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1. Introduction

The World Health Organization (WHO) estimated 1.76 million deaths caused by non-small cell lung cancer (NSCLC) in 2018. Lung cancer represents the leading cause of deaths worldwide with NSCLC representing approximately 85% of all lung malignancies [1]. Despite substantial improvements in therapy, 5-year overall survival (OS) for NSCLC does not exceed 25% ^[2][3][2,3]. Prognosis and survival of patients affected by NSCLC are correlated to disease stage, with OS being prognostically favorable by earlier diagnosis and treatment ^[4][5][4,5]. Nevertheless, a significant percent of patients are diagnosed in advanced stage with little chance to be cured.

Chronic inflammation plays a key role in tumorigenesis of NSCLC [6]. Inflammatory factors like cigarette smoking are associated with chronic bronchitis and emphysema, which lead to the development of lung cancer [7]. The process of cellular malignant transformation consists of many steps over long time periods, ranging from pre-carcinogenic chronic inflammation, progressing, if not treated, towards the development of invasive carcinoma and systemic disease ^[8][9][10][8–10]. Some chronically inflamed pre-carcinogenic environments will never result in malignant cell transformation, while others exposed to the same carcinogen will undergo tumorigenesis. This uncertainty of initiating tumorigenesis events highlights the malignant “modulating” role of genetic predisposition in cancer [11] and underscores that inflammation may assist in this process. The profile and status of the inflammatory-changed environment following the chronic carcinogen(s) exposure is exceedingly variable, and its potential for malignant transformation is related to polymorphic immune response genes affected by a diversity of anti-oxidant and DNA repair associated genes [11]. The immune system, in its cell-mediated and humoral form, is deeply involved in generation of an inflammatory environment and is considered to be the first step of tumorigenesis. Chronic exposure of normal cells to carcinogen(s) leads to initiation of immune cell activation with subsequent upregulation of the pro-inflammatory cytokines like Interleukin-1 alpha (IL-1α) and IL-1-β, and production of Cyclooxygenase (COX)-1 and COX-2 immune-regulatory enzymes in epithelial and mesenchymal. This activation of the inflammatory pathways is associated with the development of malignant disease ^{[12][13][14][15]}[12–15]. Additionally, the induction of COX-2 favors increased angiogenesis in an inflammatory environment and helps pave the way for hyper-vascularization needed for tumor development and progression ^[16][17][18][16–18].

In addition to assisting tumorigenesis, the immune system also plays a fundamental role in the defense against cancer by surveillance and identification of foreign or “non-self” from self and assisting with elimination of DNA-damaged cancer cells from the body. However, tumor cells can escape by suppressing the immune system. Furthermore, therapies, especially if they cause immune-suppression, may further aid the escape of the tumor cells from the immune system. Most patients with NSCLC will eventually require radiotherapy (RT) alone (especially those that are medically inoperable) or in combination with systemic therapy (especially those with advanced stage disease). Regardless, there are many reports that show that conventional RT induces an immunosuppression, and thereby can negatively affect the overall survival ^{[19][20][21][22]}[19–22]. Thus, the current immunogenic balance, determined by the inhibitory effects caused by tumor cells themselves and radiation therapy can lead to poor clinical outcomes. There is newer emerging evidence suggesting that immunosuppression is an “elastic process” that can be transformed into an immune-stimulating environment by “correcting” many manipulable components of this triangle radiation, tumor, and immune cells by using combination approaches that change the way RT, chemotherapy, and immunotherapy are used. Significant efforts are being deployed in the development of novel treatment strategies and protocols aimed to convert radiation- and tumor-induced immunosuppression into a predominant immunostimulation by means of immunotherapy, unconventional RT and the combination of these modalities in order to improve the outcomes of NSCLC patients.

2. Tumor-Related Immune Suppression in NSCLC

The interplay between the tumor and immune cells is the subject of an extended and ongoing research. Table 1 represents latest evidence on tumor-related immunosuppressive effects ^{[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56]}[23–56]. Tumor cells escape immune surveillance by downregulation of HLA and co-stimulatory molecules, or by production of immunosuppressive factors and upregulation of immune cell apoptosis inducing molecules ^{[23][24][25][26]}[23–26]. As a consequence, the immune system will “ignore and tolerate” tumor cell proliferation and progression. The presence of tumor-infiltrating lymphocytes (TIL) in cancer cell nests is an independent prognostic factor of survival in various types of cancers including NSCLC [57], and if used properly, could be used to help convert immune cells to fight against cancer. The inefficiency of the immune response against tumor is inversely proportional to tumor growth, being weaker in larger tumors and stronger in smaller tumors [58]. There is a gap in the current knowledge and understanding of the mechanisms behind the immune response against NSCLC, and additional attention to these mechanisms are needed if we are to improve the outcome of patients in the future.

Table 1. Tumor-related immunosuppressive effects.

