Compensation between CSF1R+ macrophages and Foxp3+ Treg cells drives resistance to tumor immunotherapy

• DOI: 10.1172/jci.insight.120631
• Publication Date: 2018-06-06T15:01:10Z
• Authors: David Gyori; Ee Lyn Lim; Francis M. Grant; Dominik Spensberger; Rahul Roychoudhuri; Stephen J. Shuttl...; Klaus Okkenhaug; Len R. Stephens; Phillip T. Hawkins
• Keywords: Cancer Immunotherapy

Redundancy and compensation provide robustness to biological systems but may contribute therapy resistance. Both tumor-associated macrophages (TAMs) Foxp3+ regulatory T (Treg) cells promote tumor progression by limiting antitumor immunity. Here we show that genetic ablation of CSF1 in colorectal cancer reduces the influx immunosuppressive CSF1R+ TAMs within tumors. This reduction CSF1-dependent resulted increased CD8+ cell attack on tumors, its effect growth was limited a compensatory increase Treg cells. Similarly, disruption activity through their experimental produced moderate effects associated with elevated numbers TAMs. Importantly, codepletion an cells, augmentation function, synergistic growth. Further, inhibition either systemic pharmacological blockade PI3Kδ, or inactivation sensitized previously unresponsive solid tumors TAM depletion enhanced CSF1R blockade. These findings identify PI3Kδ-driven as dominant cellular components microenvironment, implications for design combinatorial immunotherapies.