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Nise Yamaguchi

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    MS01 - Immunotherapy Resistance (ID 64)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MS01.04 - Smoking and Immunotherapy (Now Available) (ID 3442)

      10:30 - 12:00  |  Presenting Author(s): Nise Yamaguchi

      • Abstract
      • Presentation
      • Slides


      Smoking disrupts the homeostasis of the innate and the adaptive immune system. Carcinogenic and pro-inflammation compounds of tobacco leaves and other chemicals present in cigarette interfere with the regulation of immunity in two opposing ways. Some compounds trigger chronic inflammation inducing cell damage and transformation; others inhibit apoptosis, a protective strategy against transformed cell proliferation. Smoking attenuates response by dendritic cells (DC), natural killer cells (NK), macrophages against transformed cells1. Smoking affects as well the adaptive immune cells, B lymphocytes, T helper cells, CD4+ / CD25+ regulatory T cells, and CD8+ T cells.[1]

      Patients with NSCLC had low levels of serum bilirubin correlated with tumor progression and poor response to platinum-based chemotherapy[2]. Studies found that high normal levels of serum bilirubin indicated favorable prognosis in NSCLC and colorectal tumor.[3], [4] Bilirubin has anti-inflammatory, anti-oxidative, and anti-proliferative effects[5] and smoking decreased bilirubin in a cohort study using metabolomics profiling.[6] Zhang et al. reported that pretreatment with bilirubin correlated with overall survival (OS) in NSCLC patients with EGFR mutations.[7]

      Epithelial to mesenchymal transition (EMT) is an important process of cell-transformation that facilitates metastases and smoking induced hypoxia, inflammation, and oxidative stress, culminating in malignancy and EMT.[8],[9] The effect of smoking on EMT also occurs in other cancer histologies. A study showed that the HDAC inhibitor MS-275 restores E-cadherin expression, reversing EMT, metastases, and invasion induced by smoking.[10], [11], 8

      Smoking impairs lung cancer chemotherapy, requiring increased doses for patients who smoke. The polycyclic aromatic hydrocarbons (PAH) of smoke increases the synthesis of enzymes that metabolize many antineoplastic drugs. PAH increase clearance, requiring dose adjustments to reach toxicity levels of efficacy.[12] Smokers receiving irinotecan had increased clearance and lower exposure to therapeutic metabolites; and treatments with paclitaxel, docetaxel, irinotecan, and gemcitabine showed lesser neutropenia in smokers than in nonsmokers.12 Nicotine-derived nitrosamine ketones antagonizes cisplatin and carboplatin regimens by blocking apoptosis.[13],[14],[15]

      Erlotinib blocks the receptor for tyrosine-inhibiting epidermal growth activation (EGFR) and is metabolized by CYP3A4 and, by CYP1A2 and CYP1A1.[16] Smoking accelerates drug catabolism, decreasing erlotinib plasma concentrations and survival rates in NSCLC. Retrospective analysis of 88 patients NSCLC receiving erlotinib or pemetrexed showed better progression-free survival (PFS) with erlotinib in never smokers than in former smokers (3.5 versus 2.7 months, p = 0.005)[17] and smokers with squamous histology receiving erlotinib lived longer than former smokers.[18] A study on the efficacy of second-line docetaxel and erlotinib in NSCLC patients with smoking history versus never smokers shoed decreased overall survival (hazard ration [HR] 3.61 [1.77–7.4], p = 0.0005) in the erlotinib arm.[19]

      Nicotine affected EGFR/AKT/ERK pathways, preventing/decreasing erlotinib action in NSCLC, promoting tumor growth in the PC9 xenograft model. [20]

      [1] Qiu F. et al. (2016) Impacts of cigarette smoking on immune responsiveness: up and down or upside down? Oncotarget, 2017, Vol. 8, (No. 1), pp: 268-284.

      [2] Song Y-J. et al. (2018) Direct bilirubin levels are prognostic in non-small cell lung cancer. Oncotarget, 2018, Vol. 9, (No. 1), pp: 892-900.

      [3] Li N, et al. Elevated serum bilirubin levels are associated with improved survival in patients with curatively resected non-small-cell lung cancer. Cancer Epidemiol. 2015; 39:763–8.

      [4] Zhang Q, et al. Nomograms incorporated serum direct bilirubin level for predicting prognosis in stages II and III colorectal cancer after radical resection. Oncotarget. 2017; 8:71138–46.

      [5] Marnett LJ. Oxyradicals and DNA damage. Carcinogenesis. 2000; 21:361–70.

      [6] Wen CP et al. (2015) The ability of bilirubin in identifying smokers with higher risk of lung cancer: a

      large cohort study in conjunction with global metabolomics profiling. Clin Cancer Res. 2015; 21:193–200.

      [7] Zhang Y, et al. Pretreatment direct bilirubin and total cholesterol are significant predictors of overall survival in advanced non-small-cell lung cancer patients with EGFR mutations. Int J Cancer. 2017; 140:1645–52.

      [8] Milara, J.; Peiró, T.; Serrano, A.; Cortijo, J. Epithelial to mesenchymal transition is increased in patients with

      COPD and induced by cigarette smoke. Thorax 2013, 68, 410.

      [9] Dasgupta, P.; Rizwani,W.; Pillai, S.; Kinkade, R.; Kovacs, M.; Rastogi, S.; Banerjee, S.; Carless, M.; Kim, E.;

      Coppola, D.; et al. Nicotine induces cell proliferation, invasion and epithelial to mesenchymal transition in a

      variety of human cancer cell lines. Int. J. Cancer 2009, 124, 36–45.

      [10] Sohal, S.S.; Walters, E.H. Role of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD). Respir. Res. 2013, 14, 120.

      [11] Ibidem 10.

      [12] O’Malley et al. Effects of Cigarette Smoking on Metabolism and Effectiveness of Systemic Therapy for Lung Cancer. J Thorac Oncol. 2014;9: 917–926.

      [13] Xu J, Huang H, Pan C, Zhang B, Liu X, Zhang L. Nicotine inhibits apoptosis induced by cisplatin in human oral cancer cells. Int J Oral Maxillofac Surg 2007;36:739–744.

      [14] Zeng F, Li YC, Chen G, et al. Nicotine inhibits cisplatin-induced apoptosis in NCI-H446 cells. Med Oncol 2012;29:364–373.

      [15] Zhang J, Kamdar O, Le W, et al. Nicotine induces resistance to chemotherapy by modulating mitochondrial signaling in lung cancer. Am J Respir Cell Mol Biol 2009;40:135–146.

      [16] Ling J, Johnson KA, Miao Z, et al. Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers. Drug Metab Dispos 2006;34:420–426.

      [17] Zugazagoitia J, Puente J, González-Larriba JL, et al. Erlotinib versus pemetrexed for pretreated non-squamous non-small cell lung cancer patients in clinical practice. Oncology 2013;84:255–264.

      [18] Chiang CL, Tsai CM, Chou TY, et al. Erlotinib in patients with advanced lung squamous cell carcinoma. Cancer Chemother Pharmacol 2013;71:203–208.

      [19] Krawczyk P, Kowalski DM, Wojas-Krawczyk K, et al. The qualification of docetaxel or erlotinib for second-line therapy should be based on clinical and molecular predictive factors. Chemotherapy 2012;58:60–69.

      [20] Li H, Wang S, Takayama K, et al. Nicotine induces resistance to erlotinib via cross-talk between 1nAChR and EGFR in the non-small cell lung cancer xenograft model. Lung Cancer 88 (2015) 1–8.

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