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. 2021 Jun 29;12(7):992.
doi: 10.3390/genes12070992.

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

Sara Baglivo  1 , Fortunato Bianconi  2 , Giulio Metro  1 , Alessio Gili  3 , Francesca Romana Tofanetti  1 , Guido Bellezza  4 , Biagio Ricciuti  5 , Martina Mandarano  4 , Valeria Teti  4 , Annamaria Siggillino  1 , Maria Sole Reda  1 , Rita Chiari  6 , Lorenza Pistola  1 , Angelo Sidoni  4 , Vincenzo Minotti  1 , Fausto Roila  1 , Vienna Ludovini  1
Affiliations

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

Sara Baglivo et al. Genes (Basel). .

Abstract

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.

Keywords: PD-L1; Toll-like receptors (TLRs); immune checkpoint inhibitor (ICI); immune gene expression; immunotherapy; non-small-cell lung cancer (NSCLC); predictive biomarkers.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Heatmap of the genes differentially expressed between ICI-Responders and ICI-Non-Responders.
Figure 2
Figure 2
Box plot for TLR7 gene expression according to ICI-Responders and ICI-Non-Responders.
Figure 3
Figure 3
Kaplan–Meyer survival curves for progression-free survival (PFS) (a) and overall survival (OS) (b) according to TLR7 gene expression.
Figure 4
Figure 4
Gene correlation network by the Bayesian computational analysis.
See this image and copyright information in PMC

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