Intratumoral administration of the antisecretory peptide AF16 cures murine gliomas and modulates macrophage functions

Abstract

Glioblastoma has remained the deadliest primary brain tumor while its current therapy offers only modest survival prolongation. Immunotherapy has failed to record notable benefits in routine glioblastoma treatment. Conventionally, immunotherapy relies on T cells as tumor-killing agents; however, T cells are outnumbered by macrophages in glioblastoma microenvironment. In this study, we explore the effect of AF16, a peptide from the endogenous antisecretory factor protein, on the survival of glioma-bearing mice, the tumor size, and characteristics of the tumor microenvironment with specific focus on macrophages. We elucidate the effect of AF16 on the inflammation-related secretome of human and murine macrophages, as well as human glioblastoma cells. In our results, AF16 alone and in combination with temozolomide leads to cure in immunocompetent mice with orthotopic GL261 gliomas, as well as prolonged survival in immunocompromised mice. We recorded decreased tumor size and changes in infiltration of macrophages and T cells in the murine glioma microenvironment. Human and murine macrophages increased expression of proinflammatory markers in response to AF16 treatment and the same effect was seen in human primary glioblastoma cells. In summary, we present AF16 as an immunomodulatory factor stimulating pro-inflammatory macrophages with a potential to be implemented in glioblastoma treatment protocols.

Antisecretory factor in breastmilk is associated with reduced incidence of sepsis in preterm infants

“… 60 A recent study explored the effect of treatment with the active peptide of AF, AF-16, in glioma-bearing mice, human and murine cells and demonstrated prolonged survival, decreased tumour size, changes in macrophage and T-cells invasion, and increased pro-inflammatory markers. 61 They found modulation of several inflammatory markers, for example, IL-8, MCP2, TNFSF14, by AF-16, 61 which may strengthen the associations demonstrated in the present study with a suggested role of AF in regulation of inflammatory processes. However, the mechanisms of positive or inverse associations need to be further studied.…”

Antisecretory factor is safe to use as add-on treatment in newly diagnosed glioblastoma

“…Also, it has been proposed that AF may be involved in the complement cascade of the innate immune system [ 38 ]. Most recently, a study of AF16, an active peptide from the AF protein, showed that AF16 increased the secretion of typically proinflammatory cytokines from human and mouse M0 macrophages, and that intratumoral co-administration of TMZ and AF16 resulted in synergistically increased survival in glioma-bearing mice [ 26 ]. Taken together, the antisecretory and immunomodulatory mechanisms exerted by AF may contribute to suppressing tumor progression by reducing tumor-promoting inflammation and lowering tumoral IFP, as well as giving symptomatic relief by reducing brain edema.…”

“…They also showed that SPC-flakes combined with TMZ successfully prevented tumor growth and increased overall survival at 120 days from 30 to 100% compared to TMZ monotherapy [ 25 ]. Our own results show that intratumoral delivery of an active AF peptide, AF-16, boosts the effect of intratumoral chemotherapy and immune reactivity in an experimental glioma model [ 26 ].…”