biostudies-literatureGyori DCancer Research UKMedical Research CouncilWellcome TrustBiotechnology and Biological Sciences Research Council120631https://www.ebi.ac.uk/biostudies/studies/S-EPMC6124419biostudies-literatureUnknown3(11)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 antitumor 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, codepletion of CSF1R+ TAMs and Foxp3+ TregJCI insightCompensation between CSF1R+ macrophages and Foxp3+ Treg cells drives resistance to tumor immunotherapy.PMC6124419-C0428095198/Z/10/ZBBS/E/B/000 -C0407,-C0409,-C0427BB/N007794/1BB/J004456/1C52623/A22597194745222597BB/E009867/1105663/Z/14/ZSpensberger DShuttleworth SJOkkenhaug KGrant FMRoychoudhuri RLim ELStephens LRGyori DHawkins PTfalseCompensation between CSF1R+ macrophages and Foxp3+ Treg cells drives resistance to tumor immunotherapy.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 antitumor 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, codepletion of CSF1R+ TAMs and Foxp3+ Treg2018-01-01T00:00:00Z2018 Jun2025-04-19T10:56:10.964Z2019-03-26T23:54:58ZS-EPMC61244192987532110.1172/jci.insight.120631