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Immunotherapy in non-small cell lung cancer: the clinical impact of immune response and targeting.

ABSTRACT: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. In recent years, through a better understanding of the interactions between the immune system and tumor cells (TC), immunotherapy has emerged as a promising therapeutic strategy. Chemotherapy has long been reported to interfere with the immune response to the tumor and conversely, anti-tumor immunity may add to those effects. Anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, tumor cell vaccines and dendritic cell (DC) vaccines emerged as potent inducers of the immune response against the tumor. More recently the approval of the anti-programmed cell death 1 (anti-PD-1) monoclonal antibodies nivolumab and pembrolizumab for previously treated advanced squamous and non-squamous NSCLC, as well as other immune checkpoint inhibitors delivering promising results, has radically transformed the therapeutic landscape of NSCLC. Combination strategies now appear as the next step. Notwithstanding these successes, immunotherapy still holds significant drawbacks and currently several improvements are needed before routine use in clinical practice, including identification of robust biomarkers for optimal patient selection, as well as defining the best way to evaluate response.

SUBMITTER: Mountzios G

PROVIDER: S-EPMC4971380 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Immunotherapy in non-small cell lung cancer: the clinical impact of immune response and targeting.

Mountzios Giannis G Linardou Helena H Kosmidis Paris P

Annals of translational medicine 20160701 14

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. In recent years, through a better understanding of the interactions between the immune system and tumor cells (TC), immunotherapy has emerged as a promising therapeutic strategy. Chemotherapy has long been reported to interfere with the immune response to the tumor and conversely, anti-tumor immunity may add to those effects. Anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, tumor cel ...[more]

PMID: 27563655

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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 introduction of immune checkpoint inhibitor (ICI)-based therapy for non-oncogene addicted non-small cell lung cancer (NSCLC) has significantly transformed the treatment landscape of the disease. Inhibitors of the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint axis, which were initially considered as a late-line treatment option, gradually became the standard of care as first-line treatment for subgroups of NSCLC patients. However, a significant fraction of patients either fails to respond or progresses after a partial response to ICI treatment. Thus, the identification of mechanisms responsible for innate and acquired resistance to immunotherapy within a rapidly evolving tumor microenvironment (TME) is urgently required, as is the identification of reliable predictive biomarkers beyond PD-L1 expression. The deregulation of the epigenome is a key driver of cancer initiation and progression, and it has also been shown to drive therapeutic resistance. Tumor education of infiltrating myeloid cells towards an immuno-suppressive phenotype as well as induction of T-cell dysfunction in the TME is also driven by epigenome reprogramming. As it stands and, given their dynamic nature, epigenetic changes in cancer and non-cancer cells represent an attractive target to increase immunotherapy activity in NSCLC. Accordingly, clinical trials of combinatorial immuno-epigenetic drug regimens have been associated with tumor response in previously immunotherapy-resistant NSCLC patients irrespective of their PD-L1 status. Moreover, epigenetic signatures might represent valuable theragnostic biomarkers as they can be assayed easily in liquid biopsy and provide multiple layers of information. In this review, we discuss the current knowledge regarding the dysregulated epigenetic mechanisms contributing to immunotherapy resistance in NSCLC. Although the clinical data are still maturing, we highlight the attractive perspective that the synergistic model of immuno-epigenetic strategies might overcome the current limitations of immunotherapy alone and will be translated into durable clinical benefit for a broader NSCLC population.

Dataset Information

Immunotherapy in non-small cell lung cancer: the clinical impact of immune response and targeting.

Publications

Immunotherapy in non-small cell lung cancer: the clinical impact of immune response and targeting.

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