Immunotherapy in Non-Small-Cell Lung Cancer: from Targeted Molecules to Resistance Patterns

Brassart‐Pasco, Sylvie; Dalstein, Véronique; Brassart, Bertrand; Dewolf, Maxime; Oudart, Jean‐Baptiste

doi:10.2217/pgs-2020-0021

Cited by 7 publications

(2 citation statements)

References 91 publications

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“…[ 4 , 5 ] The reason is that the existing immune escape theory and its clinical application focus on a single immune checkpoint corresponding to T cells in the adaptive immune system, and it is difficult to cope with the extensive heterogeneity and complex carcinogenic mechanism of NSCLC. [ 6 ] Therefore, new immune escape theories and immunotherapy methods need to be explored and applied urgently.…”

Section: Introductionmentioning

confidence: 99%

A comprehensive bioinformatics analysis of FOXP3 in nonsmall cell lung cancer

Zhu

Chen

et al. 2022

Medicine

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Fork head box p3 (FOXP3), the specific transcription factors of Tregs, not only in Tregs, but also expressed in cancer cells of certain malignant tumors. The histological positioning of FOXP3 in nonsmall cell lung cancer (NSCLC) and its biological significance are still unclear. This study aims to clarify the biological function of FOXP3 in NSCLC through bioinformatics analysis. Tumor immune estimation resource database was used to analyze the mRNA expression of FOXP3 in pan cancer, and to analyze the correlation between FOXP3 expression and tumor microenvironment cell infiltration. Overall survival and disease-free survival analyses were performed using a Kaplan–Meier plotter. Immunohistochemistry staining of FOXP3 was performed using human protein atalas (HPA) database, and immunofluorescence (IF) staining was used to verify gene expression and identify cell types. Protein–protein interaction (PPI) networks were drawn using STRING and visualized by Cytoscape. The functional and pathway enrichment analysis of FOXP3 used the DAVID database. In NSCLC, whether it is lung squamous cell carcinoma (P < .001) or lung adenocarcinoma (P < .001), FOXP3 is highly expressed in cancer tissue compared with normal tissue. Immunohistochemistry results showed that FOXP3 was mainly expressed in Tregs, but not in lung cancer tissues. IF staining showed that FOXP3 and CD3 (a marker of T cells) were co-expressed in immune cells. Moreover, survival analysis showed that high FOXP3 expression could be used as a predictor of poor overall survival (HR: 1.25, P = .00065) and disease-free survival (HR: 1.88, P = 1.1E-10) in patients with NSCLC. Next, we identified an important module containing 11 genes in the PPI network, including JUN, NFATC, STAT3, IRF4, IL2, IFGN, CTLA4, TNFRSF18, IL2A, KAT5, and FOXP3. KEGG signaling pathway was enriched in T cell receptor signaling pathway, Jak-STAT signaling pathway, cytokine–cytokine receptor interaction. Finally, we observed that FOXP3 expression correlated with infiltration of CD8 + T cells (R = 0.276, P = 5.90E−10), CD4 + T cells (R = 0.643, P = 6.81E−58), neutrophils (R = 0.525, P = 1.57E−35), and dendritic cells (R = 0.608, P = 1.35E−50) in lung adenocarcinoma, the same results were observed in lung squamous cell carcinoma. The infiltration of FOXP3-positive Tregs might promote the malignant progression of NSCLC, and targeted intervention of Tregs may be a potential treatment option for patients with NSCLC.

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Section: Introductionmentioning

confidence: 99%

A comprehensive bioinformatics analysis of FOXP3 in nonsmall cell lung cancer

Zhu

Chen

et al. 2022

Medicine

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“…Newer advanced technologies can be used to explore and evaluate the tumor microenvironment and the complexities of tumor and immune system interactions, going beyond the assessment of single analytes such as PD-L1. Recent studies have suggested that Tumor Mutational Burden (TMB), Microsatellite Instability and Mismatch Repair Deficiency, assessment of the Tumor Immune Microenvironment (TME) by T-cell tumor infiltration level evaluations, and gene expression profiles (GEPs) can correlate with the clinical response to immunotherapy [ 8 , 9 , 10 ]. Recent data have also suggested that immune-related gene signatures may predict the clinical response to immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Higher TLR7 Gene Expression Predicts Poor Clinical Outcome in Advanced NSCLC Patients Treated with Immunotherapy

Baglivo

Bianconi²,

Metro

et al. 2021

Genes

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Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer. However, their clinical benefit is limited to a minority of patients. To unravel immune-related factors that are predictive of sensitivity or resistance to immunotherapy, we performed a gene expression analysis by RNA-Seq using the Oncomine Immuno Response Assay (OIRRA) on a total of 33 advanced NSCLC patients treated with ICI evaluating the expression levels of 365 immune-related genes. We found four genes (CD1C, HLA-DPA1, MMP2, and TLR7) downregulated (p < 0.05) and two genes (IFNB1 and MKI67) upregulated (p < 0.05) in ICI-Responders compared to ICI-Non-Responders. The Bayesian enrichment computational analysis showed a more complex interaction network that involved 10 other genes (IFNA1, TLR4, CD40, TLR2, IL12A, IL12B, TLR9, CD1E, IFNG, and HLA-DPB1) correlated with different functional groups. Five main pathways were identified (FDR < 0.0001). High TLR7 expression levels were significantly associated with a lack of response to immunotherapy (p < 0.0001) and worse outcome in terms of both PFS (p < 0.001) and OS (p = 0.03). The multivariate analysis confirmed TLR7 RNA expression as an independent predictor for both poor PFS (HR = 2.97, 95% CI, 1.16–7.6, p = 0.023) and OS (HR = 2.2, 95% CI, 1–5.08, p = 0.049). In conclusion, a high TLR7 gene expression level was identified as an independent predictor for poor clinical benefits from ICI. These data could have important implications for the development of novel single/combinatorial strategies TLR-mediated for an efficient selection of “individualized” treatments for NSCLC in the era of immunotherapy.

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Combination of Stereotactic Ablative Radiotherapy and Systemic Therapy in Oligoprogressive Non-small Cell Lung Cancer

Chicas-Sett¹,

Zafra-Martín²

2023

Interdisciplinary Cancer Research

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Immunotherapy in Non-Small-Cell Lung Cancer: from Targeted Molecules to Resistance Patterns

Cited by 7 publications

References 91 publications

A comprehensive bioinformatics analysis of FOXP3 in nonsmall cell lung cancer

A comprehensive bioinformatics analysis of FOXP3 in nonsmall cell lung cancer

Higher TLR7 Gene Expression Predicts Poor Clinical Outcome in Advanced NSCLC Patients Treated with Immunotherapy

Combination of Stereotactic Ablative Radiotherapy and Systemic Therapy in Oligoprogressive Non-small Cell Lung Cancer

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