Dynamic roles of inflammasomes in inflammatory tumor microenvironment.

Introduction

The complexity of the tumor microenvironment is reflected by not only heterogeneity of cancer cells but variable composition of their surrounding stromal cells 1 . The profile of infiltrated/resident immune cells and inflammatory mediators in the proximity of cancer cells defines the inflammatory tumor microenvironment 2 . The inflammatory microenvironment is now recognized as an important participant or a regulator of all stages of tumor development, from an early stage (initiation) of carcinogenesis to tumor promotion and metastatic spread to distant organs 1 – 4 .

The inflammasomes are multi-protein complexes, composed of an NOD-like receptor, apoptosis-associated speck-like protein containing a CARD domain (ASC), and pro-caspase-1, which are assembled upon pathogen- or damage-associated stimuli 5 . Activation of the inflammasomes accompanies the cleavage of pro-interleukin (IL)-1β and pro-IL-18 by caspase-1 into their active forms (Fig. 1 ). This triggers host-protective responses by promoting infiltration of inflammatory and immunocompetent cells into the inflamed site in the innate immunity 5 . Due to the critical roles of host immune defense against tissue damages or microbial infections, the inflammasomes are well-recognized as important and indispensable protein complexes for maintaining homeostasis. Fig. 1 Mechanisms of conventional inflammasome activation and alternative inflammasome activation in tumor microenvironment. Conventional inflammasome activation process comprises two main signals: Signal 1, which is induced by PRRs such as Toll-like receptors activated by PAMPs such as bacterial lipopolysaccharide (LPS). This leads to the transcriptional upregulation of IL1B , and IL18 via NF-κB signaling. Signal 2 is provided by PAMPs or DAMPs, such as ATP and crystals (e.g., asbestos, silica, or uric acid), which activates signaling events including K + efflux, reactive oxygen species (ROS), and lysosomal damage, leading to activation and recruitment of NLRP3 oligomerization and formation of NLRP3 inflammasome complex. The activation and formation of NLRP3 inflammasome provoke auto-cleavage of the active caspase-1, which then proteolytically cleaves pro-IL-1β and pro-IL-18 into their bioactive forms IL-1β and IL-18. Alternatively, the inflammasomes can be activated by cancer cell-derived soluble factors (e.g., TGF-β, sCD44, and WNT ligand), ATP from dying tumor cells, and UV in tumor microenvironment. This alternative activation of inflammasome can also include maturation and secretion of IL-1β and IL-18 in tumor microenvironment.

Although the inflammasomes mainly exert their beneficial roles in the innate immune defense, aberrant activation of the inflammasomes and concurrent overexpression/overproduction of their effector molecules have been observed in several types of human malignancies 6 . The inflammasomes are expressed in various types of cells, such as T and B lymphocytes, antigen-presenting cells, and even cancer cells in the tumor microenvironment. The effects of the inflammasomes on cancer development are influenced by several factors 6 , 7 . In this review, we will discuss cell type- and microenvironmental condition-dependent roles of the inflammasomes and their principal effector molecule, IL-1β, in the development and progression of various types of cancers (Table 1 ). Table 1 Effects of cell type-dependent expression of inflammasome components in tumor microenvironment. Cancer type Inflammasome components Cell type Roles Ref. Breast cancer IL-1β CD11c + DCs Tumor progression 30 IL-1β Macrophages Primary tumor growth & pulmonary metastasis 18 NLRC4/IL-1β F4/80 + /CD11b + macrophages Tumor growth & induction of Vegfa expression in obesity-driven breast cancer mouse model 35 IL-1β Innate immune cells Prevention of metastatic colonization of MICs 36 Colorectal cancer Nlrp3 Hematopoietic-derived cells Prevention of colonic lesion formation, colon inflammation, hyperplasia, and dysplasia 43 Nlrp6 Hematopoietic-derived cells Inhibition of tumor burden 45 Nlrp6 Epithelial & stromal cells No role in limiting tumor burden 45 Nlrc4 Hematopoietic-derived cells No effect on CAC 46 Nlrc4 Epithelial & stromal cells Prevention of tumor burden 46 IL-1β Neutrophils Induction of mucosa damage & tumor formation 48 Lung cancer IL-1β Neutrophils Reduced NF-kB inhibitor efficacy 60 IL-1β Lung cancer cells Increased development of lung metastasis 62 Skin cancer IL-1β Melanoma Promotion of tumor growth, invasiveness, and metastatic potential 71 , 72 ASC Myeloid cells Induction of tumor formation 74 ASC Keratinocytes Inhibition of tumor formation 74 Hepatocellular carcinoma IL-1β Macrophages Induction of EMT and pulmonary metastasis 80

Fundamental roles of the inflammasomes in the innate immunity

The immune system initiates clearance of pathogens and repairs damaged tissues upon recognition of microbial infection, injuries, etc., thereby restoring cellular homeostasis. One of the key complexes essential for the operation of such innate immune responses is the inflammasomes. The innate immune system employs an array of germline-encoded pattern-recognition receptors (PRRs) to sense invariant microbial motifs 8 . PRRs are expressed in many different types of cells which are at the front line of defense, including macrophages, monocytes, dendritic cells, neutrophils, and epithelial cells 8 . As important components of inflammasomes, the PRRs contain the nucleotide-binding domain, the leucine-rich repeat containing proteins (also known as NOD-like receptors, NLRs) and the absent in melanoma 2 (AIM)-like receptor (ALRs). Upon inflammasome activation by sensing pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), NLRs, AIM2, or pyrin recruits ASC to form a multimeric complex. Oligomerized ASC subsequently recruits pro-caspase-1 to this complex, which is converted into catalytically active caspase-1 by proximity-induced self-cleavage. The bioactive caspase-1 subunits p20 and p10 then proteolytically cleave pro-IL-1β and pro-IL-18 to generate mature form of bioactive IL-1β and IL-18, respectively (Fig. 1 ). Activation of the inflammasomes triggers an alarm to alert adjacent cells and tissues by releasing pro-inflammatory cytokines. This ends up with amplification of inflammatory cascade by promoting recruitment of effector cell populations required for the immune responses and tissue repair 9 .

