Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression

Abstract

Despite a deeper molecular understanding, human glioblastoma remains one of the most treatment refractory and fatal cancers. It is known that the presence of macrophages and microglia impact glioblastoma tumorigenesis and prevent durable response. Herein we identify the dual function cytokine IL-33 as an orchestrator of the glioblastoma microenvironment that contributes to tumorigenesis. We find that IL-33 expression in a large subset of human glioma specimens and murine models correlates with increased tumor-associated macrophages/monocytes/microglia. In addition, nuclear and secreted functions of IL-33 regulate chemokines that collectively recruit and activate circulating and resident innate immune cells creating a pro-tumorigenic environment. Conversely, loss of nuclear IL-33 cripples recruitment, dramatically suppresses glioma growth, and increases survival. Our data supports the paradigm that recruitment and activation of immune cells, when instructed appropriately, offer a therapeutic strategy that switches the focus from the cancer cell alone to one that includes the normal host environment.

Advances in Lipid-Based Nanoparticles for Cancer Chemoimmunotherapy

“… Cytokines released from tumor cells can recruit tumor-suppressive cells to the tumor site. IL33 produced by tumor cells can recruit TAM [ 96 ]. C-C motif chemokine ligand 2 (CCL2) produced by CXCR4+ tumor-associated microglia M1 can recruit the CC chemokine receptor 4 (CCR4)+-expressing T reg cells and MDSCs to gliomas [ 97 , 98 ].…”

“… Cytokines recruit cytotoxic T cells or/and NK cells. IL33 recruits CD4+ T helper cells and FOP3+ T reg cells to the tumor site [ 96 ]. CXCL10 recruits NK cells to the tumor site [ 107 ].…”

PAM (PIK3/AKT/mTOR) signaling in glia: potential contributions to brain tumors in aging

“…CXCL5, CXCL10) and elevations in proinflammatory cytokines [ 148 – 150 ]. Given that variation in neuroinflammatory microenvironments can augment tumor progression, the inflammatory profiles of aged astrocytes may facilitate glioma pathology and influence cancer-related outcomes in aged individuals [ 151 , 152 ]. Although balanced ROS levels are necessary for optimal functioning, astrocytes from the aging brain also display increased levels of oxidative stress compared to their youthful counterparts, which may exacerbate the elevated levels of reactive oxygen species otherwise induced by metabolically demanding glioma cells; this suggests the mitigation of oxidative stress in aging glia may serve as a novel target for treatment of glioma in the elderly [ 153 , 154 ].…”

Analysis of Tumor Microenvironment Characteristics in Bladder Cancer: Implications for Immune Checkpoint Inhibitor Therapy

“…Tumor cells grow and survive in the tumor microenvironment (TME), which not only contains cancer cells, but also stromal cells such as resident fibroblasts (cancer-associated fibroblasts), macrophages, and recruited cells such as infiltrating immune cells (bone marrow cells and lymphocytes), bone marrow-derived cells (endothelial progenitor cells and hematopoietic progenitor cells), and secreted factors (cytokines, chemokines, and growth factors) (10,11). These cancer cells trigger a variety of physiological changes through direct and indirect interactions with other TME components, such as inducing proliferation and angiogenesis, inhibiting apoptosis, avoiding hypoxia, and inducing immune tolerance.…”