Abstract
BackgroundGlioblastoma (GBM) is a primary brain tumor with a 5-year survival rate of ≤5%. We have shown earlier that GBM-antibody-linked curcumin (CC) and also phytosomal curcumin (CCP) rescue 50–60% of GBM-bearing mice while repolarizing the tumor-associated microglia/macrophages (TAM) from the tumor-promoting M2-type to the tumoricidal M1-type. However, systemic application of CCP yields only sub-IC50 concentrations of CC in the plasma, which is unlikely to kill GBM cells directly. This study investigates the role of CC-evoked intra-GBM recruitment of activated natural killer (NK) cells in the elimination of GBM and GBM stem cells.MethodsWe have used an immune-competent syngeneic C57BL6 mouse model with the mouse-GBM GL261 cells orthotopically implanted in the brain. Using immunohistochemistry and flow cytometry, we have quantitatively analyzed the role of the intra-GBM-recruited NK cells by (i) injecting (i.p.) the NK1.1 antibody (NK1.1Ab) to temporarily eliminate the NK cells and (ii) blocking NK recruitment by injecting an IL12 antibody (IL12Ab). The treatment cohorts used randomly-chosen GL261-implanted mice and data sets were compared using two-tailed t-test or ANOVA.ResultsCCP treatment caused the GBM tumor to acquire M1-type macrophages (50–60% of the TAM) and activated NK cells. The treatment also elicited (a) suppression of the M2-linked tumor-promoting proteins STAT3, ARG1, and IL10, (b) induction of the M1-linked anti-tumor proteins STAT1 and inducible nitric oxide synthase in the TAM, (c) elimination of CD133(+) GBM stem cells, and (d) activation of caspase3 in the GBM cells. Eliminating intra-GBM NK cell recruitment caused a partial reversal of each of these effects. Concomitantly, we observed a CCP-evoked dramatic induction of the chemokine monocyte chemotactic protein-1 (MCP-1) in the TAM.ConclusionsThe recruited NK cells mediate a major part of the CCP-evoked elimination of GBM and GBM stem cells and stabilization of the TAM in the M1-like state. MCP-1 is known to activate peripheral M1-type macrophages to secrete IL12, an activator of NK cells. Based on such observations, we postulate that by binding to peripheral M1-type macrophages and IL12-activated NK cells, the brain-released chemokine MCP-1 causes recruitment of peripheral immune cells into the GBM, thereby causing destruction of the GBM cells and GBM stem cells.
Highlights
Glioblastoma (GBM) is a primary brain tumor with a 5-year survival rate of ≤5%
We have recently reported that the GBM tumors that kill the Vehicle-treated mice harbor tumor-promoting arginase1 (ARG1)high, inducible nitric oxide synthaselow M2-like microglia/macrophages (TAM)
The mice rescued from GBM by both antibody-linked CC and Curcumin Phytosome Meriva (CCP) contained ARG1low, iNOShigh M1-like tumor-associated microglia/macrophages (TAM) in the scar tissue [8]
Summary
Glioblastoma (GBM) is a primary brain tumor with a 5-year survival rate of ≤5%. We have shown earlier that GBM-antibody-linked curcumin (CC) and phytosomal curcumin (CCP) rescue 50–60% of GBM-bearing mice while repolarizing the tumor-associated microglia/macrophages (TAM) from the tumor-promoting M2-type to the tumoricidal M1-type. After surgical excision of the tumor, most GBM patients are treated with radiation plus chemotherapy for a few weeks, which is followed by a chemotherapy regimen that involves a 5-day cycle of 150–200 mg/m2/day temozolomide (TMZ) every 28 days [1, 3] This 5-day cycle is applied every 28 days as opposed to a prolonged treatment with lower doses (e.g. 75 mg/m2/day) because prolonged TMZ chemotherapy yields severe lymphopenia and suppression of the immune system [4, 5] and development of chemotherapy resistance by the cancer cells [6, 7]. Instead of using xenografts in immunocompromised mice, we employed the widely used immunocompetent, syngeneic C57BL6 mouse model with orthotopically implanted mouse glioblastoma GL261 cells [8,9,10]
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