Although acute inflammation is a physiological response to infections or tissue damage, it must be properly resolved. Unresolved inflammation can lead to a chronic inflammatory state, which is implicated in the pathogenesis of a wide variety of human disorders including metabolic syndromes, autoimmune disorders, and cancer 9 . For the systematic termination of acute inflammation, it has now become evident that coordinated resolution programs start shortly after inflammatory responses begin 10 . Indeed, inflammatory cells in an early phase of inflammation undergo a functional re-polarization to get properly involved in the onset and establishment of resolution. The fine-tuning of inflammatory switch allows an effective transition from the pro-inflammatory phase to the onset of pro-resolving response 11 . In this context, it is noticeable that some pro-inflammatory molecules involved in the acute phase of inflammation can simultaneously initiate a program for active resolution. For instance, the prototypic pro-inflammatory cytokine IL-1β has been shown to trigger an anti-inflammatory cascade, resulting in the production of IL-10 11 .

Considering differential effects of IL-1β on acute inflammation and its resolution, it can be speculated that the inflammasomes that secrete a mature form of this cytokine may mediate both pro-inflammatory and pro-resolving responses. While activation of the inflammasomes initially mediates pro-inflammatory response, it culminates in the resolution of inflammation and thereby contributes to homeostatic processes 7 . This may account for a dynamic macrophage polarity gradient from pro-inflammatory to anti-inflammatory phenotypes 12 .

The inflammasomes tightly regulate the expression, maturation, and secretion of IL-1β as a master regulator of inflammation. IL-1β, which is mainly generated at the injury or infection sites, induces inflammation-associated gene expression, such as cyclooxygenase-2 and inducible nitric oxide synthase to produce prostaglandin E 2 and nitric oxide, respectively. Moreover, IL-1β increases the expression of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) in mesenchymal cells and vascular cell adhesion molecule-1 in endothelial cells, which provides favorable condition for the recruitment of inflammatory cells and immunocompetent cells from circulation to damaged or infection sites in cooperation with other chemokines 5 . In addition to IL-1β, another pro-inflammatory cytokine controlled by the inflammasomes is IL-18 which is important for induction of IL-17 expression in Th17 cells, and involved in polarization of T cells toward Th1 or Th2 cells in combination with other cytokines 5 . However, the pathophysiological role of IL-18 in tumor microenvironment has not been well-defined compared to that of IL-1β.

Given its potential roles in the innate immunity, inappropriate regulation of the inflammasomes has a strong association with a variety of inflammatory and autoimmune disorders, including neurodegenerative diseases (e.g., multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease) and metabolic disorders (e.g.,atherosclerosis, type 2 diabetes, and obesity) as well as various human malignancies 9 .

Involvement of the inflammasomes and their effector molecules in human malignancies

Breast cancer

Breast cancer is the most commonly diagnosed cancer in women worldwide, and more than 270,000 new cases of breast cancer is estimated to be diagnosed in U.S. women in 2020 13 . Breast cancer is originated from genetic alterations within pre-malignant or malignant cells, and two high-penetrance tumor suppressor genes, BRCA1 (17q21) and BRCA2 (13q13), show an autosomal-dominant inheritance pattern 14 . The most frequently mutated and/or amplified genes in the breast tumor cells are TP53 (41%), PIK3CA (30%), MYC (20%), PTEN (16%), CCND1 (16%), ERBB3 (13%), and FGFR1 (11%) 15 .

Breast cancer cells can invade surrounding tissues and spread to other parts of the body such as bone (30–60%), liver (15–32%), lung (21–32%), and brain (4–10%) 16 , and over 90% of breast cancer-related deaths are associated with metastasis 17 . The breast tumor is characterized by the inflammatory microenvironment, which is supported by the infiltrated immune and inflammatory cells, cytokines, chemokines, and growth factors. Not only proliferation and metastasis of breast cancer cells determine the tumor progressive potential of breast cancer cells, but the complex interactions among many types of cells in the tumor microenvironment can also dictate the fate of breast cancer cells.

