Novel Approaches in Cancer Immunotherapy

The immune system plays a key role in eliminating pre-cancerous or oncogenically transformed cells altered by infection or mutation. Evasion of immunosurveillance is a hallmark of cancer that is linked to disease progression. At the same time, immunotherapies that remove the brakes imposed on immune cells by tumour cells have revolutionised cancer treatment.

During tumorigenesis, cancer cells acquire different strategies to evade or escape immune surveillance mechanisms, including the expression of inhibitory immune checkpoint proteins. The aim of immunotherapy is to block immune inhibitory signals to enhance the host immune response against cancer cells.

Several cancer research groups at York have projects active in the area of immunotherapy.

Dr Ioannis Kourtzelis' group studies the regulation of myeloid cell function in the orchestration of anti-tumour immunity. They take an integrated approach, using in vitro co-culture assays, cutting-edge microscopy techniques and preclinical in vivo tumour models to characterise the mechanisms that promote phagocytosis-dependent tumour cell elimination and inform how to harness myeloid cell activity to develop combined immunotherapeutic treatments.

Key publication

Kalafati L, Kourtzelis I, Schulte-Schrepping J, Li X, Hatzioannou A, Grinenko T, Hagag E, Sinha A, Has C, Dietz S, de Jesus Domingues AM, Nati M, Sormendi S, Neuwirth A, Chatzigeorgiou A, Ziogas A, Lesche M, Dahl A, Henry I, Subramanian P, Wielockx B, Murray P, Mirtschink P, Chung KJ, Schultze JL, Netea MG, Hajishengallis G, Verginis P, Mitroulis I, Chavakis T. Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity, 2020. Cell,183(3):771-785.e12. doi: 10.1016/j.cell.2020.09.058.

Professor Dimitris Lagos has cancer research interests in the role of RNA (non-coding and regulatory) in cancer immune gene expression in clear cell renal cell carcinoma and haematological malignancies. He has interests in RNA immunotherapeutics and immune checkpoint regulation, including natural products as a source of cancer immunotherapies, and immunotherapeutic approaches to treat neglected tropical diseases.

Dr Will Brackenbury studies ion channels and is working in collaboration with Professor Dimitris Lagos to explore how the ionic microenvironment of the tumour affects immune checkpoint expression.

Key publications

Shandell MA, Capatina AL, Lawrence SM, Brackenbury WJ, Lagos D. Inhibition of the Na⁺/K⁺-ATPase by cardiac glycosides suppresses expression of the IDO1 immune checkpoint in cancer cells by reducing STAT1 activation. 2022, J Biol Chem; 298(3):101707. https://doi.org/10.1016/j.jbc.2022.101707.

Dey, N. S., Senaratne, S., Somaratne, V., Madarasinghe, N. P., Seneviratne, B., Forrester, S., Montes de Oca, M., Reis, L. C., Moulik, S., Walrad, P. B., Chatterjee, M., Goto, H., Wickremasinghe, R., Lagos, D., Kaye, P. M., & Ranasinghe, S. (2021). Early reduction in PD-L1 expression predicts faster treatment response in human cutaneous leishmaniasis. The Journal of clinical investigation, 131(22), e142765. https://doi.org/10.1172/JCI142765

The Jack Birch Unit has characterised expression of immune checkpoint genes expressed constitutively or in response to infection or inflammatory cytokines in normal human urothelium of the bladder, where the role may be to prevent runaway inflammation in the bladder. This feeds directly into potential new strategies for immunotherapy in bladder cancer.

Key publication

Baker SC, Mason AS, Slip RG, Eriksson P, Sjödahl G, Trejdosiewicz LK, Southgate J. The Urothelial Transcriptomic Response to Interferon Gamma: Implications for Bladder Cancer Prognosis and Immunotherapy. 2022, Cancers (Basel);14(21):5295. doi: 10.3390/cancers14215295.