The γδT cell: an unconventional T cell and unconventional target for immune checkpoint inhibitors?

Primary supervisor: Nnenna Kanu, UCL

Secondary supervisor: Yin Wu, King’s College London

Project

Immune checkpoint inhibitors (CPI) have revolutionised the treatment of advanced cancers by providing durable remissions, albeit for a minority of patients. Unfortunately, therapy related adverse events are common and many patients experience severe and life-long toxicities on what may ultimately be futile treatment. Thus, there is an urgent unmet need to predict which patients are most likely to respond to CPI therapy.

Current CPI therapies, particularly those targeting the PD-(L)1 axis, are thought to work by de-repressing tumour (neo)antigen-reactive αβT cells through the removal of immune checkpoint attenuation of (αβ) T cell receptor (TCR) signalling. However, some cancers do not express and/or present neoantigens and yet are highly responsive to CPI therapy implying a role for other immune cells. γδT cells are a rare and unique type of T cell found enriched in the very epithelial tissues from which carcinomas arise. These cells do not require (neo)antigens or MHC to recognise and kill cancer cells. Thus, γδT cells are both distinct from and complementary to αβT cells in terms of cancer immunosurveillance.

The presence of γδT cells within tumours is highly predictive of improved survival and, in many cases, more so than αβT cells (1 – 3). We and others have also demonstrated that γδT cells also express PD-1 (1,2). Moreover, we have demonstrated that a transcriptomic signature of their presence within tumours is predictive of response to anti-PD-1 therapy (3). Nonetheless it remains unclear if γδT cells are directly implicated in response to anti-PD-1 therapy or if observed correlations are merely epiphenomena. Our lab can efficiently extract these rare cells from primary tumours and tissues (1) to enable extensive characterisation of their function in vitro. We also have access through existing research protocols to materials from patients with non-small cell lung cancer and melanoma, two major cancer types in which CPI therapy is widely used.

Aims:

1. Establish if PD-1/PD-L1 regulates γδT cell activation in response to:
   a) TCR stimulation
   b) Innate signals within the tumour microenvironment (e.g. NKR ligands, cytokines)
2. Establish if anti-PD-(L)1 therapy restores functionality in PD-1/PD-L1 suppressed γδT cells.
3. Establish if anti-PD-(L)1 responsive γδT cells possess and epigenetic signature similar to that of anti-PD-(L)1 responsive stem-like αβT cells (4,5).
4. Confirm if γδT cells have predictive value for CPI therapy response in cancers where αβT cell immunosurveillance may be impaired (e.g. cancers with low neoantigen burden, with defects in antigen presentation, etc.).
5. Explore the extent of epigenetic regulation of additional immune cell populations in the tumor microenvironment in response to anti-PD-(L)1 therapy.

An improved understanding of γδT cells and how they may be regulated by immune checkpoints such as PD-1 will both improve our ability to rationally deploy CPI therapy as well as guide the development of new CPI therapies.

Candidate background

The candidate must demonstrate enthusiasm for cancer immunology. Previous wet lab experience, particularly of flow cytometry, molecular biology and primary cell culture are highly desirable. This project would also suit candidates with an interest in epigenetics.

Potential Research Placements

1. Yin Wu, Centre for Inflammation Biology and Cancer Immunology, King’s College London
2. Adrian Hayday, Peter Gorer Department of Immunobiology, King’s College London
3. Charles Swanton, Francis Crick Institute/ UCL

References

1. Wu, Y. et al. An innate-like Vδ1+ γδT cell compartment in the human breast is associated with remission in triple-negative breast cancer. Sci Transl Med 11, (2019).
2. Foord, E., Arruda, L. C. M., Gaballa, A., Klynning, C. & Uhlin, M. Characterization of ascites- and tumor-infiltrating γδT cells reveals distinct repertoires and a beneficial role in ovarian cancer. Sci Transl Med 13, eabb0192 (2021).
3. Wu, Y. et al. A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer. Nat Cancer 1 – 14 (2022) doi:10.1038/s43018-022-00376-z.
4. Jadhav, R. R. et al. Epigenetic signature of PD-1+ TCF1+ CD8 T cells that act as resource cells during chronic viral infection and respond to PD-1 blockade. P Natl Acad Sci Usa 116, 14113 – 14118 (2019).
5. Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science (2016) doi:10.1126/science.aaf2807.