Abbreviations: Non-small cell lung cancer (NSCLC), Major Histocompatibility Complex (MHC), Cytotoxic T-Lymphocyte-associated Protein-4 (CTLA-4), Programmed Death-Ligand 1 (PD-L1), Vascular Endothelial Growth Factor (VEGF), Prostaglandin E2 (PGE2), Tumor Growth Factor beta (TGF-β), Interleukin-10 (IL-10), Adenosine triphosphate (ATP), Adenosine diphosphate (ADP), Adenosine monophosphate (AMP).

The currently available data comes from peripheral blood or surgically removed NSCLC tumor tissue, with the latter being limited to less than a third of operable NSCLC patients. The vast majority of the patients have an unresectable disease or are inoperable and undergo radio/chemotherapy, and therefore NSCLC tumor tissue in these advanced stage patients is typically unavailable for detailed immunological analysis. However, based on the limited histological and immunological analysis obtained from the available tissue, the main components of a tumor-directed immune response are represented by a complex interaction between various immune cells operating a composite cytokine network that is supported by the surrounding mesenchymal, epithelial and endothelial cells. The immune cells are a large, highly cooperative family consisting of tumor infiltrating lymphocytes (TILs), the tumor associated macrophages (TAMs), the tumor associated neutrophils (TANs), tissue eosinophilia, and T-cell lymphocytes ^{[59][60][61][62][63][64]}[59–64]. The lung anti-tumor immune response is imitated by activation of the pulmonary antigen presenting cells (APCs), represented by macrophages and dendritic cells [65]. This is a fundamental step towards the beginning of an effective anti-tumor immune response. Following tumor antigen(s) recognition and distinguishing “self” from “non-self”, the APCs migrate to the regional lymph nodes and activate the effector immune cells that aid in destruction of tumor cells. These effector immune cells, also known as cytotoxic lymphocytes, include the CD4+ lymphocytes, natural killers, natural killer T-cells, CD8+ lymphocytes and B lymphocytes ^[66][67][68][66–68]. The activation of these cells are enhanced by the secretion of inflammatory cytokines such as IL-12 and Interferon gamma (IFN-γ). These cytokines are released by the activated macrophages, growing tumor cells, and stromal cells surrounding the tumor. Additionally, membrane-receptor induction of programmed death by the cytotoxic lymphocytes also aids cytokine release and apoptosis of tumor cells [69], as the final coordinate anti-tumor response.

For the purpose of effective antigen presentation, a critical role is played by interaction between co-stimulating molecules on antigen-presenting cells and corresponding receptors on cytotoxic lymphocyte [70]. One mechanisms of immune suppression that tumor cells use, are to block this antigen/cytotoxic lymphocyte interaction and prevent the cytotoxic lymphocytes from getting activated against the tumor (Table 1). Several additional tumor-related factors and mechanisms that result in immune suppression have also been described. One of those involved is alterations in signal transduction molecules on effector T-cells leading to the lack of tumor antigen recognition and missing anti-tumor immune response [71]. In this case, increased tumor-related anti-inflammatory humoral factors like IL-10 or Tumor Growth Factor-beta (TGF-β) induce the loss of signal transducer CD3-ε chain (CD3-ε) in TIL. With that, the signaling pathway for T-cell activation is inhibited, the immune response cannot be initiated and results in immunosuppression.

Alteration of CD3-ε, which is involved in tumor-induced T-cell apoptosis, leads to tumor induced caspase-dependent apoptosis in high proportion of tumor infiltrating T-lymphocytes ^[72][73][72,73]. Further, tumor escapes immune control through the process of immune editing, having as the target the loco-regional tumor microenvironment (TME). Several different tumor-related soluble molecules are involved in this form of immunosuppression: Vascular Endothelial Growth Factor (VEGF), Prostaglandin E2, TGF-β, IL-10, soluble phosphatidylserine, MICA Fas and FasL100 ^{[27][28][29][30][31][32][33][34]}[27–34]. Their immunosuppressive effects include inactivation of dendritic cells and T-cells, inhibition of Fas-mediated and NKG2D-mediated killing of immune cells, and release of anti-inflammatory mediators such as IL-10 and TGF-β that inhibit dendritic cells and T-cells ^{[35][36][37][38]}[35–38]. All those effects promote metastatic spread and progression in NSCLC patients ^[74][75][74,75].

Finally, the stromal cells from the TME also exhibit an important immunosuppressive role through modulation and binding of tumor antigens. By binding tumor antigens, these cells compete with the antigen-presenting cells so that many tumor antigens will be down-regulated, resulting in immunosuppression and tumor progression ^[76][77][78][76–78]. By increasing interstitial fluid pressure in the tumor, stromal cells will make significant quantity of tumor antigens to be unavailable and therefore, ignored by T-cells [79]. Besides the tumor and the TME causing immune-suppression, therapies such as convention RT and chemotherapy can also lead to additional immune suppression.

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