Poster Presentation 35th Lorne Cancer Conference 2023

The tumour immune microenvironment differs between anatomical locations in mesothelioma preclinical models (#266)

Lizeth Orozco Morales 1 2 3 , Sally Lansley 2 , Wee Loong Chin 3 4 5 , Caitlin Tilsed 1 2 3 , Nicola Principe 1 2 3 , Connull Leslie 6 , Rachael Zemek 4 , Joel Kidman 1 2 3 , Timo Lassmann 4 , Y C Gary Lee 2 , Richard A Lake 1 2 3 , W Joost Lesterhuis 1 2 3 4
  1. School of Biomedical Sciences, University of Western Australia, Crawley, Western Australia, Australia
  2. Institute for Respiratory Health, Nedlands, Western Australia, Australia
  3. National Centre for Asbestos Related Diseases, Nedlands, Western Australia, Australia
  4. Telethon Kids Institute, West Perth, Western Australia, Australia
  5. Medical School, University of Western Australia, Crawley, WA, Australia
  6. Department of Anatomical Pathology, PathWest Laboratory Medicine, Nedlands, WA, Australia

Background. Mesothelioma is an invariably lethal malignancy that originates in the pleura of the lungs and invades the surrounding tissues. Most preclinical mesothelioma models involve non-invasive subcutaneous tumours in mice, which do not represent the clinical presentation of the disease well. In addition, it has been shown that the tumour microenvironment may differ between anatomical locations.

We therefore compared the tumour microenvironments of preclinical mesothelioma in three relevant locations: intrapleural, intraperitoneal, and subcutaneous.

Methods. The syngeneic mesothelioma cell line AB1 was inoculated either subcutaneously, intraperitoneally, or intrapleurally in BALB/c mice. Whole tumours were compared using histology, RNA sequencing and flow cytometry. Additionally, tumour cells from the three different locations were sorted to analyse their intrinsic genetic signatures.

Results. Both orthotopic locations showed increased tumour growth and invasion compared to subcutaneous tumours. Whole tumour RNA sequencing analysis showed that, compared to intraperitoneal tumours, the intrapleural and subcutaneous tumours were enriched for genes associated with type I and II IFN and TNFα signalling, which was derived from infiltrating immune cells. Flow cytometry showed that peritoneal tumours were significantly enriched for tumour-associated macrophages and B cells, but contained lower numbers of CD4 T cells and NK cells.

Conclusion. The pleural and subcutaneous, but not peritoneal space induce an inflammatory microenvironment in mesothelioma.