Kennedy Trust Prize Studentships
Decoding immune surveillance within the tumor microenvironment: how the extracellular matrix enables escape from immunity
- Project No: KTPS-Clinical-2
- Intake: 2021 KTPS-Clinical
Our immune system detects tumors and activates inflammation to destroy them. However, tumors develop effective strategies to evade elimination, for example switching off cytotoxic T cells that are mobilized to kill them. Using checkpoint inhibitors to re-activate these cells after they have been disarmed by tumors has revolutionized the treatment of people with cancer. However, this approach does not work for all patients, nor all types of tumor, and can be associated with severe autoimmune side effects .
The importance of the interplay between tumor cells, stromal cells and immune cells in determining whether a tumor will be eliminated, or will thrive, provided a landmark shift in disease philosophy, opening therapeutic avenues beyond targeting the tumor cell. However, in most solid tumors these cell populations do not exist in isolation, but assemble together within a tumor specific extracellular matrix (T-ECM), which creates the framework of the tumor microenvironment (TME). Building on our work which revealed that matrix molecules can trigger inflammation, and shape the resultant immune response, we discovered how tumors exploit the immuno-modulatory properties of the matrix to escape immune surveillance. We showed that the T-ECM creates distinct sub-tumoral niches which control immune cell infiltration, localization and phenotype, and we identified new subpopulations of tumor-associated myeloid cells whose behaviour is programmed by microenvironmental cues. We also developed therapeutic antibodies targeting matrix molecules, which prevent tumor growth and spread, by enhancing the infiltration of cytotoxic T cells and macrophages into the tumor, and by driving macrophage polarization towards a tumoricidal phenotype [3, 4].
This project will further investigate how crosstalk between the T-ECM and tumor, stromal and immune cells dictates the balance between an immunogenic and a tolerogenic TME. Using an interdisciplinary approach incorporating state of the art computational genomics, multiplex and high resolution tissue imaging, and therapeutic manipulation of the extracellular matrix in vivo, our aims are: 1) to provide a better understanding at single cell resolution of how distinct leukocyte subpopulations drive tumor growth and spread, 2) to dissect the precise roles of distinct components, and compartments, of the T-ECM in modulating tumor infiltrating immune cell behaviour, and 3) to determine whether targeting molecules within the T-ECM is a viable strategy with which to treat human disease.
Tumor immunology, immunotherapy, extracellular matrix, myeloid cells, macrophage polarization
The Kennedy Institute is a world-renowned research centre, located in the heart of the University of Oxford’s Old Road campus, housing basic and clinician scientists working on diverse aspects of immunology and inflammation. This project focuses on a newly emerging area of cancer research, designed to improve our understanding of immune-mediated tumor elimination, and which has the potential to impact patient care by supporting the development of novel immunotherapies. Work will combine cutting edge cellular immunology, tissue biology and bioinformatics; training will be provided in a range techniques including in vivo models of breast cancer, multichannel flow cytometry analysis, FACS/MACS cell sorting, ex vivo tumor-immune cell co-cultures, human biopsy tissue imaging (GE Celldive, light sheet microscopy), analysis of our existing single cell RNA seq datasets and publically available human datasets, as well as generation of novel RNA seq data. The PhD programme also includes a core curriculum of 20 lectures in the first term of year 1, students will attend weekly group meetings, and will be expected to attend seminars in the department and relevant seminars in the wider University. Students will present their work at national and international meetings.
- Fridman, W., Zitvogel, L., Sautès–Fridman, C. et al. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol 14, 717–734 (2017).
- Pickup, M.W., J.K. Mouw, and V.M. Weaver, The extracellular matrix modulates the hallmarks of cancer. EMBO Rep, 2014. 15(12): p. 1243-53).
- Deligne C, Murdamoothoo D, Gammage AN, Gschwandtner M, Erne W, Loustau T, Marzeda AM, Carapito R, Paul N, Velazquez-Quesada I, Mazzier I, Sun Z, Orend G, Midwood KS. Matrix-Targeting Immunotherapy Controls Tumor Growth and Spread by Switching Macrophage Phenotype. Cancer Immunol Res. 2020 Mar;8(3):368-382.
- mmobilization of infiltrating cytotoxic T lymphocytes by tenascin-C and CXCL12 enhances lung metastasis in breast cancer. Murdamoothoo, D., Sun, Z., Yilmaz, A., Deligne, C., Velazquez-Quesada, I., Erne, W., Mörgelin, M., Midwood, K.S., Orend, G. Under review EMBO J.
- Haider S, McIntyre A, van Stiphout RG, Winchester LM, Wigfield S, Harris AL, Buffa FM. Genomic alterations underlie a pan-cancer metabolic shift associated with tumour hypoxia. Genome Biol. 2016;17(1):140.
Tumor Immunology, Inflammation, Tissue Microenvironment, Translational Medicine