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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 efficacy.
Nasr, Sahar; Li, Lin; Asad, Mohammad; Moridi, Mahroo; Wang, Megan; Zemp, Franz J; Mahoney, Douglas J; Wang, Edwin.
Afiliação
  • Nasr S; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, T2N 1N4, Canada.
  • Li L; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, T2N 1N4, Canada; Faculty of Medicine, Dalian University of Technology, Dalian, Liaoning, 116024, China. Electronic address: lli@dlut.edu.cn.
  • Asad M; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, T2N 1N4, Canada.
  • Moridi M; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, T2N 1N4, Canada.
  • Wang M; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, T2N 1N4, Canada.
  • Zemp FJ; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, T2N 1N4, Canada.
  • Mahoney DJ; Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, T2N 1N4, Canada.
  • Wang E; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, T2N 1N4, Canada. Electronic address: edwin.wang@ucalgary.ca.
EBioMedicine ; 104: 105167, 2024 Jun.
Article em En | MEDLINE | ID: mdl-38805852
ABSTRACT

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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Linfócitos do Interstício Tumoral / Biologia Computacional / Inibidores de Checkpoint Imunológico / Neoplasias Limite: Animals / Humans Idioma: En Revista: EBioMedicine Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Linfócitos do Interstício Tumoral / Biologia Computacional / Inibidores de Checkpoint Imunológico / Neoplasias Limite: Animals / Humans Idioma: En Revista: EBioMedicine Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Canadá