TY - JOUR
T1 - Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry
AU - van Maldegem, Febe
AU - Valand, Karishma
AU - Cole, Megan
AU - Patel, Harshil
AU - Angelova, Mihaela
AU - Rana, Sareena
AU - Colliver, Emma
AU - Enfield, Katey
AU - Bah, Nourdine
AU - Kelly, Gavin
AU - Tsang, Victoria Siu Kwan
AU - Mugarza, Edurne
AU - Moore, Christopher
AU - Hobson, Philip
AU - Levi, Dina
AU - Molina-Arcas, Miriam
AU - Swanton, Charles
AU - Downward, Julian
N1 - Funding Information: J.D. has acted as a consultant for AstraZeneca, Bayer, Jubilant, Theras, Vividion and Novartis, and has funded research agreements with BMS, Revolution Medicines and Boehringer Ingelheim. C.S. receives grant support from Archer Dx, AstraZeneca, Boehringer Ingelheim and Ono Pharmaceutical; has consulted for AstraZeneca, Bicycle Therapeutics, Celgene, Genentech, GRAIL, GSK, Illumina, Medicxi, MSD, Novartis and the Sarah Cannon Research Institute; receives grant support and has consulted for Bristol Myers Squibb, Pfizer and Roche–Ventana; is an advisory board member and is involved in trials sponsored by AstraZeneca; has stock options in Apogen Biotechnologies, Epic Sciences, GRAIL; and has stock options and is a co-founder of Achilles Therapeutics. The remaining authors declare no competing interests. Funding Information: We thank David Barry, Leigh-Anne McDuffus, Richard Mitter and Julia Handl for helpful discussions. We thank the science technology platforms at the Francis Crick Institute including Biological Research Facility, Scientific Computing, Bioinformatics and Biostatistics, Flow Cytometry, Experimental Histopathology, Advanced Light Microscopy and Cell Services. This work was supported by funding to J.D. from the Francis Crick Institute—which receives its core funding from Cancer Research UK (FC001070), the UK Medical Research Council (FC001070), and the Wellcome Trust (FC001070)—from the European Research Council Advanced Grant RASImmune, from a Wellcome Trust Senior Investigator Award 103799/Z/14/Z and from a Cancer Research UK Cancer ImmunoTherapy Accelerator Award (CITA-CRUK; C33499/A20265). K.E. is supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 838540 and research grant funding from Bristol Myers Squibb. Publisher Copyright: © 2021, The Author(s).
PY - 2021/10
Y1 - 2021/10
N2 - Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection of mechanisms through chemical and genetic manipulations that are not feasible in the clinical setting. In studies of the tumour microenvironment (TME), multiplexed imaging methods can provide a rich source of information. However, the application of such technologies in mouse tissues is still in its infancy. Here we present a workflow for studying the TME using imaging mass cytometry with a panel of 27 antibodies on frozen mouse tissues. We optimise and validate image segmentation strategies and automate the process in a Nextflow-based pipeline (imcyto) that is scalable and portable, allowing for parallelised segmentation of large multi-image datasets. With these methods we interrogate the remodelling of the TME induced by a KRAS G12C inhibitor in an immune competent mouse orthotopic lung cancer model, highlighting the infiltration and activation of antigen presenting cells and effector cells.
AB - Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection of mechanisms through chemical and genetic manipulations that are not feasible in the clinical setting. In studies of the tumour microenvironment (TME), multiplexed imaging methods can provide a rich source of information. However, the application of such technologies in mouse tissues is still in its infancy. Here we present a workflow for studying the TME using imaging mass cytometry with a panel of 27 antibodies on frozen mouse tissues. We optimise and validate image segmentation strategies and automate the process in a Nextflow-based pipeline (imcyto) that is scalable and portable, allowing for parallelised segmentation of large multi-image datasets. With these methods we interrogate the remodelling of the TME induced by a KRAS G12C inhibitor in an immune competent mouse orthotopic lung cancer model, highlighting the infiltration and activation of antigen presenting cells and effector cells.
UR - http://www.scopus.com/inward/record.url?scp=85116802309&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-021-26214-x
DO - https://doi.org/10.1038/s41467-021-26214-x
M3 - Article
C2 - 34625563
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5906
ER -