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High-throughput discovery of mechanisms underlying tumour immunosuppression using functional genetics

  • Full or part time
  • Application Deadline
    Wednesday, January 01, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

T cells have a powerful ability to recognise and kill cancer cells but their function is often suppressed within tumours limiting effective anti-tumour immunity and immunotherapy. In part, the interstitial environment of tumours contributes to immunosuppression. The purpose of the proposed research is to apply a genome-scale functional genetic screen to identify host-encoded factors rendering T cells susceptible to suppression by the tumour microenvironment. CRISPR/Cas9- mediated genetic perturbation screening will be performed using genome-wide libraries in pooled populations of CD8+ T cells. Mutations conferring resistance to suppression will be recovered using high-throughput sequencing. The validated data will be used to construct a global map of the complement of genetic factors involved in suppression of T cell activation by the factors present in the interstitial environment of tumours. Identified genes will be further validated using CRISPR/Cas9-mediated genetic targetting in CD8+ T cells using a mouse model of adoptive immunotherapy. Identification of novel immunosuppressive mechanisms may enable development of new immunotherapies for cancer. This project will benefit from a collaboration with the laboratory of Prof Klaus Okkenhaug at the Department of Pathology.

Funding Notes

Funding* will cover the student’s stipend at the current Research Council rate and University Fees. The studentships will be funded for three years in the first instance subject to eligibility**, with the possibility of additional funding in the fourth year depending on circumstances.

**The studentships are available to students who qualify for Home/EU fees

Applications from ineligible candidates will not be considered.

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References

Eil R, Vodnala S.K., Clever D, Klebanoff C.A., Sukumar M, Pan JH, Palmer DC, Gros A, Yamamoto TN, Patel SJ, Guittard GC, Yu Z, Carbonaro V, Okkenhaug K, Schrump DS, Linehan WM, Roychoudhuri R, Restifo NP (2016). Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537:539-543.

Roychoudhuri R, Clever D, Li P, Wakabayashi Y, Quinn KM, Klebanoff CA, Ji Y, Sukumar M, Eil RL, Yu Z, Spolski R, Palmer DC, Pan JH, Patel SJ, Macallan DC, Fabozzi G, Shih HY, Kanno Y, Muto A, Zhu J, Gattinoni L, O'Shea JJ, Okkenhaug K, Igarashi K, Leonard WJ, Restifo NP (2016). BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancers. Nat Immunol 17:851-60.

Henning AN, Roychoudhuri R, Restifo NP (2018). Epigenetic control of CD8(+) T cell differentiation. Nat Rev Immunol. 18:340-356.

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