The expression of the inflammasome components, such as IL1B , IL18 , NLRP3 , PYCARD , and CASP1 , is significantly up-regulated in most types of breast cancer compared to that in normal tissues (Fig. 2 ). In addition, breast cancer patients show highly increased serum levels of IL-1β which is dependent on tumor stage 18 , 19 . This elevated expression of IL-1β is more likely to be associated with establishment of inflammatory tumor microenvironment and breast cancer progression 18 , 20 – 22 . Further, significant correlation was noticed between IL-1β expression and subsequent development of metastasis 23 , 24 . In a syngeneic orthotopic breast cancer mouse model, IL-1β deficiency failed to induce 4T1 breast cancer cell growth and metastasis, which results from the insufficient recruitment of inflammatory monocytes into tumor site 25 . Consistently, Nlrp3 –/– and Casp1 –/– knockout (K/O) mice deficient in inflammasome components showed significantly reduced growth of primary tumor and lung metastasis 22 , 26 . Disruption of IL-1β–IL-1R signaling by use of a monoclonal IL-1β antibody and an IL-1R antagonist, or by genetic disruption of IL-1R signaling lowered the growth of primary tumor and metastasis to lung and bone in the breast cancer mouse model 20 – 22 , 26 . Fig. 2 Relative expression of inflammasome components in various cancer. A Relative mRNA expression of IL1B in various cancers from Oncomine database 104 – 114 . B Relative mRNA expression of IL18 in various cancers from Oncomine database and The Cancer Genome Atlas (TCGA) 106 , 108 – 110 , 114 – 120 . C Relative mRNA expression of NLRP3 in various cancers 105 , 108 , 109 , 112 , 114 , 116 , 117 , 121 – 123 . D Relative mRNA expression of CASP1 in various cancers 104 , 106 , 109 , 111 , 112 , 114 , 123 – 130 . E Relative mRNA expression of PYCARD in various cancers from Oncomine database and TCGA 106 , 112 , 115 , 117 , 119 , 122 , 127 , 131 . * P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001 (see Supplementary Table S1 for further methodologic details).

Although breast cancer shares the inflammatory characteristics with other types of cancers, this malignancy is rarely associated with inflammation-induced cancer (extrinsic pathway), but rather related to cancer-associated inflammation (intrinsic pathway) for the development of inflammatory microenvironment. Therefore, development of the inflammatory conditions and activation of the inflammasomes largely rely on the interaction among components of the breast tumor microenvironment. Accumulating evidence suggests that antigen-presenting cells, such as dendritic cells and macrophages, are primarily responsible for releasing IL-1β in the breast tumor microenvironment 27 – 29 . According to Wu et al. 30 , interaction between breast cancer cells and CD11c + dendritic cells induced caspase-1-dependent IL-1β secretion from CD11c + dendritic cells which was stimulated by breast cancer cell membrane-derived transforming growth factor β-1 (Figs. 1 and 3 ). In addition, ATP released from dying tumor cells upon chemotherapy induced NLRP3 inflammasome activation and IL-1β secretion from dendritic cells through P2X7 purinergic receptor in the breast tumor microenvironment 27 (Figs. 1 and 3 ). IL-1β released by dendritic cells promoted differentiation of IL-13-producing CD4 + T cells and interferon (IFN)-γ-producing CD8 + T cells in breast cancer-bearing humanized mice 27 (Fig. 3 ). CD4 + T effector cells that express high levels of IL-13 accelerated development of mammary carcinomas and their metastasis to the lung by enhancing pro-tumorigenic potential of tumor-associated macrophages 31 , 32 (Fig. 3 ). IFN-γ derived from CD8 + T cells, when primed by IL-1β, reduced the chemotherapeutic efficacy of oxaliplatin 27 . Patients with estrogen receptor (ER)α-positive breast cancer were responsive to tamoxifen, but IL-1β diminished its chemotherapeutic efficacy by down-regulating ERα expression 33 . Fig. 3 Mechanisms of breast cancer progression mediated through intrinsic inflammasome activation. In breast tumor microenvironment, sCD44 and WNT ligand released by breast cancer cells induce secretion of IL-1β from macrophages. In addition, TGF-β produced by breast cancer cells and ATP released from dying tumor cells stimulate IL-1β secretion from dendritic cells, which promotes IL-13 production in CD4 + T cells. This promotes breast cancer progression and metastasis.

In addition to dendritic cells, other types of immune cells also have potential to release IL-1β in the breast tumor microenvironment 27 – 29 . According to Jang et al. 18 , macrophages are also major cellular sources for IL-1β secretion, and triple-negative breast cancer cells induced ASC oligomerization and speck formation for inflammasome activation in macrophages. Notably, depletion of macrophages decreased serum levels of IL-1β, and alleviated breast cancer progression in a syngeneic orthotopic breast cancer mouse model 18 . The secretion of IL-1β from macrophages is surmised to be mediated by breast cancer cell membrane-derived soluble CD44 (sCD44), as antibody neutralization of sCD44 hampered secretion of IL-1β from macrophages 18 (Figs. 1 and 3 ).

WNT ligand-induced IL-1β secretion from macrophages was reported by Wellenstein et al. 34 (Figs. 1 and 3 ). Deletion mutation of TP53 in breast cancer cells conferred secretion of WNT ligands 34 . This, in turn, promoted IL-1β secretion from tumor-associated macrophage, leading to systemic inflammation for breast cancer metastasis 34 . Moreover, bone marrow-derived IL-1β promoted colonization of breast cancer cells in the bone via induction of nuclear factor (NF)-κB/CREB-WNT signaling in breast cancer cells 21 . Obesity-induced NLRC4 inflammasome activation in F4/80 + /CD11b + macrophages facilitated tumor growth and angiogenesis through upregulation of adipocyte-mediated Vegfa expression in the breast tumor microenvironment 35 . Major cellular sources for IL-1β secretion are antigen-presenting cells, but endogenous expression of IL-1β in breast cancer cells also increased metastatic potential, which was correlated with bone metastasis in breast cancer patients 20 .

