Abstract
The tumor microenvironment consists of an intricately organized system through which immune cells and cancer cells may communicate to regulate anti-tumor immunogenicity. To this end, non-small cell lung cancer (NSCLC) has been shown to activate a variety of immunological mechanisms, thereby broadening our understanding of lung cancer immunobiology. However, while recent work has highlighted the importance of NSCLC immunology and prognosis, studies have not yet examined the tumor microenvironment (TME) globally in regards to the survival outcomes between two major NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). In the present study, we identify an immunogenic tumor microenvironment state in NSCLC that is enriched for the lung adenocarcinoma subtype. By utilizing TME cell enrichment scores and RNA-seq expression data, we show that the inflamed TME is associated with favorable patient survival in lung adenocarcinoma, but this does not hold true for lung squamous cell carcinoma. Moreover, differentially regulated pathways between immune-inflamed and immune-excluded tumors within LUAD and LUSC were not subtype specific. Instead, immune-inflamed LUSC samples possessed elevated immune checkpoint marker expression when compared to those of the LUAD samples, thereby offering a putative explanation for our prognostic observations. These results shed light on the immunological prognostic effects within lung cancer and may encourage further TME exploration between these two subtypes as the landscape of NSCLC therapy progresses.
Highlights
Lung cancer is the leading cause of cancer-related deaths [1], non-small cell lung cancer (NSCLC) immunotherapy has emerged as a relatively promising area of research
By utilizing tumor microenvironment (TME) cell enrichment scores and RNA-seq expression data, we show that the inflamed TME is associated with favorable patient survival in lung adenocarcinoma, but this does not hold true for lung squamous cell carcinoma
In order to determine whether the clusters produced were indicative of immunogenic TMEs, we examined gene expression levels of several immunogenic activation markers between cluster1 and cluster2, namely CD8A, PRF1, HLA-A, and GZMA, which are shown to be favorably expressed in immunogenic tumors [4, 5, 17,18,19,20,21]
Summary
Lung cancer is the leading cause of cancer-related deaths [1], non-small cell lung cancer (NSCLC) immunotherapy has emerged as a relatively promising area of research. Much work remains to elucidate lung tumor immunobiology and how alternative tumor microenvironments (TME) can affect patient survival across different NSCLC subtypes. The TME has surfaced as a fascinating area of study across various tumor types [3]. Immune-inflamed TMEs (‘hot’ tumors) express high levels of cytotoxic lymphocytes and immune activation markers (e.g., CD8, PRF1) [3,4,5]. Tumors with this TME subtype are often associated with a favorable prognosis [6]. Patients with immuneexcluded TMEs (‘cold’ tumors) exhibit the opposite trend in survival [3, 6,7,8]. Recent work has encouraged further prognostic analysis of the TME to better understand the immune, stromal, and cancer signals that are integral to the clinical aftermath of this highly complex environment
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