Various cytokines, including chemokines, and their associated receptors play important roles in lung cancer-associated inflammatory response. Interleukins, such as IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, cytokines such as tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), stromal cell derived factor 1 (SDF1), chemokine C-X-C motif ligand 10 (CXCL10), chemokine C-C motif ligand 2 (CCL2), and cytokine receptors such as chemokine C-X-C motif receptors 2 and 4 (CXCR2 and CXCR4) have been shown to be linked to various stages of lung cancer development [12–14]. Importantly, the aforementioned inflammatory mediators have been shown to be produced by both lung cancer cells and the microenvironment comprising innate and adaptive immune cells. Notably, mounting evidence suggests that the profile of activated cytokines, as well as recruited leukocytes, lymphocytes, and macrophages vary based on the stage of lung cancer development and whether preneoplastic or neoplastic lung lesions have already been formed [2, 4]. Neoplastic microenvironments favor polarized chronic protumorigenic inflammatory states that are of the T helper 2 (T_h2) type inflammatory response [2]. This type of inflammatory response involves suppression of cytotoxic CD8 ⁺ T-lymphocytes, production of IL-4 by innate immune cells, and of IL-8 and IL-1β by tumor cells themselves further perpetuating the inflammatory lung tumor microenvironment [2, 4]. In contrast, T_h1 is the predominant inflammatory response before development of lung lesions (e.g., in COPD) that promotes a cytotoxic immune response comprising increased production of IL-12 rather than IL-4 [2, 14].

Various proteinases, including elastases and matrix metallopeptidases (MMPs), have been implicated in the proinflammatory response associated with lung cancer development and progression. Neutrophil elastase (NE) is a major player in inflammatory pathological conditions in the lung such as COPD and emphysema [14]. NE was shown to degrade elastin in the lung and contributes to cigarette smoke-induced emphysema in mice [60]. Houghton and colleagues demonstrated that NE promoted lung carcinogenesis in the mutant K-rasG12D (LSL-K-ras) mouse model for lung adenocarcinoma [61]. The tumorigenic effects of NE were attributed to activation of the phosphatidyl inositol 3-kinase (PI3K) pathway activation through degradation of insulin receptor substrate 1 (IRS1) to induce lung tumor cell proliferation [61].

The transcription factor, NF-κB, is considered to be a lynchpin in inflammation-associated cancer with major proinflammatory and protumorigenic roles [71]. Mounting evidence suggests that chronic inflammation contributes to lung cancer development and progression through activation of NF-κB [15]. In NSCLC cell lines, it has been demonstrated that tobacco components stimulate NF-κB dependent survival [72] and the COX2 inhibitor celecoxib suppresses NF-κB activation induced by several carcinogens [73]. There are limited comprehensive studies on the expression patterns of NF-κB in lung tumors and lung preneoplastic lesions. Increased nuclear NF-κB expression was reported in a limited number of moderate and severe squamous dysplasias obtained from smokers without cancer relative to normal bronchial epithelium specimens [74]. In a study utilizing a relatively large series of primary lung cancer and preneoplastic histological tissue specimens, nuclear NF-κB (p65) immunohistochemical expression was prevalent in lung tumors and significantly higher in SCLCs compared to non-small cell lung cancers (NSCLCs) [75]. In adenocarcinomas, nuclear NF-κB expression level was significantly higher in advanced (III–IV) than earlier (I–II) stages [75]. Moreover, a relatively high level of nuclear NF-κB was detected in normal and mildly abnormal epithelium, and a progression with increasing histology severity was detected in preneoplastic lesions [75]. In addition, immunohistochemical expression of interleukin-1 receptor–associated kinase (IRAK-1), a kinase that relays signaling from IL-1R and TLRs to NF-κB activation was also reported to be elevated in squamous dysplasias compared to normal bronchial epithelium and the combination of its expression with that of NF-κB was a significant predictor of poor clinical outcome in lung cancer patients [76].

