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

Abstract

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.

Macrophage Origin, Metabolic Reprogramming and IL-1β Signaling: Promises and Pitfalls in Lung Cancer

“…Consistently, reduced NLRP3-dependent IL-1β secretion is observed in AMs isolated from the bronchoalveolar lavage of lung cancer patients despite a systemic higher NLRP3 inflammasome activation and IL-1β secretion in peripheral blood leukocytes from these patients [230,231]. Thus, the elevated IL-1β concentration in TME [232] could either derive directly from oncogenic lung cancer cells [233] or eventually from another TAM population (i.e., infiltrated MoTAMs) [230]. In the first scenario, combination of canakinumab with anti-PD-1 therapy, as initiated in phase I trial, may be beneficial by dual targeting of cancer and immune cells.…”

“…While macrophages are the main source of IL-1β secretion in the immune response to pathogen [226,227,228], the TME of established tumors is characterized by an immunosuppression dominated by a M2 alternatively activated TAM phenotype that inhibits NLRP3-dependent IL-1β secretion [229]. Consistently, reduced NLRP3-dependent IL-1β secretion is observed in AMs isolated from the bronchoalveolar lavage of lung cancer patients despite a systemic higher NLRP3 inflammasome activation and IL-1β secretion in peripheral blood leukocytes from these patients [230,231]. Thus, the elevated IL-1β concentration in TME [232] could either derive directly from oncogenic lung cancer cells [233] or eventually from another TAM population (i.e., infiltrated MoTAMs) [230].…”

Clinical Value of Serum and Exhaled Breath Condensate miR-186 and IL-1β Levels in Non-Small Cell Lung Cancer

“…IL-1β is involved in NSCLC progression and may be involved in immunosuppression and in promoting NSCLC development. 29 A study proposed the possibility that anti-inflammatory therapy by targeting IL-1β may reduce the prevalence of lung cancer among patients who have higher CRP. 30 Recently, a phase 3 clinical trial has reported an interesting result, anakinumab, an inhibitory antibody targeting IL-1β, could significantly reduce the incidence and mortality of lung cancer.…”

Dynamic roles of inflammasomes in inflammatory tumor microenvironment

“…In addition, tumor-associated macrophages isolated from lung tumor bearing mice exhibited increased production of IL-1β when stimulated with LPS plus ATP 58 . Similarly, peripheral blood leukocytes from patients with primary lung cancer released more IL-1β and IL-18 than did those from healthy individuals 59 . In addition, an important role of IL-1β derived from neutrophils was elucidated in relation to the impaired efficacy of NF-κB inhibitor against lung carcinogenesis 60 .…”