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 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.