Although IL-1β released upon activation of inflammasomes is known to induce tumor progression, it also has a tumor suppressive function in the breast tumor microenvironment 36 , 37 . The metastasis-initiating cancer cells (MICs) play roles in metastasis, recurrence, and therapeutic resistance of cancer cells. According to Castano et al., 36 IL-1β can keep MICs in a ZEB1-positive differentiation state, thereby preventing them from generating exceedingly proliferative E-cadherin-positive progeny in a metastatic microenvironment. Thus, colonization and secondary tumor formation are inhibited by sustained IL-1β. In agreement with such differential effects of IL-1β, blockade of its receptor (IL-1R), in combination with paclitaxel, slightly reduced primary breast tumor growth, but potentiated pulmonary metastasis 37 . In another study, Il-1β -deficient mice exhibited profound regression of primary tumor growth in a syngeneic orthotopic breast cancer mouse model 25 . Both CD11b + dendritic cells and activated CD8 + T cells are mainly considered to exert immunosuppression and anti-tumor immunity by releasing IL-12, IFN-γ, and Granzyme B 25 . Il-1β -deficient mice failed to infiltrate inflammatory monocytes, but CD11b + dendritic cells and activated CD8 + T cells were more predominant in tumor tissues compared to wild type (WT) mice 25 .

Colorectal cancer

Colorectal cancer (CRC) is the third most common form of cancer in western countries. CRC is frequently associated with prolonged inflammation in the intestine, as exemplified in patients with inflammatory bowel disease (IBD). Crohn’s disease and ulcerative colitis are two major types of IBD, characterized by a prolonged inflammatory response against luminal bacteria or sustained mucosal danger signals, leading to over-activated immune response in the intestinal tract. Patients with IBD are at high risk for colitis-associated colorectal cancer (CAC). Aspirin and some other non-steroidal anti-inflammatory drugs have been known to reduce risk of CRC, which supports the critical involvement of inflammatory processes in the onset and development of CRC 38 . The CRC microenvironment is composed of epithelial cells, stromal cells, and heterogeneous infiltrating immune and inflammatory cells, including macrophages, dendritic cells, T lymphocytes, B cells, NK cells, regulatory T cells, and myeloid-derived suppressor cells 39 . A dynamic interaction of CRC cells with the surrounding stroma can influence not only development of CRC, but its progression and metastasis.

Among genes encoding inflammasome components, IL1B and NLRP3 are highly expressed in colon cancer tissues (Fig. 2 ) 40 , 41 , and accumulating evidence points to critical roles of the inflammasomes and IL-1β in dextran sulfate sodium (DSS)-induced colitis and azoxymethane (AOM) plus DSS-induced CAC. In this mouse model, AOM is used as an initiator capable of causing DNA damages in intestinal epithelial cells. Repeated administration of DSS in drinking water causes damages to the intestinal epithelial barrier, resulting in the induction of inflammation in the colonic mucosa and promotes development of CRC. In an AOM plus DSS-induced CAC mouse model, mice deficient for the inflammasome components were highly susceptible to development of CAC as demonstrated by increased morbidity, histopathology, and colonic polyp formation 42 – 45 . In the CAC induced by AOM and DSS, the inflammasomes in hematopoietic-derived cells exerted more potent effects on regulation of intestinal tumorigenesis than those in other types of cells in the intestinal tract, such as epithelial cells, tumor-derived cells, or stromal cells 43 , 45 . Allen et al. 43 reported suppressive effects of Pycard and Casp1 as well as Nlrp3 , on acute and recurring colitis induced by DSS, and found that Pycard and caspase-1 were essential for survival in AOM plus DSS-induced CAC mouse model. Significantly increased colonic lesions and the number of colonic macroscopic polyps were observed in WT mice receiving bone marrow from Nlrp3 K/O mice when compared with those in mice receiving WT bone marrow 43 . These preclinical data using chimeric animals by adoptive bone marrow transplantation indicate that NLRP3 in hematopoietic-derived cells plays a tumor suppressive role in the CAC microenvironment 43 (Fig. 4 ). NLRP6 also showed predominant protective effects in hematopoietic-derived cells against colitis-induced tumorigenesis 45 . Nlrp6 -deficient hematopoietic-derived cells were more susceptible to inflammation-induced tumorigenesis due to the impairment of resolution of inflammation and repairing damaged epithelium (Fig. 4 ). NLRP6 in colon epithelial and stromal cells, however, did not show a tumor suppressive effect on the development of CAC, although these cells have higher expression of NLRP6 compared to other types of cells such as lamina propria, granulocytes, and monocyte lineage cells 45 . Similarly, NLRC4 in colon epithelial and hematopoietic cells was found to play protective roles in CAC development 44 , 46 (Fig. 4 ), and the expression of NLRC4 was associated with p53-dependent cancer cell death 47 . Direct induction of NLRC4 gene expression by p53 enhanced p53-dependent apoptosis 47 . Therefore, NLRC4 in hematopoietic cells and epithelial cells is likely to be important for limiting tumorigenesis 44 , 46 . Fig. 4 Mechanisms of CRC regulation mediated by extrinsic inflammasome activation. In colorectal tumor microenvironment, IL-1β derived from infiltrated neutrophils, macrophages, and dendritic cells enhances CRC progression through production of IL-6 and IL-17A from lamina propria, macrophages, and dendritic cells. On the other hand, NLRP3 in bone marrow cells, NLRC4 and NLRC6 in hematopoietic cells, and NLRC4 in colon epithelial cells play tumor suppressive roles in CAC development.

