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Monday, November 26, 2018

Inflammatory Immune Responses in Lung Cancer



            Lung cancer is one of the most common forms of cancer affecting men and women, with estimates that there will be 234,030 new cases diagnosed in the United States in 2018 (1).  Additionally, an estimated 154,050 deaths will be attributed to this type of cancer (1).  Like most cancers, exposure to carcinogens such as tobacco smoke, asbestos, and radon as well as some genetic predispositions, can increase the risk of developing this disease (2).  Recently, researchers have investigated the role of the immune system and possible immunotherapeutic targets in the development and treatment of cancer. 
            The inflammasome is a complex of proteins activated in cells in response to pathogen and danger signaling (3).  Intracellular signaling then activates caspase 1, which cleaves and releases IL-1b and Il-18, which are pro-inflammatory cytokines, or messenger signals (3).  This signaling is an innate immune response that can influence proliferation, movement, and interactions with other cells in the immune system.  Inflammatory danger signaling normally functions to aid in tumor surveillance while inducing cell death mechanisms such as apoptosis.  In cancerous cells, this signaling can interact with the microenvironment around the tumor and promote proliferation, metastasis, or immunosuppression depending on the circumstances (3,4).  Thus, researchers studied the activity of the inflammasome in a specific subset of cells, alveolar macrophages, in patients with lung cancer to assess the tumor induced immunosuppression and its relation to potential targets for immunotherapy (4). 
            In this specific study, the NLRP3 inflammasome was studied.  It is commonly associated with inflammatory diseases since many pathogen and damage ligands can activate the transcription factor NF-kB which stimulates the NLRP3 proteins and pro-inflammatory cytokine signaling cascade (5).  This inflammasome activity, specifically chronic inflammatory signaling, has been implicated in relation to progression of lung tumors (5).  Alveolar macrophages are located in the lung environment and are important regulators of cytokines and can also phagocytose pathogens (4).  Previous studies have found high NLRP3 protein mRNA expression in alveolar macrophages, further suggesting a linkage to lung cancer development (5). 
            Researchers in this study used lipopolysaccharide (LPS) to artificially stimulate the inflammasome followed by second stimulation with ATP (4).  Activity of the inflammasome, detected through gene expression and cytokine secretion, was compared between the alveolar macrophages and the peripheral blood leukocytes from a sample of bronchoalveolar fluid to see the role of the tumor environment on the activity (4). Following stimulation, the key finding showed that IL-1b secretion did not increase in the cancerous alveolar macrophages compared to the increases seen in the control alveolar macrophages or both groups of peripheral blood leukocytes (Figure 2).  In both peripheral blood leukocytes and alveolar macrophages, IL-18 secretion decreased from controls to cancerous cells (4).  They confirmed that this altered cytokine secretion was due to the inflammasome activity by adding a caspase-1 inhibitor, which decreased all expression of both IL-18 and IL-1b (Figure 2).  It appears that the inflammasome activity is decreased in the lung cancer alveolar macrophages. 



Figure 2. IL-1b and IL-18 secretion in peripheral blood leukocytes and alveolar macrophages following different levels of stimulation in cells from patients with and without lung cancer.  IL-1b decreases in cancerous AMs, but not PBMCs, whereas IL-18 decreases in cancerous AMs and PBMCs.


Additional evidence from qPCR data in Figure 3 shows the decreased expression of mRNA for the NLRP3 inflammasome proteins in lung cancer alveolar macrophages, suggesting a role of the decreased inflammasome activity in lung cancer (4).


Figure 3a. Both non-small cell and small cell lung cancer cells had lower levels of NLRP3 mRNA expression.


 Other pro-inflammatory cytokines such as IL-6 and TNFa were decreased in lung cancer alveolar macrophages (4). 



Figure 4a, d, g, h. Following LPS stimulation, lung cancer AMs had decreased levels of IL-6 and TNF-a secretion and cancerous PBMCs showed increases in TNF-a secretion.


            Based upon these results, the authors suggest that innate immune responses in the alveolar macrophages of patients with lung cancer are not functioning effectively (4).  Interestingly, the peripheral blood leukocytes continued to secrete the pro-inflammatory cytokines upon stimulation of the inflammasome, suggesting a systemic presence of chronic inflammation in the surrounding environment, contributing to the development of cancer (4).  Chronic stimulation of the inflammasome from environmental toxins like cigarette smoke and asbestos could lead to the constant release of danger signaling prompting inflammatory responses that drive tumorigenesis (5,6).  However, the alveolar macrophages were not secreting high levels of inflammatory cytokines.  Other studies have shown chronic NFkB and inflammatory signaling eventually begins to polarize the macrophages towards an immunosuppressive response, allowing for a downregulation of the killer T cell response and increased presence of Tregs, which help to establish tolerance (7).  With decreased inflammasome activity and a microenvironment that suppresses immune responses, lung tumors can evade the immune system and potentially metastasize throughout the body.  This study shows the importance of balance and regulation in the immune system’s inflammatory responses and provides the background for further exploration into the mechanism of macrophage polarization as well as potential targets for lung cancer immunotherapy. 



Sources:
1.     “Key Statistics for Lung Cancer.” American Cancer Society, American Cancer Society , www.cancer.org/cancer/non-small-cell-lung-cancer/about/key-statistics.html.
2.     “Causes, Risk Factors, and Prevention.” American Cancer Society, American Cancer Society. https://www.cancer.org/cancer/non-small-cell-lung-cancer/causes-risks-prevention/risk-factors.html.
3.     He, Q., Fu, Y., Tian, D., & Yan, W. (2018). The contrasting roles of inflammasomes in cancer. American journal of cancer research8(4), 566-583.
4.     Lasithiotaki I, Tsitoura E, Samara KD, Trachalaki A, Charalambous I, Tzanakis N, et al. (2018) NLRP3/Caspase-1 inflammasome activation is decreased in alveolar macrophages in patients with lung cancer. PLoS ONE 13(10): e0205242. https://doi.org/10.1371/journal.pone.0205242
5.     Moosavi, M. Parsamanesh, N., Bahrami, A., Atkin, S.L., & Sahebkar, A. (2018). Role of the NLRP3 inflammasome in cancer. Molecular Cancer, 17(158). https://doi.org/10.1186/s12943-018-0900-3. 
6.     De Nardo, D., De Nardo, C. M., & Latz, E. (2014). New insights into mechanisms controlling the NLRP3 inflammasome and its role in lung disease. The American journal of pathology184(1), 42-54. doi:10.1016/j.ajpath.2013.09.007.
7.     Zaynagetdinov, R., Sherrill, T. P., Gleaves, L. A., Hunt, P., Han, W., McLoed, A. G., Saxon, J. A., Tanjore, H., Gulleman, P. M., Young, L. R., … Blackwell, T. S. (2015). Chronic NF-κB activation links COPD and lung cancer through generation of an immunosuppressive microenvironment in the lungs. Oncotarget7(5), 5470-82.  doi: 10.18632/oncotarget.6562.




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