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

Abstract

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 while overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas re-establish 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 (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.

Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors

“…In this regard, our studies indicate that IGF blockade increases pancreatic tumors' response to gemcitabine without affecting immune cell infiltration, including macrophage infiltration, or without affecting macrophage polarization. Interestingly, a recent elegant study also describes macrophage-derived IGF as a key driver of resistance to CSF-1R inhibition in glioblastoma (51). …”

A Portal Vein Injection Model to Study Liver Metastasis of Breast Cancer

“…These models typically use well-studied human breast cancer cell lines such as MCF-7 and MDA-MB-231 and Nude, Rag1 -/-, or SCID immune compromised murine hosts [26][27][28][29] . Xenograft models provide the advantage of involving human derived cancer cell lines, however, given the recent appreciation for immune cells in metastasis [30][31][32] and in therapeutic resistance [33][34][35] , the study of metastasis in a fully immune competent host is paramount. Models to study breast cancer metastasis to the liver in immune competent hosts include orthotopic injection of syngeneic tumor cells (e.g., 4T1 and D2A1 cell lines) into the mammary fat pad, with or without surgical resection of the primary tumor, and subsequent assessment of metastasis [36][37][38] .…”

p53 Mutation: Critical Mediator of Therapy Resistance against Tumor Microenvironment

“…However, studies are rare to investigate how resistance emerges in response to continuous long-term CSF-1R blockade in GBM. Recent study published in journal “Science”, identified that although overall survival is significantly prolonged in response to long-term CSF-1R inhibition, subset of tumors recur eventually in >50% of mice [45]. Transplantation of recurrent tumor cells into naïve animals, GBM reestablish sensitivity to CSF-1R inhibition, indicating that resistance is microenvironment driven [45].…”

“…Recent study published in journal “Science”, identified that although overall survival is significantly prolonged in response to long-term CSF-1R inhibition, subset of tumors recur eventually in >50% of mice [45]. Transplantation of recurrent tumor cells into naïve animals, GBM reestablish sensitivity to CSF-1R inhibition, indicating that resistance is microenvironment driven [45]. Consequently, combining IGF-1R or PI3K blockade with continuous CSF-1R inhibition in recurrent tumors significantly prolonged overall survival [45].…”

“…Transplantation of recurrent tumor cells into naïve animals, GBM reestablish sensitivity to CSF-1R inhibition, indicating that resistance is microenvironment driven [45]. Consequently, combining IGF-1R or PI3K blockade with continuous CSF-1R inhibition in recurrent tumors significantly prolonged overall survival [45]. However, study did not answer whether resistance to anti-CSF1R targeting TAMs in TME is depended on mutational status of the tumor cells.…”