On the other hand, oncogenic potential of IL-1β in the CAC microenvironment has been reported 48 , 49 . In the CAC pathogenesis, infiltrated neutrophils are considered major cell type responsible for producing IL-1β 48 , 49 . Therefore, depletion of neutrophils and blockade of IL-1β activity attenuated mucosal damage and reduced the tumor burden 48 (Fig. 4 ). IL-1β derived from infiltrated neutrophils induced secretion of IL-6 from lamina propria, resident dendritic cells, and macrophages in the CAC milieu 48 (Fig. 4 ). IL-6 has been known to have critical roles in CAC progression, and prolonged disease-free survival was observed in CRC patients with low IL-6 expression in their primary tumors 50 . In addition, IL-1β was required for secretion of IL-17A from intestine-resident myeloid cells in an autocrine or a paracrine manner 49 . Secretion of IL-6 and IL-17A by intestinal myeloid cells (predominantly dendritic cells and macrophages) enhanced proliferation and decreased apoptosis of pre-neoplastic intestinal epithelial cells via the signal transducer and activator of transcription 3 and the NF-κB-dependent signaling pathways in the CAC microenvironment 49 , 51 , 52 (Fig. 4 ). Overproduction of pro-inflammatory cytokines, such as tumor necrosis factor-α, IL-1β, and IL-17A, is closely associated with the development of CAC 48 , 49 , 51 – 54 .

Lung cancer

Lung cancer is the leading cause of cancer-related death with a poor 5-year survival of less than 19% 13 . Human lung adenocarcinoma encompasses unique subtypes of lung cancer with distinct cellular and mutational heterogeneity 55 . Importantly, this heterogeneity is not only limited to tumor cells but also spans the tumor microenvironment, including vasculature, extracellular matrix, cancer-associated fibroblast, and infiltrating immune cells. In human non-small-cell-lung cancer (NSCLC), stage-dependent tumor-associated immune cells infiltration indicates strong association of the tumor microenvironment with lung carcinogenesis and prognosis of lung cancer 56 , 57 .

The relationship between IL-1β and lung cancer has not been well-defined in the context of tumor microenvironment. Indeed, the expression of the inflammasome components in lung cancer tissues did not much differ from those in normal pulmonary tissues (Fig. 2 ). However, the role for inflammasome components, especially IL-1β attracted attention by the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial. The CANTOS trial was a randomized, double-blinded, placebo-controlled trial that investigated the use of canakinumab, a monoclonal antibody targeting IL-1β, in high-risk patients with established atherosclerotic disease who had already survived a myocardial infarction. The report showed that among the 129 cases of lung cancer in the follow-up period of 3.7 years (median), the incidence of lung cancer was significantly less frequent in the groups receiving the 150 and 300 mg of canakinumab, not in the group receiving 50 mg. The CANTOS trial suggests the role for IL-1β in lung cancer progression. Based on the CANTOS trial, three parts of phase III CANOPY clinical trials to evaluate canakinumab in patients with mid- to late-stage of NSCLC have been undertaken.

In lung cancer, tumor-associated macrophages have been suggested as the principal cellular sources of IL-1β secretion, and macrophage depletion alleviated N -methyl- N -nitroso-urea-induced pulmonary cancer development 58 . 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 . Thus, an NF-κB inhibitor shows limited effects for lung cancer treatment, although NK-κB signaling in epithelial cells has been known to play an essential role in lung carcinogenesis 60 . Specific inhibition of NF-κB in myeloid cells increased IL-1β processing in neutrophils, thereby stimulating proliferative activity of epithelial cells 60 . In lung cancer patients who received the NF-κB inhibitor, the serum levels of IL-1β were increased, and co-treatment of an IL-1R antagonist and the NF-κB inhibitor decreased formation of lung cancer in mice 60 .

According to Carmi et al. 61 , secretion of IL-1β mainly released from myeloid cells in the lung tumor microenvironment is prerequisite for the recruitment and activation of IL-17 producing γ/δ T cells. They also suggested the importance of IL-1β balance to prevent stimulation of cancer progression in the lung tumor microenvironment 61 . Specifically, poor prognosis of lung cancer and reduced T cell activity have been observed in both IL-1β K/O and IL-1R antagonist K/O mice 61 . The absence of IL-1 signaling in IL-1β K/O mice promoted regulatory T cell development that suppressed anti-tumor immunity 61 . On the other hand, the increased activity of IL-1 by using an IL-1R antagonist K/O mice enhanced accumulation of myeloid-derived suppressor cells, resulting in suppression of T cell function in the lung tumor microenvironment 61 . Except hematopoietic cells, IL-1β overexpressing lung cancer cells acquired an aggressive phenotype for cancer development by increasing the expression of ICAM-1 and matrix metalloproteinase-2 62 . Moreover, IL-1β-overexpressing cells, when injected intravenously, were more likely to metastasize to the lung, which was blocked by anti-IL-1β antibody treatment 62 .

