Research Article

The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas

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Science  20 May 2016:
Vol. 352, Issue 6288, aad3018
DOI: 10.1126/science.aad3018

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Another pathway to cancer resistance

Therapies targeting the tumor microenvironment show promise for treating cancer. For example, antibodies targeting colony-stimulating factor-1 receptor (CSF-1R) inhibit protumorigenic macrophages and regress tumors in mouse models of glioblastoma multiforme (GBM), a deadly form of brain cancer. Quail et al. found that although CSR-1R blockade prolonged survival in mouse models of GBM, more than 50% of tumors eventually recurred. Recurrence was correlated with elevated PI3-K activity in tumors, driven by macrophage-secreted IGF-1. Blocking PI3-K and IGF-1 signaling in rebounding tumors prolonged survival. Thus, tumors can acquire resistance to therapy through intrinsic changes and through changes in their microenvironment.

Science, this issue p. 10.1126/science.aad3018

Structured Abstract


Therapies targeted against the tumor microenvironment (TME) represent a promising approach for treating cancer. This appeal arises in part from the decreased likelihood of acquired resistance through mutations in target TME cells, as is frequently observed with cancer cell–targeted therapies. Although classical mechanisms of tumor cell–intrinsic resistance to cytotoxic and targeted agents have been well-defined—including aberrant drug metabolism and transport, drug target mutation, and activation of alternative survival pathways—it still remains unclear whether resistance to TME-directed therapies follows similar principles. Given that TME-targeted agents are increasingly being evaluated in the clinic, it is becoming critical to mechanistically define how resistance may evolve in response to these therapies in order to provide long-term disease management for patients.


Macrophages and microglia are of the most abundant noncancerous cell types in glioblastoma multiforme (GBM), in some cases accounting for up to 30% of the total tumor composition. Macrophages accumulate with GBM progression and can be acutely targeted via inhibition of colony-stimulating factor–1 receptor (CSF-1R) to regress high-grade gliomas in animal models. However, it is currently unknown whether and how resistance emerges in response to sustained CSF-1R blockade in GBM. Despite this, multiple clinical trials are currently underway testing the efficacy of CSF-1R inhibition in glioma patients. Therefore, determining whether long-term CSF-1R inhibition can stably regress GBM by using animal models is an important and timely question to address.


Using genetic mouse models of GBM, we show that although overall survival is significantly prolonged in response to CSF-1R inhibition, tumors recur eventually in >50% of mice. Upon isolation and transplantation of recurrent tumor cells into naïve animals, gliomas reestablish sensitivity to CSF-1R inhibition, indicating that resistance is microenvironment-driven. Through RNA-sequencing of glioma cells and macrophages purified from treated tumors and ex vivo cell culture assays, we found elevated phosphatidylinositol 3-kinase (PI3K) pathway activity in recurrent GBM after CSF-1R inhibition, driven by macrophage-derived insulin-like growth factor–1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Consequently, combining IGF-1R or PI3K blockade with continuous CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. In contrast, monotherapy with IGF-1R or PI3K inhibitors in rebound or treatment-naïve tumors was less effective, indicating the necessity of combination therapy to expose PI3K signaling dependency in recurrent disease. Mechanistically, we found that activation of macrophages in recurrent tumors by IL4 led to elevated Stat6 and nuclear factor of activated T cells (NFAT) signaling upstream of Igf1, and inhibition of either of these pathways in vivo was sufficient to significantly extend survival.


We have identified a mechanism of drug resistance that can circumvent therapeutic response to a TME-targeted therapy and promote disease recurrence in the absence of tumor cell–intrinsic alterations. Specifically, we have uncovered a heterotypic paracrine signaling interaction that is initiated by the TME and drives resistance to CSF-1R inhibition through IGF-1R/PI3K signaling. Given that PI3K signaling is aberrantly activated in a substantial proportion of GBM patients, and that recent clinical trial results show limited efficacy in recurrent (albeit very advanced) GBM, it is possible that this pathway could similarly contribute to intrinsic resistance to CSF-1R inhibition. Our findings underscore the importance of bidirectional feedback between cancer cells and their microenvironment and support the notion that although stromal cells are less susceptible to genetic mutation than are cancer cells, a tumor can nonetheless acquire a resistant phenotype by exploiting its extracellular environment.

Resistance to CSF-1R inhibition in glioma.

(A) Macrophages contribute to GBM progression by creating a protumorigenic niche associated with M2-like gene expression. CSF-1R is a critical receptor for macrophage biology and is under clinical evaluation as a therapeutic target in glioma . (B) Targeting CSF-1R early in glioma­genesis significantly prolongs survival in mouse models. CSF-1R inhibition reprograms macrophages to become antitumorigenic by down-regu­lating M2-like genes and enhancing phagocytosis. Tumor-derived survival factors sustain macrophage viability despite CSF-1R blockade. (C) After prolonged treatment, a subset of GBMs acquire resistance to CSF-1R inhibition, and tumors recur. This is driven by elevated macrophage-derived IGF-1 and high IGF-1R on tumor cells, resulting in PI3K pathway activation and enhanced glioma cell survival and invasion. Blocking this pathway and CSF-1R in preclinical trials yields a substantial survival benefit.


Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor–1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that although overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas reestablish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment–driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor–1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors.

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