Cyclooxygenase 2 catalyzes the synthesis of prostaglandin endoperoxidase H2 (PGH2) from the membrane phospholipid arachidonic acid [7, 87]. PGH2 is then converted to potent inflammatory and growth-promoting molecules named prostaglandins (e.g., prostaglandin E2/PGE2) by the action of tissue specific isomerases [7, 87]. Various studies have demonstrated the involvement of the eicosanoid pathway and COX2 in the pathogenesis of lung cancer [15]. COX2 is an intermediate early response gene induced and activated by growth factors, oncogenes, carcinogens, and tumor promoters, such as phorbol esters and exerts pro-inflammatory effects in a PGE2-dependent manner, which contributes to carcinogenesis and tumor progression [7, 87]. Cigarette smoke exposure can induce COX2 expression and activity, increase PGE2 release, and lead to an imbalance in PGI2 and thromboxane A (TxA2) production in favor of the latter [88]. COX2 has been shown to be over-expressed in lung adenocarcinomas and squamous cell carcinomas (SCCs) [89] and COX2 immunohistochemical expression was demonstrated to be highly expressed in bronchial squamous dysplasias, especially those exhibiting high-grade histology (severe dysplasia and carcinoma in situ) [90]. Expression of this cyclooxygenase has been shown to be associated with poor outcome in lung cancer patients [91]. Multiple lines of evidence suggest that targeting COX2 may be an effective strategy for lung cancer prevention and therapy as well as for the clinical management of inflammatory pulmonary conditions such as COPD [13, 14]. As mentioned before, epidemiological studies revealed that long-term usage of non-steroidal anti-inflammatory drugs, which target cyclooxygenases , reduces cancer risk [13]. Celecoxib inhibits survival and induce apoptosis of immortalized and premalignant lung epithelial cells [92]. Furthermore, Kim and colleagues showed that the COX2-specific inhibitor celecoxib decreased proliferation and KI67 expression in normal bronchial epithelia of phenotypically healthy smokers [20] .

The transcription factor NRF2 is a master regulator of intracellular homeostasis and oxidative stress [93]. Basally, NRF2 is kept inactive through binding to its inhibitor Kelch-like ECH-associated protein 1 (KEAP1) that causes NRF2 degradation [93]. The NRF2 and KEAP1 pathway has been extensively studied in various pathological conditions and cancer and has garnered tremendous interest owing to the important roles this pathway plays. Upon activation and translocation to the nucleus, NRF2 transactivates the expression of various genes with antioxidant response elements (AREs) that can reduce oxidative and genotoxic stress induced by agents such as cigarette smoke or proinflammatory cells such as macrophages and neutrophils [94]. Experiments in mice, in particular using mice with knockout of both alleles of the Nrf2 gene, revealed cytoprotective and tumor suppressor roles for this transcription factor [93–96]. Nrf2 knockout mice exhibit increased epithelial cell apoptosis and emphysema compared to their wild type littermates following exposure to tobacco carcinogens [95]. Satoh and colleagues demonstrated that Nrf2-deficient mice exhibit a higher number of lung metastatic nodules, increased numbers of inflammatory cells, including myeloid-derived suppressor cells (MDSCs), a potent population of immunosuppressive cells that attenuate CD8 ⁺ cytotoxic T-lymphocytes [2], and elevated ROS levels compared to wild type mice [96]. These findings point to the potential use of activators of NRF2 function (e.g., oltipraz, [97]) for the prevention and therapy of lung cancer. However, recent reports have alluded to an oncogenic role for this transcription factor [93]. DeNicola and colleagues reported the activation of Nrf2 by various oncogenes, such as K-ras, B-raf, and myc, with concomitant cytoprotection, ROS decrease and tumorigenesis [98]. NRF2 was also shown to promote lung cancer cell proliferation and resistance to cisplatinum treatment [99]. Using 304 histological tissue specimens of human lung cancer, Solis and colleagues demonstrated abnormally high immunohistochemical expression of NRF2 in a large fraction of the tumors and low expression of its inhibitor, KEAP1, in adenocarcinomas [100]. Moreover, high or low expression of NRF2 and KEAP1, respectively, were significantly associated with poor prognosis [100]. Notably, the same study revealed that high or positive immunohistochemical expression of nuclear NRF2 was a significant predictor of poor response to adjuvant chemotherapy in lung SCCs [100]. Similar findings have been observed in other malignancies [93]. More recently, studies from the cancer genome atlas using next-generation sequencing (NGS) technology have confirmed and identified gain-of-function mutations in NRF2 and loss-of-function mutations in KEAP1 [101, 102]. The same studies also reported deletion of KEAP1 in a fraction of tumors and that loss of KEAP1 function or expression was the fourth most recurrent and significant event in lung adenocarcinomas [102]. These studies strongly point to an oncogenic role for the NRF2 transciption factor and a tumor suppressor function for its inhibitor KEAP1. Therefore, NRF2, as mentioned for proinflammatory responses above, seems to exhibit paradoxical functions and properties in tumor progression with both tumor suppressive and oncogenic roles. However, this begs the question whether NRF2 function is dependent on the stage of tumorigenesis [93] where its role in tumor initiation or cancer-free inflammatory lung diseases (e.g., COPD) is different from that in later stages of lung cancer. Indeed, it has recently been shown that NRF2 exhibits suppressive roles in tumor initiation and promoting roles during lung cancer progression [103]. Nrf2 deficient mice exhibited increased number of tumors compared to their wild type littermates following urethane exposure [103]. However, at later time points (16 weeks), the number of invasive adenocarcinomas was significantly higher in the wild type mice [103]. Importantly, whereas all Nrf2 wild type tumors exhibited K-ras mutations, tumors that developed in the knockout mice seldom exhibited mutations in this oncogene [103].