Skin cancer

The most important environmental risk factor for skin cancer is ultraviolet (UV) radiation, which has been known to cause DNA damage, immunosuppression, and inflammation 63 , 64 . Basal cell carcinoma, the most common type of skin cancers, accounts for up to 80% of all malignant skin cancers and higher levels of pro-inflammatory cytokines (e.g., IL-1β, IL-5, and IL-6), compared to those in squamous cell carcinomaoma 65 . The most aggressive form of skin cancer is melanoma which is characterized by upregulation of several pro-inflammatory cytokines, including IL-6, IL-8, CCL5, and IL-1β, the expression of which can be regulated by IL-1β 5 , 64 , 66 . In addition, expression of the inflammasome components, such as IL1B , PYCARD , and CASP1 , was detected at higher levels in squamous cell carcinoma than in normal skin tissues (Fig. 2 ).

In skin cancer, UV radiation is a powerful inducer of IL-1β, and melanoma-derived IL-1β is more likely to promote tumor growth, angiogenesis, invasion, and metastasis 67 – 73 (Fig. 1 ). However, the roles of the inflammasomes and IL-1β in skin cancer vary, depending on the types of cells. Several studies using a two-stage mouse skin carcinogenesis model revealed that the inflammasomes and IL-1 have dual functions in the development of inflammation-induced skin carcinogenesis. According to the study by Drexler et al., Il-1r1 −/− and Casp1 −/− mice treated with 7,12-dimethylbenz( a )anthracene (DMBA) as an initiator and 12- O -tetradecanoylphorbol-13-acetate (TPA) as a promoter showed the reduced incidence and the multiplicity of skin tumors compared to WT mice, suggesting the tumor supportive role of the IL-1β–IL-1R axis in two-stage skin carcinogenesis 74 . On the other hand, Asc −/− mice showed no significant functional difference in the tumor burden and the incidence compared to WT mice in response to DMBA and TPA treatment 74 .

Notably, ASC showed completely different behavior in either keratinocytes or myeloid cells in tissue-specific conditional K/O mice 74 . Mice with exclusive deletion of ASC in myeloid cells developed fewer tumors than WT mice, but the number and the incidence of tumors were higher in mice deficient for ASC in keratinocytes, although the onset of tumor formation was delayed for a few weeks when compared to WT control 74 . The results from ASC tissue-specific conditional K/O mice imply cell-type-dependent dual functions of the inflammasome components in a skin carcinogenesis mouse model. Consistent with these pleiotropic results, ASC expressed by primary melanoma exerted an inhibitory effect on tumorigenesis by suppressing IκB kinase α/β phosphorylation and NF-κB transcriptional activity 75 . On the other hand, relatively up-regulated expression of ASC in metastatic melanoma increased NF-κB activity and the inflammasome-mediated IL-1β secretion 75 . Knock-down of NLRP1 in melanoma cells attenuated their tumor-promoting properties through regulation of the inflammasomes and the apoptotic pathway in both in vitro and in vivo 76 . Considering the absence of NLRP3 expression in keratinocytes, myeloid cells appear to have a major responsibility for the development of NLRP3 inflammasome-mediated skin cancer development and progression 29 , 77 .

Liver cancer

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Hepatitis C virus (HCV) infection is a main cause of advanced hepatic fibrosis and cirrhosis, associated with significantly increased risk of HCC development. Kupffer cells (resident macrophages in liver) and HCC cells have been known as major sources of IL-1β secretion in HCV-mediated progression of HCC 78 , 79 . HCV induces assembly of the NLRP3 inflammasome complex in human HCC cells, and up-regulated expression of NLRP3 and PYCARD was observed in HCC tissues (Fig. 2 ). HCV-induced NLRP3 inflammasome activation in Kupffer cells led to increased serum levels of IL-1β in HCV-infected patients 78 , 79 . Necrotic debris of HCC cells formed under hypoxic conditions also induced secretion of IL-1β from macrophages in the HCC microenvironment 80 . Secretion of IL-1β enhanced epithelial-mesenchymal transition (EMT) and metastasis of HCC cells through stabilization of hypoxia-inducible factor-1α 80 . On the contrary, the up-regulated expression of IL-1β and NF-κB extended disease-free survival of HCC patients after hepatectomy 81 . Likewise, the expression of NLRP3 inflammasome components, including NLRP3, ASC, caspase-1, and IL-1β, showed inverse correlation with pathological grades and clinical stages in the HCC patient tissues. Compared with peritumoral non-cancerous liver tissues, NLRP3 inflammasome components were down-regulated in hepatic parenchymal cells in human HCC, which was associated with more advanced clinical stages 82 . During the development of HCC, massive loss of hepatocytes is accompanied by chronic hepatic inflammation. Dying hepatocytes release danger signals, and their accumulation causes liver damage, which may further increase the risk of liver cancer 83 . NLRP3 inflammasomes have essential roles in sensing danger signals. Therefore, loss of NLRP3 inflammasome components during the development of HCC leads to failure of sensing danger signals, which may result in manifestation of an aggressive phenotype of liver cancer development.

