Tumor Microenvironment and Early-Stage Lung Cancer: Comparison
Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Paul Chiroi.

Lung cancer is the leading cause of cancer-related death worldwide, accounting for more than 1.8 million fatalities each year. It is also the second most frequent type of malignancy, with more than 2.2 million cases diagnosed annually. Recent advances in cancer biology and genomics research have the potential of revealing more biomarkers for diagnostic, prognostic, and targeted therapies. A new source of biomarkers are the non-coding RNAs, especially miRNAs. In this research article, we aimed to investigate the TME and miRNA tumor profile in a subset of 51 early-stage lung cancer samples to better understand early tumor and TME organization and molecular dysregulation. We analyzed the immunohistochemistry expression of CD4, CD8, E-cadherin, and p53. Starting from these 4 markers, we identified and validated 4 miRNAs that target TP53 and regulate EMT, which can be further investigated as potential early-stage lung cancer biomarkers.

  • early-stage lung cancer
  • tumor microenvironment
  • p53
  • E-cadherin
  • CD4
  • CD8
  • hsa-miR-25-3p
  • hsa-miR-29b-3p
  • hsa-miR-181a-5p
  • hsa-miR-205-5p

1. Introduction

Lung cancer is the leading cause of cancer-related death worldwide, accounting for more than 1.8 million fatalities each year. It is also the second most frequent type of malignancy, with more than 2.2 million cases diagnosed annually [1]. Lung cancers are broadly divided into two main histological groups: NSCLC, which accounts for 80–85% of all lung cancer cases, and SCLC, consisting of 10–15%. NSCLC can be further divided into three principal histological subtypes: lung adenocarcinomas (LUADs) (45–60% of cases), squamous cell carcinoma (LUSC) (20–25% of cases), and neuroendocrine carcinomas (NE LC) (10–15%) [1][2]. These histological types differ in terms of treatment approaches and overall survival (OS). NSCLC is the most studied type, with multiple targeted therapies available and with a 5-year OS rate of 23%, while SCLC is treated mainly with platinum-based chemotherapy and has a median survival time of less than 1 year [3][4]. This high mortality is due to late diagnosis and the paucity of effective screening regimens. Lung cancer detected in early-stage has a 5-year OS of up to 70% [5], highlighting the need for better early-stage biomarkers. Chest X-ray, computed tomography, magnetic resonance imaging, positron emission tomography, sputum analysis, and lung biopsy are all common clinical investigations currently used for identifying lung cancer. However, despite recent advances in cancer screening and diagnosis, 57% of all patients are detected only after the tumor has progressed to the metastatic stage. Under these circumstances, the remission chances are minimal, and the 5-year survival rate for metastatic lung cancer is less than 6% [6]. Therefore, identifying new methods for early-stage lung cancer detection is a central focus of cancer research. In this regard, understanding the alterations in the lung tumor microenvironment (TME) throughout the early stages of cancer evolution could be a viable avenue for biomarker discovery [7][8]. The main risk factor associated with lung cancer is tobacco smoking, which is responsible for about 80–90% of all lung cancer cases. It triggers an aggressive mutational burden, an increase in cytosine to adenine nucleotide transversions, and an enhancement in KRAS and TP53 mutations. KRAS mutations are the most common driver mutations, being present in about 35% of NSCLC cases [6]. TP53 is the most important tumor suppressor gene and is the target of multiple mutations early in lung cancer tumorigenesis, its alterations being present in more than 90% of SCLCs and 50% of NSCLCs [9][10][11]. Recent advances in cancer biology and genomics research have allowed us to characterize the mutational landscape of lung cancer, and, in recent years, next-generation sequencing (NGS) has become an essential tool for diagnosis and effective therapeutic management [9][10]. Improvements in the understanding of lung cancer genomics have led to the identification of major driver mutations genes, including EGFR, KRAS, ALK, BRAF, HER2, PIK3CA, AKT1, MAP2K1, and MET [12][13]. The identification of these mutations has led to major progress in therapy for LUAD patients, with the introduction of tyrosine kinase inhibitors and, more recently, KRAS G12C inhibitors [14][15][16]. The identification of these mutations changed clinical practice and pathological diagnosis. Nowadays, searching for driver mutations is mandatory for a complete and accurate diagnosis. From the early development of the lung cancer cellular niche, the tumor starts to organize a complex cellular and molecular habitat that is known as the TME. This entity consists of a complex stromal and cellular network of tumor cells, various normal and immune cell populations, and molecules trafficked in this environment [17]. The principal non-tumoral populations are represented by tumor-infiltrating lymphocytes (TILs), tumor-associated fibroblasts, tumor-associated macrophages, and endothelial progenitor cells [18]. This ecosystem is designed to support the tumor from its early development in acquiring the hallmarks of cancer and support its progression toward more advanced stages [19]. The interest in the restudyearch of TME increased with the introduction of anti-PD1/anti-PD-L1 and anti-CTLA4 immunotherapy. The introduction of immunotherapy managed to reactivate the dormant immune population from the environment and became a valuable resource in lung cancer therapy [20]. Currently, all major cellular components of the TME are being intensively studied to identify new targets that can enhance their antitumor activity [21]. Epithelial-to-mesenchymal transition (EMT) is a dynamic process that takes place early in lung cancer tumorigenesis, being an essential step for tumor cells to acquire invasive and metastatic potential [22][23]. The EMT phenotype was identified as early as stage IA in a cohort of LUAD patients. The presence of the mesenchymal phenotype, reduced E-cadherin and high Vimentin expression, was associated with shorter disease-free survival and reduced OS [24]. Additionally, circulating tumor cells, a marker of EMT, were shown to be detected as early as in situ stages of lung cancer in the blood of patients, supporting the early onset of EMT [25]. A better understanding of EMT in the early stages of cancer is essential for understanding tumor progression and for identifying the molecular mechanisms that can be modulated to limit progression and spread to distant sites [26]. NGS, including single-cell analysis, has been used in TME investigation [18][21][27][28]. These methods have shown promising results, highlighting the possible prognostic role of tumor-infiltrating lymphocytes (TILs) in lung cancer. Additionally, approaches that used immunohistochemistry (IHC) for specific TIL subpopulations revealed that the abundance of CD3, CD4, CD8, and FOXP3+ subpopulations can be used as an independent prognostic marker for patient outcome [18][29]. Another conceivable source of biomarkers is represented by the non-coding RNAs (ncRNAs), especially microRNAs (miRNAs); they are short (18–28 nucleotides long) ncRNA sequences found to be involved in the post-transcriptional regulation of gene expression. Thus, miRNAs are potent regulators of cell proliferation, differentiation, development, and apoptosis, among other cellular processes. Furthermore, these ncRNAs were also found involved in various malignancies, including lung cancer [30][31][32]. Moreover, under certain circumstances, miRNAs can act as oncogenes or tumor suppressors. Therefore, different cancer hallmarks, such as sustaining proliferative signals, evading growth suppressors, resisting cell death, activating invasion and metastasis, and initiating angiogenesis, have been linked to dysregulated miRNAs.

