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A computational pipeline for identifying gene targets and signalling pathways in cancer cells to improve lymphocyte infiltration and immune checkpoint therapy efficacyResearch in context

Authors :
Sahar Nasr
Lin Li
Mohammad Asad
Mahroo Moridi
Megan Wang
Franz J. Zemp
Douglas J. Mahoney
Edwin Wang
Source :
EBioMedicine, Vol 104, Iss , Pp 105167- (2024)
Publication Year :
2024
Publisher :
Elsevier, 2024.

Abstract

Summary: Background: Tumour-infiltrating lymphocytes (TILs) are crucial for effective immune checkpoint blockade (ICB) therapy in solid tumours. However, ∼70% of these tumours exhibit poor lymphocyte infiltration, rendering ICB therapies less effective. Methods: We developed a bioinformatics pipeline integrating multiple previously unconsidered factors or datasets, including tumour cell immune-related pathways, copy number variation (CNV), and single tumour cell sequencing data, as well as tumour mRNA-seq data and patient survival data, to identify targets that can potentially improve T cell infiltration and enhance ICB efficacy. Furthermore, we conducted wet-lab experiments and successfully validated one of the top-identified genes. Findings: We applied this pipeline in solid tumours of the Cancer Genome Atlas (TCGA) and identified a set of genes in 18 cancer types that might potentially improve lymphocyte infiltration and ICB efficacy, providing a valuable drug target resource to be further explored. Importantly, we experimentally validated SUN1, which had not been linked to T cell infiltration and ICB therapy previously, but was one of the top-identified gene targets among 3 cancer types based on the pipeline, in a mouse colon cancer syngeneic model. We showed that Sun1 KO could significantly enhance antigen presentation, increase T-cell infiltration, and improve anti-PD1 treatment efficacy. Moreover, with a single-cell multiome analysis, we identified subgene regulatory networks (sub-GRNs) showing Stat proteins play important roles in enhancing the immune-related pathways in Sun1-KO cancer cells. Interpretation: This study not only established a computational pipeline for discovering new gene targets and signalling pathways in cancer cells that block T-cell infiltration, but also provided a gene target pool for further exploration in improving lymphocyte infiltration and ICB efficacy in solid tumours. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Details

Language :
English
ISSN :
23523964
Volume :
104
Issue :
105167-
Database :
Directory of Open Access Journals
Journal :
EBioMedicine
Publication Type :
Academic Journal
Accession number :
edsdoj.177976b0157f46519e49a5171c255ca9
Document Type :
article
Full Text :
https://doi.org/10.1016/j.ebiom.2024.105167