Therapeutic approaches and clinical trials

For the therapeutic purpose, attempt has been made to repress the aberrant activation of the inflammasomes. Although some natural compounds have been shown to inhibit overactivation of the inflammasomes or their components, most studies aimed to test their ability to ameliorate simply inflammatory symptoms, not to prevent/treat cancer (Table 2 ) 84 , 85 . Therefore, it will be worthwhile determining chemopreventive or chemotherapeutic effects of natural and synthetic compounds exerted through regulation of the inflammasomes. However, the tumor microenvironment comprises various types of cells that interact one another. Therefore, the dynamic interaction among various cells in the tumor microenvironment should be considered for the inflammasomes-targeted cancer prevention/treatment. Table 2 Regulation of inflammasomes by natural compounds. Natural compounds Mechanisms Ref. Curcumin Reduced expression of NLRP3, inhibition of caspase-1 cleavage, and secretion of IL-1β 132 Curcumin Inhibition IL-1β secretion in bone marrow-derived macrophages (BMDMs) by preventing K + efflux, ROS generation, and cathepsin B release 133 , 134 Resveratrol Inhibition of NLRP3 inflammasome via preventing assembly of ASC and NLRP3 on the mitochondria and ER 135 cis -resveratrol Inhibition of IL-1β secretion by suppression of P2X7R and ROS production 136 Sulforaphane Inhibition of Aβ1-42-induced caspase-1 dependent inflammasome activation via inhibition of STAT-1 phosphorylation and activation of the Nrf2/HO-1 signaling cascade 137 Sulforaphane Reduced monosodium urate (MSU) crystal-induced IL-1β secretion in peritonitis model, and inhibited NLRP1b, NLRP3, NAIP5/NLRC4 and AIM2 inflammasomes in BMDMs 138

In addition to natural and synthetic compounds, some biological agents (e.g., anakinra and canakinumab) targeting IL-1β or its receptor are now used to treat several inflammatory or autoimmune diseases, such as rheumatoid arthritis. IL-1β mainly contributes to the establishment of systemic inflammation in the tumor microenvironment and tumor progression 86 . Based on these findings, several trials have been launched using IL-1β neutralizing antibody and IL-1R antagonists (Table 3 ). Antibody neutralization of IL-1β and use of IL-1R antagonists showed significant anti-cancer effects in preclinical studies, and their safety was confirmed. According to Holen et al., an IL-1R1 antagonist (anakinra) significantly reduced the growth of primary tumor and its bone metastasis in a breast cancer mouse model 26 . Although anakinra did not induce apoptosis of tumor cells, it significantly inhibited cancer cell proliferation and angiogenesis 26 . In agreement with these results, Wu et al. 30 reported inhibitory effects of an IL-1R1 antagonist on breast cancer progression. Notably, anakinra treatment prevented breast cancer progression with a substantial decrease in the proportion of IL-13 producing tumor-infiltrating CD4 + T cells and a concomitant increase of IFN-γ producing CD4 + T cells in a humanized mouse model 30 . In other studies, administration of anakinra suppressed growth and lymph node metastasis of the LNM35 human lung tumor xenograft in mice 87 . In addition, a recombinant human IL-1R antagonist plus one of the standard chemotherapy regimens, gemcitabine, significantly reduced tumor burden when compared to the gemcitabine treatment alone in a pancreatic ductal adenocarcinoma orthotopic xenograft mouse model 88 . Table 3 Pharmaceutical target of inflammasome in cancer. Therapeutic agents (Trade name) Targets Mechanisms of action Cancer type Status Ref. Anakinra (Kineret) IL-1 receptor IL-1R antagonist Metastatic breast cancer Phase I NCT01802970 Anakinra (Kineret) IL-1 receptor IL-1R antagonist Metastatic CRC Phase II NCT02090101 Anakinra (Kineret) IL-1 receptor IL-1R antagonist Multiple myeloma & plasma cell neoplasm Phase II NCT00635154 Canakinumab (Ilaris) IL-1β Anti-IL-1β monoclonal antibody CRC, triple-negative breast cancer, NSCLC Phase I NCT02900664 Gevokizumab IL-1β Anti-IL-1β monoclonal antibody Metastatic CRC, gastroesophageal cancer, renal cell carcinoma Phase I NCT03798626 MCC950 NLRP3 inflammasome Inhibition of ASC oligomerization Head and neck squamous cell carcinoma Preclinical 139 Oxidized ATP P2X7 receptor Selective P2X7 antagonist P2X7-expressing tumors, melanoma NA 139 , 140

In the Palucka pilot clinical trial with 11 HER2-negative metastatic breast cancer patients, 100 mg/daily of anakinra was subcutaneously administered for a 2-week run-in treatment period 30 . This was followed by continuous daily anakinra administration along with one of the standard chemotherapy regimens for HER2-negative breast cancer patients for a median duration of 4 months. In this preclinical study, 2 of 11 patients had a considerably reduced tumor size, 4 had stable disease, 2 stopped anakinra administration due to injection site reactions, and the other 3 had progressive disease. Some patients showed reduced pain and increased quality of life on anakinra plus chemotherapy, and anakinra also reduced chemotherapy-associated “sickness syndrome”. Canakinumab was approved for use as an anti-IL-1β neutralizing mAb by US FDA in 2009. In a randomized, double-blind, placebo-controlled trial with 10,061 atherosclerosis patients, canakinumab showed a significantly reduced incidence and a mortality of lung cancer compared to the placebo group 89 .

