Abstract 4577: Appropriately delivered curcumin causes recruitment of natural killer cells into glioblastoma brain, stabilizing M1 polarization of tumor-associated microglia

Abstract

Abstract Glioblastoma (GBM) is the most insidious form of primary adult brain tumor with a mean life expectancy of 12-24 months. Previously, we have used the non-invasive strategies of (1) intranasal delivery of a glioblastoma-directed curcumin (CC) adduct (CC-CD68Ab) and (2) the intraperitoneal (i.p.) infusion of a lipid-encapsulated formulation of CC-phytosome to rescue orthotopically GL261-implanted GBM mice and study the effect of CC on the phenotype of the tumor-associated microglial cells (TAMs). Both treatment regimens not only caused tumor remission in 50-60% of GL261-implanted GBM mice, but also induced a dramatic change in the tumor-associated Iba1+ TAMs, suppressing the tumor-promoting Arginase1high, IL10high, iNOSlow, IL12low M2-type TAMs, while simultaneously inducing the Arginase1low, IL10low, iNOShigh, IL12high M1-type TAMs. Concurrently, we observed a marked induction and phosphorylation-mediated activation of microglial p65 NF-kB and STAT1, with concomitant suppression and inactivation of STAT3. p-STAT1high, p-STAT3low M1 microglia are known to cause IL12-dependent recruitment/activation of tumoricidal NKp46high natural killer (NK) cells. In determining the kinetics of CC-induced M1 repolarization of M2-TAMs, we observed that five days of CCP treatment (i.p.) was sufficient to induce a dramatic change in the tumor-associated Iba1+ TAMs, inhibiting the tumor-promoting M2-type TAM population, while activating M1-type microglia. As expected, we observed a concomitant recruitment of NKp46high NK cells into the GBM tumor. Cognizant of the fact that NK cells activate and stabilize the M1-microglia, we eliminated the NK cells in these GBM mice using the NK cell-targeted antibody NK1.1 Ab to observe a significant reduction in CC-evoked repolarization of TAMs. Our results demonstrate a unique oncoimmunotherapeutic function of CC, which when appropriately delivered, not only eliminates GBM directly, but also indirectly elicits recruitment and activation of tumoricidal NK cells and M1-TAMs. Furthermore, maintenance of this CC-evoked M1 phenotype is contingent upon CC-induced recruitment and activation of NK cells. Thus, when delivered appropriately, CC functions on GBM both directly as well as by stimulating and recruiting an army of immune cells that eliminate both GBM and GBM-initiating cells. Citation Format: Sumit Mukherjee, Angela Fried, Rahman Hussaini, Richard White, Aheli Chatterjee, Probal Banerjee. Appropriately delivered curcumin causes recruitment of natural killer cells into glioblastoma brain, stabilizing M1 polarization of tumor-associated microglia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4577. doi:10.1158/1538-7445.AM2017-4577