2. Tumor Microenvironment and Early-Stage Lung Cancer

2.1. Study design

Based on bioinformatics analysis using dysregulated genes in early-stage lung cancer, TME analysis, and literature search, wresearchers were able to identify 4 miRNAs (hsa-miR-29b-3p, hsa-miR-181a-5p, hsa-miR-25-3p, and hsa-miR-205-5p) that target the TP53 gene, modulate EMT pathway in lung cancer and have the potential of being used as a diagnostic panel for early-stage lung cancer.

WResearchers investigate a 4-miRNA panel for early-stage lung cancer diagnosis, consisting of two tumor suppressors and two tumor promoter miRNAs known for their roles in essential cancer regulatory processes, such as EMT, angiogenesis, metastasis, and clinical parameters such as response to therapy and OS.

In this restudy, weearch, researchers present a translational approach for biomarker identification in early-stage lung cancer. WeResearchers used a comprehensive characterization of the selected cases that included morphology, IHC, bioinformatics analysis, and investigation of specific miRNAs expression using qRT-PCR. WeResearchers included early-stage LUAD, LUSC, and NE LC to better understand lung cancer progression and TME organization in the early stages of carcinogenesis across the different histologic subtypes.

2.2. Discussions

WResearchers performed a translational analysis of the tumor and TME in early-stage lung cancer with the aim of identifying the main patterns of TME organization and tumor molecular alterations. The IHC profile of E cadherin and p53 markers allowed us to evaluate early phase EMT and the loss of the main tumor suppressor gene.

