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Lung Cancer Subtypes Generate Unique Immune Responses.

ABSTRACT: Lung cancer, the leading cause of cancer-related deaths worldwide, is a heterogeneous disease comprising multiple histologic subtypes that harbor disparate mutational profiles. Immune-based therapies have shown initial promise in the treatment of lung cancer patients but are limited by low overall response rates. We sought to determine whether the host immune response to lung cancer is dictated, at least in part, by histologic and genetic differences, because such correlations would have important clinical ramifications. Using mouse models of lung cancer, we show that small cell lung cancer (SCLC) and lung adenocarcinoma (ADCA) exhibit unique immune cell composition of the tumor microenvironment. The total leukocyte content was markedly reduced in SCLC compared with lung ADCA, which was validated in human lung cancer specimens. We further identified key differences in immune cell content using three models of lung ADCA driven by mutations in Kras, p53, and Egfr Although Egfr-mutant cancers displayed robust myeloid cell recruitment, they failed to mount a CD8+ immune response. In contrast, Kras-mutant tumors displayed significant expansion of multiple immune cell types, including CD8+ cells, regulatory T cells, IL-17A-producing lymphocytes, and myeloid cells. A human tissue microarray annotated for KRAS and EGFR mutations validated the finding of reduced CD8+ content in human lung ADCA. Taken together, these findings establish a strong foundational knowledge of the immune cell contexture of lung ADCA and SCLC and suggest that molecular and histological traits shape the host immune response to cancer.

SUBMITTER: Busch SE

PROVIDER: S-EPMC5116260 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Lung Cancer Subtypes Generate Unique Immune Responses.

Busch Stephanie E SE Hanke Mark L ML Kargl Julia J Metz Heather E HE MacPherson David D Houghton A McGarry AM

Journal of immunology (Baltimore, Md. : 1950) 20161031 11

Lung cancer, the leading cause of cancer-related deaths worldwide, is a heterogeneous disease comprising multiple histologic subtypes that harbor disparate mutational profiles. Immune-based therapies have shown initial promise in the treatment of lung cancer patients but are limited by low overall response rates. We sought to determine whether the host immune response to lung cancer is dictated, at least in part, by histologic and genetic differences, because such correlations would have importa ...[more]

PMID: 27799309

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Project description:Lung cancer (LC) is one of the most frequently diagnosed cancers and the leading cause of cancer death worldwide, and most LCs are non-small cell lung cancer (NSCLC). Radiotherapy is one of the most effective treatments for patients with lung cancer, either alone or in combination with other treatment methods. However, radiotherapy responses vary considerably among NSCLC patients. The efficacy of radiotherapy is influenced by several factors, among which autophagy is of importance. Autophagy is induced by radiotherapy and also influences cell responses to radiation. We explored the clinical significance of autophagy-related genes (ARGs) and gene sets (ARGSs) and the underlying mechanism in NSCLC patients treated with radiotherapy. First, differentially expressed ARGs (SNCA, SESN3, DAPL1, and ELAPOR1) and miRNAs (miR-205-5p, miR-26a-1-3p, miR-6510-3p, miR-194-3p, miR-215-5p, and miR-375-3p) were identified between radiotherapy-resistant and radiotherapy-sensitive groups. An autophagy-related radiosensitivity risk signature (ARRS) by nine ARmRNAs/miRNAs and an autophagy-related overall survival risk signature (AROS) by three ARmRNAs were then constructed with estimated AUCs of 0.8854 (95% CI: 0.8131-0.9576) and 0.7901 (95% CI: 0.7168-0.8685), respectively. The correlations between ARGSs or prognostic signatures and clinicopathological factors, short-term radiotherapy responses (radiotherapy sensitivity), long-term radiotherapy responses (overall survival), and immune characteristics were analyzed. Both ARGSs and prognostic signatures were related to immune checkpoint inhibitors (ICIs), infiltration of tumor-infiltrating immune cells (TIICs), and the activity of the cancer immune cycle. Finally, after target prediction and correlation analysis, circRNA (hsa_circ_0019709, hsa_circ_0081983, hsa_circ_0112354, hsa_circ_0040569, hsa_circ_0135500, and hsa_circ_0098966)-regulated miRNA/ARmRNA axes (miR-194-3p/SESN3, miR-205-5p/ELAPOR1, and miR-26a-1-3p/SNCA) were considered potential modulatory mechanisms by influencing the regulation of autophagy, macroautophagy, and chaperone-mediated autophagy.

