Breaking the feed forward inflammatory cytokine loop in the tumor microenvironment of PDGFB-driven glioblastomas
C. Ryan Miller, Anita B. Hjelmeland
C. Ryan Miller, Anita B. Hjelmeland
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Commentary

Breaking the feed forward inflammatory cytokine loop in the tumor microenvironment of PDGFB-driven glioblastomas

Abstract

Glioblastoma (GBM) tumor-associated macrophages (TAMs) provide a major immune cell population contributing to growth and immunosuppression via the production of proinflammatory factors, including IL-1. In this issue of the JCI, Chen, Giotti, and colleagues investigated loss of ll1b in the immune tumor microenvironment (TME) in GBM models driven by PDGFB expression and Nf1 knockdown. Survival was only improved in PDGFB-driven GBM models, suggesting that tumor cell genotype influenced the immune TME. IL-1β in the TME increased PDGFB-driven GBM growth by increasing tumor-derived NF-κB, expression of monocyte chemoattractants, and increased infiltration of bone marrow–derived myeloid cells (BMDMs). In contrast, no requirement for IL-1β was evident in Nf1-silenced tumors due to high basal levels of NF-κB and monocyte chemoattractants and increased infiltration of BMDM and TAMs. Notably, treatment of mice bearing PDGFB-driven GBM with anti–IL-1β or an IL1R1 antagonist extended survival. These findings suggest that effective clinical immunotherapy may require differential targeting strategies.

Authors

C. Ryan Miller, Anita B. Hjelmeland

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Figure 1

PDGFB-driven GBM cells and TAMs that express IL-1β establish a feed-forward loop.

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PDGFB-driven GBM cells and TAMs that express IL-1β establish a feed-forw...
(A) Chen, Giotti, et al. determined that the requirement for IL-1β in GBM growth differed based on tumor cell genotype. The RCAS/Ntv-a system was used to drive GBMs based on elevated PDGFB expression or Nf1 knockdown in a genetic background with or without IL-1β knockout. Survival of mice with PDGFB-driven but not Nf1-silenced GBMs was increased in Il1b-knockout mice. In PDGFB-driven GBMs, IL-1β stimulated NF-κB activity and MCP production to increase BMDM infiltration. In contrast, high basal levels of NF-kB activity in Nf1-silenced GBMs drove growth via MCP production and BMDM infiltration. (B) IL-1β specifically from the TME drives tumor growth. Targeting of IL-1β or its receptor IL1R1 improved the survival of mice bearing PDGFB-driven GBMs. Similarly, Il1b loss in the TME, but not GBM, cells limited GBM growth and increased survival in mice.