G, la Marca G, Calorini L, Bagnoli P, Chiarugi P, Pupi A, Azzari C, Geppetti P, Favre C, Filippi L (2019) β3-Adrenoceptor as a potential immuno-suppressor agent in melanoma. Br J Pharmacol 176(14):2509–2524CrossRef

20.

Bruno G, Cencetti F, Pini A, Tondo A, Cuzzubbo D, Fontani F, Strinna V, Buccoliero AM, Casazza G, Donati C, Filippi L, Bruni P, Favre C, Calvani M (2020) β3-adrenoreceptor blockade reduces tumor growth and increases neuronal differentiation in neuroblastoma via SK2/S1P2 modulation. Oncogene 39(2):368–384CrossRef

21.

O'Brate A, Giannakakou P (2003) The importance of p53 location: nuclear or cytoplasmic zip code? Drug Resist Update 6(6):313–322CrossRef

22.

Hodge DR, Hurt EM, Farrar WL (2005) The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 41(16):2502–2512CrossRef

23.

Tsukamoto H, Senju S, Matsumura K, Swain SL, Nishimura Y (2015) IL-6-mediated environmental conditioning of defective Th1 differentiation dampens antitumour immune responses in old age. Nat Commun 7(6):6702CrossRef

24.

Pouniotis DS, Plebanski M, Apostolopoulos V, McDonald CF (2006) Alveolar macrophage function is altered in patients with lung cancer. Clin Exp Immunol 143(2):363–372CrossRef

25.

Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter JM, McQuattie-Pimentel AC, Chen CI, Anekalla KR, Joshi N, Williams KJN, Abdala-Valencia H, Yacoub TJ, Chi M, Chiu S, Gonzalez-Gonzalez FJ, Gates K, Lam AP, Nicholson TT, Homan PJ, Soberanes S, Dominguez S, Morgan VK, Saber R, Shaffer A, Hinchcliff M, Marshall SA, Bharat A, Berdnikovs S, Bhorade SM, Bartom ET, Morimoto RI, Balch WE, Sznajder JI, Chandel NS, Mutlu GM, Jain M, Gottardi CJ, Singer BD, Ridge KM, Bagheri N, Shilatifard A, Budinger GRS, Perlman H (2017) Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med 214(8):2387–2404CrossRef

26.

Tsukamoto H, Nishikata R, Senju S, Nishimura Y (2013) Myeloid-derived suppressor cells attenuate TH1 development through IL-6 production to promote tumor progression. Cancer Immunol Res 1(1):64–76CrossRef

Title: ADRB3 expression in tumor cells is a poor prognostic factor and promotes proliferation in non-small cell lung carcinoma
Authors: Meng Zheng
Zhiling Zhou
Xiangting Tian
Dingzhang Xiao
Xinghua Hou
Zhi Xie
Haidan Liang
Shuguang Lin
Publication date: 01-11-2020
Publisher: Springer Berlin Heidelberg
Keywords: NSCLC
Lung Cancer
Lung Cancer
NSCLC
SCLC
Lung Cancer
SCLC
Published in: Cancer Immunology, Immunotherapy / Issue 11/2020
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02627-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 11/2020

Immune resilience in response to cancer therapy

Cell composition and expansion strategy can reduce the beneficial effect of AKT-inhibition on functionality of CD8+ T cells

Combination of cyclin-dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer

Metabolomic profiling of tumor-infiltrating macrophages during tumor growth

Influence of antigen density and immunosuppressive factors on tumor-targeted costimulation with antibody-fusion proteins and bispecific antibody-mediated T cell response

IL-6-induced CD39 expression on tumor-infiltrating NK cells predicts poor prognosis in esophageal squamous cell carcinoma

Keynote webinar | Spotlight on antibody–drug conjugates in cancer