Relationship between IFNγ-dependent tumour escape and immunotherapy

Tumours actively escape the immune system by inducing an immunosuppressive state where intra-tumoural CD8 T-cells are “exhausted”, lacking effector functions. Checkpoint blockade is a therapy designed to reinvigorate those exhausted T-cells. It has shown unprecedented success in treating aggressive cancers such as metastatic melanoma (1).  But the response rates are still only 15 to 30%, in part because tumours have developed strategies to escape checkpoint blockade. The most reported pressure during checkpoint blockade is induced by CD8 T-cells. Patients who progressed after initially responding to checkpoint blockade often carry tumours deficient in IFNγ signalling pathway (2). IFNγ exerts cytotoxic or cytostatic effects on tumours and induces Major histocompatibility complex (MHC) expression. MHC expression is necessary for CD8 T-cells to recognise and kill tumour cells. Therefore, down-regulation of the IFNγ pathway leads to tumour escape by inhibiting T-cell recognition. How the immune system responds to this has been largely overlooked. It, however, has the capacity to sense changes in its environment. For example, we recently found that CD8 T-cells sense IFNγ present in the tumour microenvironment, which restricts their anti-tumour response (3). The paradigm is that immune cells, in particular T-cells, are inhibited or simply can no longer recognise cancer cells during IFNγ-dependent escape. However, recent metadata analysis is challenging this dogma, suggesting that patients with mutations in the IFNγ signalling pathway can still respond to checkpoint blockade (4), challenging this dogma.

Our preliminary data demonstrate that the immune system adapt to IFNγ-dependent escape. We observe an extensive remodelling and priming of many immune cells, including CD8 T-cells and myeloid cells. But we do not know whether and how this remodelling affects response to immunotherapy. This project will therefore characterise whether IFNγ-dependent tumour escape can trigger an immune response that can be leveraged during immunotherapies. To do this, we will recreate IFNγ-dependent tumour escape and explore whether they are sensitive to multiple immunotherapy strategies, such as checkpoint blockade, cancer vaccine and small engagers. Our preliminary data suggests that this is indeed the case, at least in cancer vaccines. We will then study which immune network elicited during tumour escape underlies response to immunotherapy, both in time and space. To do so, you will use in vivo mouse models, conventional immunological assays, and microscopy. Finally, the project will leverage publicly available datasets to confirm the relevance of our findings.

The goal is to understand how to leverage this newly generated immune response to provide alternative strategies to control tumours.

KEYWORDS (5 WORDS)

Cancer, immune response, melanoma, imaging, tumour escape

TRAINING OPPORTUNITIES

The student will be embedded in the Kennedy Trust at Oxford. The Kennedy Institute is a world-renowned research centre and is housed in a brand new state-of-the-art research facility, including flow cytometry and imaging. Full training will be provided in a range of cell and molecular biology techniques, and imaging. A core curriculum of 20 lectures will be taken in the first term of year 1 to provide a solid foundation in immunology and data analysis. Students will attend weekly departmental meetings and will be expected to attend seminars within the department and those relevant in the wider University. Students will also attend external scientific conferences where they will be expected to present the research findings.

KEY PUBLICATIONS (5 maximum)

1. Iwai, Y., Hamanishi, J., Chamoto, K. & Honjo, T. Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci 24, 26 (2017). 

2. Gao, J. et al. Loss of IFN-gamma Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy. Cell 167, 397-404 e399 (2016).

3. Mazet, J.M. et al. IFNgamma signaling in cytotoxic T cells restricts anti-tumor responses by inhibiting the maintenance and diversity of intra-tumoral stem-like T cells. Nat Commun 14, 321 (2023).

4. Song, E. & Chow, R.D. Mutations in IFN-gamma signaling genes sensitize tumors to immune checkpoint blockade. Cancer cell (2023).

THEMES

Immunity

Programme

Applicants should apply for the D.Phil in Molecular and Cellular Medicine (course code RD_MP1).

Funding

This studentship provides a grant for living expenses of £21k per year, for 4 years, and covers fees at the home rate.

CONTACT INFORMATION

For questions about this project, please email audrey.gerard@kennedy.ox.ac.uk. For any administrative or application process queries, please email graduate.studies@ndorms.ox.ac.uk.