Date of Degree


Document Type


Degree Name





Probal Banerjee

Committee Members

Krisnaswami Raja

Mohammed Junaid

Khosrow Kashfi

Marc Symons

Subject Categories

Cancer Biology | Immunity | Nanomedicine | Neoplasms


Glioblastoma (GBM), Curcumin, Cancer therapy, Tumor-associated microglia/macrophages (TAM), NK cells, GBM stem cells, Oncoimmunotherapy


Glioblastoma (GBM) is one of the most deadly forms of cancer with a mean 5-year survival rate of ≤5%. We have used the non-invasive strategy of long-term intranasal (IN) delivery of a glioblastoma-directed adduct of curcumin (CC), CC-CD68Ab, into the brain of murine GBM cell line GL261-implanted mice to study the therapeutic effect of CC on GBM remission. The treatment caused GBM tumor remission in 50% of GL261-implanted GBM mice. A similar rescue rate (60%) was also achieved through long-term intraperitoneal (i.p) infusion of a highly bioavailable phosphotidylcholine (PC)-encapsulated formulation of CC, Curcumin Phytosome Meriva (CCP), into the GL261-implanted GBM mice. However, it has been reported that systemic application of CCP yields only sub-IC50 concentrations of CC in the plasma, which is not likely to kill GBM cells directly. Exploring the oncoimunotherapeutic potential of CC on the tumor microenvironment, we found a striking CCP- and CC-CD68Ab-evoked alteration in the activation phenotype of the Iba1(+) tumor-associated microglia/macrophages (TAM). This involved suppression of the tumor-promoting Arginase1(ARG1)high, IL10high, inducible nitric oxide synthase (iNOS)low, IL12low M2-like TAM along with a concomitant, dramatic expansion of the tumoricidal ARG1low, IL10low, iNOShigh, IL12high M1-like TAM. Simultaneously, we observed a sharp inhibition of activated STAT3 and induction of both activated STAT1 and activated p65 NF-kB in the TAM. TAM-associated activated p65 NF-kB and activated STAT1 are known to synergistically cause the observed expression of iNOS and IL12. Therefore, our novel findings indicate that appropriately delivered CC most likely kills GBM cells via repolarization of the M2-like TAMs to the tumoricidal M1-like phenotype. Additionally, we also observed that long-term CC evoked intra-GBM recruitment of tumoricidal activated natural killer (NK) cells. Since NK cells are known to boost the M1-like phenotype of TAM, we further investigated the function of these NK cells in the repolarization of TAM and in the elimination of GBM and GBM stem cells. To this end, a short-term CCP treatment (five days) caused the GBM tumor to acquire a large number of M1-type macrophages (50-60% of the TAM) and activated NK cells. The treatment also elicited (a) suppression of the M2-like TAM-associated tumor-promoting proteins STAT3, ARG1, and IL10, (b) induction of the M1-like TAM-associated anti-tumor proteins STAT1, iNOS and IL12, (c) elimination of CD133(+) and SOX2(+) GBM stem cells, and (d) activation of caspase3 (apoptosis) in the GBM cells. Eliminating intra-GBM NK cell recruitment and abrogating IL12-mediated NK cell activation and recruitment caused a partial reversal of each of all of these effects. Concomitantly, we observed a CCP-induced potent induction of the chemokine monocyte chemotactic protein-1 (MCP-1) in the TAM. Thus, our results demonstrate that the recruited NK cells mediate a major part of the CCP-evoked elimination of GBM and GBM stem cells and cause stabilization of the M1-like phenotype of the TAM. MCP-1 is known to compromise the blood-brain barrier, exit the brain, and activate peripheral M1-type macrophages which in turn are known to activate NK cells. Based on these observations, we postulate that by binding to peripheral M1-type macrophages and IL12-activated NK cells, the chemokine MCP-1 produced by the GBM-associated M1-like microglia causes recruitment of peripheral immune cells into the GBM to cause elimination of the GBM cells and GBM stem cells.