Compensation between CSF1R+ macrophages and Foxp3+ Treg cells drives resistance to tumor immunotherapy.
Grant, Francis M
Shuttleworth, Stephen J
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Gyori, D., Lim, E. L., Grant, F. M., Spensberger, D., Roychoudhuri, R., Shuttleworth, S. J., Okkenhaug, K., et al. (2018). Compensation between CSF1R+ macrophages and Foxp3+ Treg cells drives resistance to tumor immunotherapy.. JCI insight, 3 (11)https://doi.org/10.1172/jci.insight.120631
Redundancy and compensation provide robustness to biological systems but may contribute to therapy resistance. Both tumor-associated macrophages (TAMs) and Foxp3+ regulatory T (Treg) cells promote tumor progression by limiting anti-tumor immunity. Here we show that genetic ablation of CSF1 in colorectal cancer cells reduces the influx of immunosuppressive CSF1R+ TAMs within tumors. This reduction in CSF1-dependent TAMs resulted in increased CD8+ T cell attack on tumors, but its effect on tumor growth was limited by a compensatory increase in Foxp3+ Treg cells. Similarly, disruption of Treg cell-activity through their experimental ablation produced moderate effects on tumor growth and was associated with elevated numbers of CSF1R+ TAMs. Importantly, co-depletion of CSF1R+ TAMs and Foxp3+ Treg cells resulted in an increased influx of CD8+ T cells, augmentation of their function and a synergistic reduction in tumor growth. Further, inhibition of Treg cell-activity either through systemic pharmacological blockade of PI3Kδ, or its genetic inactivation within Foxp3+ Treg cells, sensitized previously unresponsive solid tumors to CSF1R+ TAM depletion and enhanced the effect of CSF1R blockade. These findings identify CSF1R+ TAMs and PI3Kδ-driven Foxp3+ Treg cells as the dominant compensatory cellular components of the immunosuppressive tumor microenvironment with implications for the design of combinatorial immunotherapies.
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 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 and 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).
Wellcome Trust (095198/Z/10/Z)
External DOI: https://doi.org/10.1172/jci.insight.120631
This record's URL: https://www.repository.cam.ac.uk/handle/1810/278964
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
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