In a phase 2 clinical study, the activity and safety of 5-fluorouracil plus bevacizumab and anakinra were tested in unresectable metastatic CRC patients 90 . The patients were treated with a simplified folinic acid plus 5-fluorouracil regimen and bevacizumab for every 2 weeks, and anakinra was injected subcutaneously once daily for 2 months. In this study, the median progression-free survival (PFS) and the overall survival (OS) were 5.4 (95% CI, 3.6–6.6) and 14.5 months (95% CI, 9–20.6), respectively, and no treatment-related deaths or serious adverse effects were observed 90 . Although it is hard to define the direct effects of this combination therapy in metastatic CRC patients due to the absence of a comparable group, the PFS and OS were extended compared to the Regorafenib study [PFS: 2.8 months (95% CI 1.4–3.7) versus 1.8 months (95% CI 1.3–1.7), median OS: 6.4 months (95% CI 3.6–11.8) versus 5.0 months (95% CI 2.8–10.4)] and TAS-102 trial [median PFS: 2.0 months (95% CI, 1.9 to 2.1) in the TAS-102 group and 1.7 months (95% CI, 1.7 to 1.8) in the placebo group, median OS improved from 5.3 months (95% CI, 4.6–6) to 7.1 months (95% CI, 6.5–7.8)]. Given the extended PFS and OS, this combination therapy can be suggested as an option for refractory metastatic CRC patients 90 – 92 . Based on these findings, further studies will be necessary to achieve better clinical results qualified for use in cancer patients. In addition, the timing, duration, and dosing for the inflammasome inhibition should be considered as important factors, since excessive suppression of the inflammasomes can cause severe immunosuppression, which may increase the risk of serious infections.

There are several trials that utilize inflammasome components as a biomarker in chronic diseases and systemic injuries, including stroke 93 , traumatic brain injury 94 , multiple sclerosis 95 , and Alzheimer’s disease 96 . Although IL1B gene polymorphism is associated with the risk of lung cancer 97 , inflammasome components are barely used for cancer diagnosis due to its non-specificity. As previously discussed, inflammasomes are not only expressed in cancer, but also activated in many types of inflammation or immune-associated disorders. Nonetheless, the inflammasome components can be considered as prognostic markers of cancer, but the changes in their activation and overexpression of their components according to the status of cancer progression need systematic validation.

Conclusion and perspectives

The inflammasomes are involved in the whole range of tumorigenesis. The consequence of aberrantly activated inflammasomes in cancer development and progression varies depending on types of tumors, location of inflammasomes, cells, stages of cancer, and profile and composition of the tumor microenvironment (Table 1 ). The roles of inflammasomes, especially those of hematopoietic lineage, in stimulating tumor progression have been well demonstrated in CRC and breast cancer 27 , 42 , 45 . In CRC development, NLRP3 and NLRC4 in hematopoietic-derived cells have differential effects on tumor formation 43 , 46 . Moreover, NLRP6 showed differential roles depending on cell types for its expression in CAC 45 . Ironically, NLRP3 and NLRP6 expressed in bone marrow cells play tumor suppressive roles 43 , 45 , but their byproduct, IL-1β is more likely to induce tumor progression in the CRC microenvironment 48 . Such discrepancy may imply the importance of the inflammasomes and IL-1β and their balance in the tumor microenvironment. In inflammation-induced cancer, deficient or impaired activation of the inflammasomes and expression/processing of their components may provoke failure in engaging inflammation and its resolution in an early stage of chemically induced carcinogenesis 43 . Failure of systemic inflammatory responses, such as inflammation initiation, amplification, and resolution, leads to severe tissue damages, accumulation of PAMPs or DAPMs, and delayed tissue repair, resulting in tumor development 83 . The roles and effects of the inflammasomes can be influenced by various factors, and more detailed study for its expression pattern and interaction with microenvironment is needed.

Pyroptosis is a highly inflammatory form of cell death characterized by pore-formation, cell swelling, plasma membrane rupture, and intracellular contents release in immune cells as well as some epithelial cells 8 . This unique process is initiated by inflammasome activation upon recognition of PAMPs or DAMPs 8 . The association between pyroptosis and cancer is complex and not clearly defined. Thus, the effects of pyroptosis on cancer development and progression vary, based on the types of tissues and genetic backgrounds 98 – 100 . On the one hand, pyroptosis inhibits proliferation and migration of cancer cells 101 , 102 . Thus, expression of some pyroptotic inflammasomes has been found to decreased in cancer cells. Recent studies have focused on simvastatin and non-coding RNA molecules inducing pyroptotic cell death in several types of cancers 101 , 102 . On the other hand, pyroptosis can provide a suitable microenvironment for growth of cancer cells and thereby stimulates tumor growth by releasing IL-1β and IL-18.

In this review, we highlighted the differential roles of inflammasomes and its effector molecules, particularly IL-1β, in tumor development and progression. Inflammasomes and inflammation components have both tumor suppressive and promoting functions 103 . These depend on cell types, malignancy types, downstream effector molecules, and stages of cancers. More systematic and integrative studies on the roles for inflammasomes as well as IL-1β and IL-18 in specific stages of cancer, from tumor initiation to progression and metastasis, merit further investigations.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Supplementary information

Supplementary Table S1

Reporting Summary

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

The online version contains supplementary material available at 10.1038/s41698-021-00154-7.

Acknowledgements

This research was supported by the Global Core Research Center (GCRC) grant (No. 2011-0030001) and the BK21 FOUR Program (5120200513755) of the National Research Foundation (NRF) funded from the Ministry of Education, Republic of Korea.

Author contributions

J.-H.J. wrote the manuscript. J.-H.J., D.-H.K., and Y.-J.S. contributed to the conception and design of paper.

Data availability

The data used to create Fig. 2 were obtained from Oncomine database using the free, publicly available databases or a free, publicly available web-based analytical platform, respectively (see Supplementary Table S1 ).

Competing interests

The authors declare no competing interests.

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