Investigating tumour immune exclusion in colorectal cancer

Prof Owen Sansom

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Labs: Colorectal Cancer and Wnt Signalling
Duration: 4 years, starting Oct 2023
Closing Date: 6th January 2023

Project Description

Immune exclusion in colorectal cancer (CRC) occurs at the very earliest stages of carcinogenesis. However recent studies have shown that for mismatch repair deficient CRC and a subset of mismatch proficient CRC immune checkpoint inhibition may have patient benefit. Therefore, the purpose of this project is to determine whether resistance to immune checkpoint inhibition is impacted by immune exclusion.

We will investigate the mechanisms which underpin immune cell exclusion from both primary tumour and liver metastasis in colorectal cancer in vivo, using organoids, mouse models, human tumour tissue and computational approaches. The project will focus upon KRAS mutant colorectal cancer, where there are currently no effective targeted therapeutic approaches, and will examine how epithelial-stroma-immune cell interactions lead to immune exclusion. We use novel approaches to increase immunogenicity of tumours, allowing us to examine whether this impacts immune exclusion, and finally whether increased immunogenicity and/or increased immune cell infiltration drives sensitivity to immune checkpoint inhibition in vivo.

We will perform spatially resolved multiplex imaging using tissue sections from mouse models and patient samples of CRC to reveal spatial components of immune exclusion. We will develop novel computational approaches to quantitatively characterise spatial neighbourhoods and communities of epithelial, stromal, and immune cells, allowing us to identify similarities and variations of spatial cell communities among different subsets and stages of colorectal cancers, and to uncover associations of cell community features with sensitivity and resistance to immune checkpoint inhibition.

For informal enquiries or further details on the project, please contact Dr Andy Campbell (a.campbell@beatson.gla.ac.uk).

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Publications

Jackstadt R, van Hooff SR, Leach JD, Cortes-Lavaud X, Lohuis JO, Ridgway RA, Wouters VM, Roper J, Kendall TJ, Roxburgh CS, Horgan PG, Nixon C, Nourse C, Gunzer M, Clark W, Hedley A, Yilmaz OH, Rashid M, Bailey P, Biankin AV, Campbell AD, Adams DJ, Barry ST, Steele CW, Medema JP, Sansom OJ. Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis. Cancer Cell. 2019 Sep 16;36(3):319-336.e7.

Lannagan TR, Jackstadt R, Leedham SJ, Sansom OJ. Advances in colon cancer research: in vitro and animal models. Curr Opin Genet Dev. 2021 Feb;66:50-56.

Lenz HJ, Van Cutsem E, Luisa Limon M, Wong KYM, Hendlisz A, Aglietta M, GarcĂ­a-Alfonso P, Neyns B, Luppi G, Cardin DB, Dragovich T, Shah U, Abdullaev S, Gricar J, Ledeine JM, Overman MJ, Lonardi S. First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study. J Clin Oncol. 2022 Jan 10;40(2):161-170.

Palla G, Fischer DS, Regev A, Theis FJ. Spatial components of molecular tissue biology. Nat Biotechnol. 2022 Mar;40(3):308-318.

Failmezger H, Muralidhar S, Rullan A, de Andrea CE, Sahai E, Yuan Y. Topological Tumor Graphs: A Graph-Based Spatial Model to Infer Stromal Recruitment for Immunosuppression in Melanoma Histology. Cancer Res. 2020 Mar 1;80(5):1199-1209.

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