Project description:BackgroundNon-small cell lung cancer (NSCLC) was usually associated with poor prognosis and invalid therapeutical response to immunotherapy due to biological heterogeneity. It is urgent to screen reliable biomarkers, especially immunotherapy-associated biomarkers, that can predict outcomes of these patients.MethodsGene expression profiles of 1026 NSCLC patients were collected from The Cancer Genome Atlas (TCGA) datasets with their corresponding clinical and somatic mutation data. Based on immune infiltration scores, molecular clustering classification was performed to identify immune subtypes in NSCLC. After the functional enrichment analysis of subtypes, hub genes were further screened using univariate Cox, Lasso, and multivariate Cox regression analysis, and the risk score was defined to construct the prognostic model. Other microarray data and corresponding clinical information of 603 NSCLC patients from the GEO datasets were applied to conduct random forest models for the prognosis of NSCLC with 100 runs of cross-validation. Finally, external datasets with immunotherapy and chemotherapy were further applied to explore the significance of risk-scores in clinical immunotherapy response for NSCLC patients.ResultsCompared with Subtype-B, the Subtype-A, associated with better outcomes, was characterized by significantly higher stromal and immune scores, T lymphocytes infiltration scores and up-regulation of immunotherapy markers. In addition, we found and validated an eleven -gene signatures for better application of distinguishing high- and low-risk NSCLC patients and predict patients' prognosis and therapeutical response to immunotherapy. Furthermore, combined with other clinical characteristics based on multivariate Cox regression analysis, we successfully constructed and validated a nomogram to effectively predict the survival rate of NSCLC patients. External immunotherapy and chemotherapy cohorts validated the patients with higher risk-scores exhibited significant therapeutic response and clinical benefits.ConclusionThese results demonstrated the immunological and prognostic heterogeneity within NSCLC and provided a new clinical application in predicting the prognosis and benefits of immunotherapy for the disease.

Project description:The magnitude of the immune response is closely associated with clinical outcome in patients with cancer. However, finding potential therapeutic targets for lung cancer in the immune system remains challenging. Here, we constructed a vital immune-prognosis genes (VIPGs) based cluster of lung adenocarcinoma (LUAD) from IMMPORT databases and The Cancer Genome Atlas. A transcription factor regulatory network for the VIPGs was also established. The tumor microenvironment of LUAD was analyzed using the ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) algorithm and single-sample Gene Set Enrichment Analysis. The immune checkpoints and genomic alterations were explored in the different immune clusters. We identified 15 VIPGs for patients with LUAD and clustered the patients into low-immunity and high-immunity subtypes. The immune score, stromal score and ESTIMATE score were significantly higher in the high-immunity subtype, whereas tumor purity was higher in the low-immunity subtype. In addition, the immune checkpoints cytotoxic T lymphocyte associate protein-4(CTLA4), programmed cell death protein-1 and programmed death-ligand were elevated in the low-immunity subtype. The genomic results also showed that the tumor mutation burden was higher in the high-immunity subtype. Finally, Gene Set Enrichment Analysis showed that several immune-related gene sets, including interleukin-2/STAT5 signaling, inflammatory response, interleukin-6/Janus kinase(JAK)/signal transducer and activator of transcription 3 (STAT3) signaling, interferon-gamma response and allograft rejection, were elevated in the high-immunity subtype. Finally, high-immunity patients exhibited greater overall and disease-specific survival outcome compared with low-immunity patients (log rank P = 0.013 and P = 0.0097). Altogether, here we have identified 15 immune-prognosis genes and a potential immune subtype for patients with LUAD, which may provide new insights into the prognosis and treatment of LUAD.

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Lung Cancer Subtypes Generate Unique Immune Responses.

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Lung Cancer Subtypes Generate Unique Immune Responses.

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