Main article:
NLRP3/Caspase-1 Inflammasome activation is decreased in alveolar macrophages inpatients with 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 research, 8(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 pathology, 184(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. Oncotarget, 7(5),
5470-82. doi: 10.18632/oncotarget.6562.
No comments:
Post a Comment