In research published today, Babraham Institute researchers have shown that some tumours use not one but two levels of protection against the immune system. Knocking out one level boosted the protective effects of the second and vice versa. The research demonstrates that a two-pronged approach targeting both cell types simultaneously may offer a promising route for the development of new cancer immunotherapies.
The development and growth of a cancerous tumour often occurs despite a fully functioning immune system, capable of recognising and killing cancer cells. Tumours hijack certain cells in our immune system to create a growth-permissive environment and give protection from the anti-tumour elements. In particular, tumours recruit immune cell allies, cells called tumour-associated macrophages (TAMs) and regulatory T cells (Treg), to evade immune attack.
Specifically inhibiting the recruitment of TAMs by blocking the actions of a protein called colony-stimulating factor 1 (CSF1) reduces tumour growth in mouse models. Although clinical trials of inhibitors targeting TAMs are underway, results in patients haven’t been as effective as hoped. A lack of understanding of how TAMs promote tumour progression potentially limits the therapeutic value of these inhibitors.
Likewise, inhibiting the action of Treg cells in mice by inactivating a key enzyme called PI3K delta gives protection against a range of tumours. A PI3K delta inhibitor is approved for treatment of chronic lymphocytic leukaemia (CLL) and follicular non-Hodgkin lymphoma (NHL), but the potential for PI3K delta inhibitors for the treatment of solid cancers in humans is yet to be demonstrated.
The research published today used a mouse model of colorectal cancer to explore the synergy between TAMs and Treg cells, showing that each cell type was able to compensate for the effects of the loss of the other to maintain the tumour’s protection from the immune system. However, jointly inhibiting TAMs and Treg cells substantially inhibited tumour growth.
Dr David Gyori, first author on the paper, said: “Strikingly, preventing tumour immunosuppression by both TAMs and Treg cells caused almost complete tumour rejection by the immune system and half of the mice became completely tumour-free. Taken together, our findings provide a convincing rationale for assessing the clinical value of combinatorial therapies targeting the CSF1 receptor and PI3K delta.”
Professor Klaus Okkenhaug, one of the authors on the study by Gyori et al. and a parallel study by Lim et al. said: “Harnessing the power of the immune system to kill cancer cells is becoming a successful therapeutic strategy. These studies demonstrate the importance of fully understanding the interplay between the many elements of the immune system to ensure that combinatorial therapies are both synergistic and effective.”
Main publication reference
Gyori, D., Lim, E.L., Grant, F., Spensberger, D., Roychoudhuri, R., Shuttleworth, S.J., Okkenhaug, K., Stephens, L.R., Hawkins, P.T. Compensation between CSF1R+ macrophages and Foxp3+ Treg cells drives resistance to tumor immunotherapy. JCI Insight 2018
Related research publication
Lim, E.L., Cugliandolo, F.M., Rosner, D.R., Gyori, D., Roychoudhuri, R., Okkenhaug, K. Phosphoinositide-3-kinase δ inhibition promotes anti-tumour responses but antagonizes checkpoint inhibitors. JCI insight 2018.
D. Gyori was funded by a research grant from Karus Therapeutics. E.L. Lim was supported by a Yousef Jameel Scholarship (Cambridge Trust). R. Roychoudhuri and K. Okkenhaug received institute support from the Biotechnology and Biological Sciences Research Council (BBSRC) (BBS/E/B/000 -C0407, -C0409, -C0427 and -C0428). K. Okkenhaug was also supported by Wellcome Trust grant 095198/Z/10/Z. L.R. Stephens and P.T. Hawkins were supported by an institute grant from the BBSRC (BB/J004456/1). R. Roychoudhuri is supported by the Wellcome Trust/Royal Society (Grant 105663/Z/14/Z), the UK Biotechnology and Biological Sciences Research Council (Grant BB/N007794/1), and Cancer Research UK (Grant C52623/A22597).
Dr Louisa Wood, Communications Manager, email@example.com
CSF1R+ cells (red) co-localising with CD8+ cells (magenta) in primary mouse tumours (cyan = nuclei). Image credit: Dr Fabien Garcon, Babraham Institute.
Affiliated authors (in author order)
David Gyori – Signalling Programme, Babraham Institute at the time of this research. Now Semmelweis University School of Medicine, Budapest, Hungary
Ee Lyn Lee, Francis Grant – Lymphocyte Signalling Programme, Babraham Institute
Dominik Spensberger – Head of Gene Targeting Facility, Babraham Institute
Rahul Roychoudhuri – Group leader, Lymphocyte Signalling Programme, Babraham Institute
Klaus Okkenhaug – Group leader, Lymphocyte Signalling Programme, Babraham Institute at the time of this research. Now Head of the Division of Immunology, Department of Pathology, University of Cambridge
Len Stephens and Phill Hawkins – Group leaders, Signalling Programme, Babraham Institute
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. Animals are only used in Babraham Institute research when their use is essential to address a specific scientific goal, which cannot be studied through other means. The main species used are laboratory strains of rodents, with limited numbers of other species. We do not house cats, dogs, horses or primates at the Babraham Research Campus for research purposes.
Mice were used in this research to investigate immune responses against tumours and were housed in the Biological Support Unit at the Babraham Institute under specific pathogen-free conditions. The use of animals in these studies was performed in accordance with the Babraham Institute’s Animal Welfare and Ethical Review Body (AWERB) and the Animals in Science Regulation Unit (ASRU) of the UK Home Office, with all protocols approved and detailed under Home Office Project Licences PPL 70/8100 and 70/7661.
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About the Babraham Institute
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute receives core funding from the Biotechnology and Biological Sciences Research Council (BBSRC) through an Institute Core Capability Grant.
06 June 2018