E-cadherin is a glycoprotein that plays an important morphogenetic role in epithelial cell stabilization by maintaining intercellular connections through calcium-dependent adhesion. Additionally, it regulates cancer cell differentiation and reduces cancer cells’ ability to spread beyond their local site. Thus, reduced or absent E-cadherin expression in several cancers is linked to impaired differentiation and enhanced metastatic capacity. Depletion of E-cadherin expression causes EMT, which enhances the metastatic potential. Deconstruction of cell polarity, cytoskeleton restructuration, and changes in signaling pathways all contribute to EMT, which increases motility and promotes metastasis by increasing cancer cell invasiveness, resulting in a poor prognosis [33]. EMT signature has also been inversely associated with T-cell infiltration in NSCLC [34][35]. In ouresearchers' cohort, the E-cadherin staining was present in all the investigated cases, but a difference in intensity was noted among samples, with 37.3% of cases having high-intensity staining and 62.7% of these samples expressing a moderate staining intensity. This loss of staining intensity can be interpreted as an early sign of EMT, as it was shown in recent years that EMT in lung cancer is a process that starts from the early stages [24].
P53 is a tumor suppressor protein that controls cell division and proliferation that has also been linked to early lung cancer carcinogenesis [36][37]. The presence of p53 IHC staining generally indicates a mutation in the TP53 gene [38]. In ouresearchers' series, p53 IHC was positive in 62.7% of the cases, supporting the importance of p53 mutation as an early-mutational event in early-stage lung cancer. Higher positivity rates were found in groups that included more advanced stages of lung cancer [39].
A critical element in lung cancer initiation and progression is represented by the organization of the TME, which takes place early in tumorigenesis [8][33][40]. Consequently, decoding the lung cancer-associated TME heterogeneity into a collection of prognostic, diagnostic, or predictive biomarkers has become an area of intensive research. Since then, several valuable findings have pinpointed the TME as a potential source for novel early-stage lung cancer biomarkers [8][37][41]. An important constituent at this level is represented by the immune cell populations, which are involved in the immune surveillance and tumor immune escape mechanisms. These two processes are in a dynamic equilibrium, with immune surveillance slowing tumor progression through tumor cell identification and suppression and progressing tumor immune escape by reducing the antitumor activity of the immune compartment as the tumor starts to produce inhibitory molecules and secrete cytokines [42][43]. Moreover, the TME-related immune signature has led to further investigations, especially in LUAD cases, where its diagnostic and prognostic role has been recently proposed [44]. In this regard, TILs play a significant role in the tumor immune milieu and can be a reliable early-stage biomarker [29][45][46]. Two of the most studied TILs that are believed to be associated with the early stages of lung cancer are CD4 and CD8 [47][48][49], commonly known for their important roles in the regulation of both antitumor and protumorigenic processes [50][51]. Using the IHC characterization of TILs, wresearchers found that CD4 lymphocytes were high and very high within the stromal compartment in 84.4% of the early-stage lung cancer cohort, while the CD8 cells were lower in abundance, showing a moderate and low abundance in 64.7% of the cases. Meanwhile, the intratumor compartment was scarce in TILs, with minor differences between CD4 and CD8 TILs. Therefore, ourresearchers' findings take usthem a step closer to validating the association between TILs (CD4/CD8) and early-stage tumorigenesis in lung cancer [18][49]. The presence of CD4 cells was correlated with hsa-miR-181a expression, as indicated by the in silico analysis and further validated on the TCGA dataset and ouresearchers' tumor samples. The tumor suppressor hsa-miR-181a was upregulated in the adjacent normal tumoral tissue, which contains the cellular elements of the TME, and downregulated at the tumoral level.
The immune cell populations in the TME were shown to be organized in cellular aggregates that resemble secondary lymphoid organs in morphology and their composition being commonly defined as TLS. Moreover, histologically, these structures were shown to become phenotypically active when they start to develop germinal centers [52]. These structures are partially involved in mediating the host immune response, becoming a subject of interest in the study of TME [53][54]. In early-stage lung cancer, TLS were shown to actively drive the immune response against tumor cells, which is generally considered a sign of active tumor immunity and positive prognosis [49][55][56][57]. In ouresearchers' group, TLS were present in 74.5% of the early-stage lung cancer cases, and among these, 34.2% of cases with TLS showed the presence of active germinal centers. LUADs showed a higher presence of active germinal centers, suggesting they are more immunologically active compared with LUSCs and NE LCs.
In the past decade, ourthe understanding of cancer biology has quantitatively and qualitatively increased, due to the intensive genomic studies, especially regarding the roles of miRNAs in human cancers [58][59]. Different cancers have different miRNA expression levels, distinctive from those within normal tissues. Thus, abnormal miRNA expression patterns have been oftentimes considered a crucial carcinogenesis marker and may have the potential of becoming novel biomarkers for minimally invasive, early-stage lung diagnosis [50][60].


We present an in-depth characterization of the TME in a cohort of 51 early-stage lung cancer patients. Our analysis showed that these tumors are immunologic-active tumors that present a moderate-to-high inflammatory TME in 80.4% of the cases and that the inflammatory infiltrate is localized in the stromal compartment, where the TLS were also found in 74.5% of the cases. The main component of the TME is represented by CD4 cells, which are the most abundant cellular population. The abundance of CD4 cells was associated with a higher expression of hsa-miR-181a-5p in the adjacent normal tissue. The intratumor compartment is scarce in TILs, and a minor increase in CD8 cells is seen at this level.

In this study, we investigated a 4-miRNA panel consisting of two tumor suppressors and two oncomiRs that were altered in early-stage lung cancer tumors compared with the adjacent normal tissue. Among them, has-miR-181a-5p was found consistently downregulated in all lung cancer tumor types. Tumor suppressor miRhashsa-miR-29b-3p, down-regulated in advanced lung cancer, was upregulated in our early-stage lung cancer cohort, suggesting that its silencing occurs as a later event. A novel finding is represented by the upregulation of tumor suppressor miRNAs hsa-miR-29b-3p and hsa-miR-181a-5p in the p53 IHC-positive tumors.

The current diagnostic and therapeutic approaches in lung cancer care face major limitations that prevent early detection and effective treatment of these tumors. Therefore, an integrated approach to this heterogeneous pathology, including histology and molecular pathology, can allow us to assemble different pieces of the same puzzle in the quest for novel biomarkers and therapeutic target identification.


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