Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: Combating tumor evasion of antiangiogenic therapy

Saul J. Priceman, James L. Sung, Zory Shaposhnik, Jeremy B. Burton, Antoni X. Torres-Collado, Diana L. Moughon, Mai Johnson, Aldons J. Lusis, Donald A. Cohen, M. Luisa Iruela-Arispe, Lily Wu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

220 Scopus citations

Abstract

Tumor-infiltrating myeloid cells (TIMs) support tumor growth by promoting angiogenesis and suppressing antitumor immune responses. CSF-1 receptor (CSF1R) signaling is important for the recruitment of CD11b+F4/80+ tumor-associated macrophages (TAMs) and contributes to myeloid cell-mediated angiogenesis. However, the impact of the CSF1R signaling pathway on other TIM subsets, including CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs), is unknown. Tumor-infiltrating MDSCs have also been shown to contribute to tumor angiogenesis and have recently been implicated in tumor resistance to antiangiogenic therapy, yet their precise involvement in these processes is not well understood. Here, we use the selective pharmacologic inhibitor of CSF1R signaling, GW2580, to demonstrate that CSF-1 regulates the tumor recruitment of CD11b+Gr-1loLy6Chi mononuclear MDSCs. Targeting these TIM subsets inhibits tumor angiogenesis associated with reduced expression of proangiogenic and immunosuppressive genes. Combination therapy using GW2580 with an anti-VEGFR-2 antibody synergistically suppresses tumor growth and severely impairs tumor angiogenesis along with reverting at least one TIM-mediated antiangiogenic compensatory mechanism involving MMP-9. These data highlight the importance of CSF1R signaling in the recruitment and function of distinct TIM subsets, including MDSCs, and validate the benefits of targeting CSF1R signaling in combination with antiangiogenic drugs for the treatment of solid cancers.

Original languageEnglish (US)
Pages (from-to)1461-1471
Number of pages11
JournalBlood
Volume115
Issue number7
DOIs
StatePublished - Feb 18 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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