As mentioned before, the types of proinflammatory responses in chronic inflammatory lung diseases or in very early phases of lung cancer development are different from that occurring during later stages of lung tumor progression [2]. Several lines of evidence have pointed to the suppression of cytotoxic T-cell function facilitating evasion of tumor cells from immunosurveillance and anti-tumor immunity [2]. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and PD-1 ligand (PD-L1) have emerged as key mediators and suppressors of cytotoxic T-cell function [104]. The CTLA-4 receptor regulates the amplitude of early activation of naïve and memory T-cells [104] evidenced by the significant immune toxicity observed in mice with knockout of this receptor. Several preclinical studies suggest that targeting CTLA-4 function may be an efficacious strategy for lung cancer strategy [105]. In a phase II clinical trial, ipilimumab, an antibody against CTLA-4, with chemotherapy was effective against squamous NSCLC [106, 107]. The PD-1 receptor and its ligand PD-L1 is an important pathway that functions to limit the activity of T-cells during an acute inflammatory response to infection and to limit autoimmunity as well [104]. T-cells with higher expression of PD-1 exhibit impaired immune function and cytokine production and proliferative capacities. Several studies have demonstrated that PD-L1 is up-regulated in different tumor types inhibiting local anti-tumor T-cell responses by binding to the T-cell PD-1 receptor [108, 109]. Moreover, PD-1 was found to be expressed on the majority of tumor infiltrating CD8 ⁺ lymphocytes, which was lower compared to that on T-cells of healthy controls [110]. Several preclinical studies in mice have demonstrated the usefulness of blocking the PD-1/PD-L1 pathway for cancer immunotherapy [104]. Targeting the PD-1/PD-L1 pathway is a promising strategy for the clinical management of patients with advanced lung cancer. In a recent phase-I clinical trial, a human IgG4-blocking monoclonal antibody directed against PD-1 (BMS-936558, nivolumab), was tested in 296 patients with advanced solid tumors (76 NSCLC patients) who had prior chemotherapy and targeted therapy [111]. Durable responses were observed in 18 % of NSCLC patients [111]. Importantly, the same study demonstrated that tumor immunohistochemical expression of the receptors ligand PD-L1 was significantly associated with objective responses as 36 % of patients with PD-L1 positive tumors exhibited an objective response [111]. A separate phase I clinical trial also tested an antibody directed against the PD-1 ligand PD-L1 in 75 advanced NSCLC patients [112]. Despite toxic effects observed in a fraction of patients, complete or partial responses were observed in approximately 10 % of NSCLC patients [112]. These significant findings provide strong proof for clinical relevance of reactivating the dampened antitumor immune response as a therapeutic strategy for lung cancer.