Compensation 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(+) 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 PI3K delta, 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 PI3K delta-driven Foxp3(+) Treg cells as the dominant compensatory cellular components of the immunosuppressive tumor microenvironment, with implications for the design of combinatorial immunotherapies.