Lung Adenocarcinoma and Squamous Cell Carcinoma Gene Expression Subtypes Demonstrate Significant Differences in Tumor Immune Landscape

Faruki, Hawazin; Mayhew, Gregory M.; Serody, Jonathan S.; Hayes, D. Neil; Perou, Charles M.; Lai-Goldman, Myla

doi:10.1016/j.jtho.2017.03.010

Cited by 134 publications

(140 citation statements)

References 33 publications

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“…We here observed that LUSC seems to be immune-compromised with a signature of massive down-regulation of the complement cascade and other key genes for native immune response. Our results nicely fit within the recent scenario of overall difference in tumor immune landscape in LUAD and LUSC [61].…”

Section: Discussionsupporting

confidence: 90%

Different molecular signatures in lung cancer types from integrative bioinformatic analyses of RNASeq data

Lucchetta

Piedade

Mounir

et al. 2018

Preprint

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BackgroundGenomic initiatives such as The Cancer Genome Atlas (TCGA) project contain data on profiling of thousands of tumors with different-omics approaches, providing a valuable source of information which may be used to decipher cancer signaling and related alterations. Managing and analyzing data from large-scale projects such as TCGA is a demanding task. Indeed, it is difficult to dissect the high complexity hidden in genomic data and to adequately account for tumor heterogeneity.ResultsIn this study, we used a robust statistical framework along with the integration of diverse bioinformatic tools to analyze next-generation sequencing data from more than 1000 patient samples from two different lung cancer subtypes, i.e., the lung adenocarcinoma (LUAD) and the squamous cell carcinoma (LUSC). In particular, we used RNA-Seq gene expression data to identify both co-expression modules and differentially expressed genes to accurately discriminate between LUAD and LUSC. Moreover, we identified a group of genes which could act as specific oncogenes or tumor suppressor genes in one of the two lung cancer types, as well as two dual role genes. Our results have also been cross-validated against other transcriptomics data of lung cancer patients.ConclusionsOur integrative approach allowed to identify two key features: a substantial up-regulation of genes involved in O-glycosylation of mucins in LUAD, and a compromised immune response in LUSC. The immune-profile associated with LUSC is linked to the activation of three specific oncogenic pathways which promote the evasion of antitumor immune response, providing new future directions for the design of target therapies.

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Section: Discussionsupporting

confidence: 90%

Different molecular signatures in lung cancer types from integrative bioinformatic analyses of RNASeq data

Lucchetta

Piedade

Mounir

et al. 2018

Preprint

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“…In expression subtypes, earlier findings of more immunological activity in the AD TRU and PI expression subtypes and the SCC secretory expression subtype were confirmed (Faruki et al ., ). In AD, all expression subtypes showed higher estimates of the three T effector cells Th1 cells, Th2 cells, and Tgd cells compared to normal lung.…”

Section: Discussionmentioning

confidence: 99%

The immune microenvironment in non‐small cell lung cancer is predictive of prognosis after surgery

et al. 2019

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The impact of the tumor immune microenvironment on overall survival in non‐small cell lung cancer ( NSCLC ) has been studied, but there is little information on its relevance for risk of relapse after surgery. Understanding more about the immune microenvironment in previously untreated NSCLC could help in identifying high‐risk patients and patients more likely to benefit from neoadjuvant/adjuvant immunotherapy. Here, we examined gene expression in 399 surgically derived NSCLC samples and 47 samples from normal lung, using Agilent microarray and RNA sequencing. In 335 of the tumor samples, programmed death‐ligand 1 ( PD ‐L1) expression was evaluated by immunohistochemistry. Gene expression was used to estimate content of immune cells and to calculate an immune score. Properties of the immune microenvironment, and its impact on prognosis, were compared in histological subgroups and gene expression subtypes. Tumors with an active immune microenvironment were found for both adenocarcinomas ( AD ) and squamous cell carcinomas ( SCC ). In AD , high immune score and high estimates of several immune cell types belonging to the adaptive immune system were associated with better progression‐free survival ( PFS ), while in SCC , no association between immune characteristics and PFS was found. The immune microenvironment, including PD ‐L1 expression, and its impact on prognosis showed clear differences in AD and SCC gene expression subtypes. In conclusion, the NSCLC immune microenvironment is predictive of prognosis after surgery. Lung AD and SCC gene expression subtypes should be investigated as potential prognostic biomarkers in patients treated with immune checkpoint inhibitors.

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“…Comparison of expression between subtypes was performed using Kruskal-Wallis ANOVA. Immune signatures were calculated as previously described (30)(31)(32).…”

Section: Bioinformaticsmentioning

confidence: 99%

Antibody Targeting of B7-H4 Enhances the Immune Response in Urothelial Carcinoma

Podojil¹,

Glaser

Baker

et al. 2019

Preprint

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AbstractLocally advanced urothelial carcinoma has a poor survival despite a response to immunotherapy in approximately 25% of patients. To develop new therapies targeting other immune checkpoints, we identified increased expression of the T cell inhibitor protein, B7-H4 (VTCN1, B7S1, B7X), during tumor development of murine bladder cancer. Evaluation of B7-H4 in human bladder cancer by single-cell RNA-Seq and immune mass cytometry showed that B7-H4 is expressed by luminal tumors that are not normally responsive to PD-1 inhibitors. Additionally, overexpression B7-H4 was associated with significantly worse patient survival. In support of clinical translation, treatment of human monocyte and T cell co-cultures with a B7-H4 blocking antibody resulted in enhanced IFN-γ secretion by CD4+ and CD8+ T cell. While the study of B7-H4 in mouse cancer models has been difficult using tumor cell lines, our findings show that B7-H4 expression increased at 3 months after exposure to BBN on CD11b+ monocytes/macrophages and delivery of anti-B7-H4 antibody resulted in decreased tumor size and increased CD8 immune cell infiltration with increased CD8+/IFN-γ-producing T cells and a complimentary decrease in tumor infiltrating T regulatory cells (Tregs). Furthermore, treatment with a combination of anti-PD-1 and anti-B7-H4 antibodies resulted in a significant reduction in tumor stage. This data suggests that novel anti-B7-H4 antibodies maybe a viable target for bladder cancers unresponsive to PD-1 checkpoint inhibitors.

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Lung Adenocarcinoma and Squamous Cell Carcinoma Gene Expression Subtypes Demonstrate Significant Differences in Tumor Immune Landscape

Abstract: Molecular expression subtypes of lung AD and SCC demonstrate key and reproducible differences in immune host response. Evaluation of tumor expression subtypes as potential biomarkers for immunotherapy should be investigated.

Cited by 134 publications

References 33 publications

Different molecular signatures in lung cancer types from integrative bioinformatic analyses of RNASeq data

Different molecular signatures in lung cancer types from integrative bioinformatic analyses of RNASeq data

The immune microenvironment in non‐small cell lung cancer is predictive of prognosis after surgery

Antibody Targeting of B7-H4 Enhances the Immune Response in Urothelial Carcinoma

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