Research Article: NLRP3/Caspase-1 inflammasome activation is decreased in alveolar macrophages in patients with lung cancer

Date Published: October 26, 2018

Publisher: Public Library of Science

Author(s): Ismini Lasithiotaki, Eliza Tsitoura, Katerina D. Samara, Athina Trachalaki, Irini Charalambous, Nikolaos Tzanakis, Katerina M. Antoniou, Aamir Ahmad.


Lung cancer (LC) remains the leading cause of cancer-related mortality. The interaction of cancer cells with their microenvironment, results in tumor escape or elimination. Alveolar macrophages (AMs) play a significant role in lung immunoregulation, however their role in LC has been outshined by the study of tumor associated macrophages. Inflammasomes are key components of innate immune responses and can exert either tumor-suppressive or oncogenic functions, while their role in lung cancer is largely unknown. We thus investigated the NLRP3 pathway in Bronchoalveolar Lavage derived alveolar macrophages and peripheral blood leukocytes from patients with primary lung cancer and healthy individuals. IL-1β and IL-18 secretion was significantly higher in unstimulated peripheral blood leukocytes from LC patients, while IL-1β secretion could be further increased upon NLRP3 stimulation. In contrast, in LC AMs, we observed a different profile of IL-1β secretion, characterized mainly by the impairment of IL-1β production in NLRP3 stimulated cells. AMs also exhibited an impaired TLR4/LPS pathway as shown by the reduced induction of IL-6 and TNF-α. Our results support the hypothesis of tumour induced immunosuppression in the lung microenvironment and may provide novel targets for cancer immunotherapy.

Partial Text

Lung cancer remains the leading cause in cancer-related mortality in both males and females. Approximately 85% of lung tumours are non-small cell lung cancer (NSCLC), including adenocarcinoma, squamous cell carcinoma and large cell carcinoma [1]. Although the majority of lung cancer patients are smokers, only a minority among smokers will develop this disease, strongly suggesting that additional environmental determinants including infections, in a background of genetic susceptibility, drive disease initiation and progression[2].

The NLRP3 inflammasome expression and role in lung cancer is relatively unknown, while inflammatory reactions can exert a dual influence on tumor growth and progression (14). Recently, studies have proposed a strong relationship between lung cancer risk factors and alterations in inflammatory cytokine levels, oxidative stress markers and immune cell composition [4]. In this view, we aimed to investigate a central innate immune response pathway, the NLRP3 inflammasome, in lung cancer PBMCs and AMs, in order to gain insight on inflammatory processes related to LC. Our primary finding, that alveolar macrophages show decreased transcriptional and secretional TLR4 mediated NLRP3 activation markers, suggests that in human lung cancer innate immune responses in alveolar macrophages are compromised. Additionally, the LC group exhibited a pro-inflammatory state systemically, which could be attributed to the pro-inflammatory state of the patients that lead to the LC, supporting the inflammation induced cancer hypothesis[25].

Through cytokine phenotyping, we suggest that alveolar macrophages, in lung cancer microenvironment, are impaired. In AMs the activation of TLR4/NLRP3 inflammasome was found severely decreased, adding to the hypothesis of cancer mediated immunesuppression. By contrast, systemically a pro-inflammatory state was observed, which may constitute a pro-inflammatory environment that leads to cancer incidence and progression. To date, several antagonists have being developed against components of the inflammasome, and have been proposed as anti-cancer therapy. Novel targeting of IL-1β could reduce the incidence of Lung cancer in healthy individuals, as already suggested [18], however, such treatment should be used with caution in established lung cancer, since our results suggest that NLRP3 inflammasome pathway is already impaired in lung cancer microenvironment. Given the ability of NLRP3 in promoting immunogenic cell death, the activation/ reprogramming of dysfunctional AMs, could be a novel add-on therapy in established lung cancer.




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