Ccl5 establishes an autocrine high-grade glioma growth regulatory circuit critical for mesenchymal glioblastoma survival

Abstract

Glioblastoma (GBM) is the most common malignant brain tumor in adults, with a median survival of 15 months. These poor clinical outcomes have prompted the development of drugs that block neoplastic cancer cell growth; however, non-neoplastic cell-derived signals (chemokines and cytokines) in the tumor microenvironment may also represent viable treatment targets. One such chemokine, Ccl5, produced by low-grade tumor-associated microglia, is responsible for maintaining neurofibromatosis type 1 (NF1) mouse optic glioma growth in vivo. Since malignant gliomas may achieve partial independence from growth regulatory factors produced by non-neoplastic cells in the tumor microenvironment by producing the same cytokines secreted by the stromal cells in their low-grade counterparts, we tested the hypothesis that CCL5/CCL5-receptor signaling in glioblastoma creates an autocrine circuit important for high-grade glioma growth. Herein, we demonstrate that increased CCL5 expression was restricted to both human and mouse mesenchymal GBM (M-GBM), a molecular subtype characterized by NF1 loss. We further show that the NF1 protein, neurofibromin, negatively regulates Ccl5 expression through suppression of AKT/mTOR signaling. Consistent with its role as a glioblastoma growth regulator, Ccl5 knockdown in M-GBM cells reduces M-GBM cell survival in vitro, and increases mouse glioblastoma survival in vivo. Finally, we demonstrate that Ccl5 operates through an unconventional CCL5 receptor, CD44, to inhibit M-GBM apoptosis. Collectively, these findings reveal an NF1-dependent CCL5-mediated pathway that regulates M-GBM cell survival, and support the concept that paracrine factors important for low-grade glioma growth can be usurped by high-grade tumors to create autocrine regulatory circuits that maintain malignant glioma survival.

Serum Chemokine-release Profiles in AML-patients Might Contribute to Predict the Clinical Course of the Disease

“…CCL5 is secreted by tumor cells in various types of cancer and hematological malignancies like Multiple Myeloma (Aldinucci and Colombatti 2014). In mesenchymal glioblastoma, tumor cells express high levels of CCL5 as an autocrine signal to increase cell survival (Pan et al 2017). In subtypes of aggressive breast cancer (Triple-negative breast cancer) CXCL8, CCL2 and CCL5 act as pro-metastatic factors in the tumor microenvironment (Liubomirski et al 2019).…”

The power of the few

“…Similarly, EGFR mutant glioblastoma cells increase IL-8 production, which additionally enhances glioblastoma stem cell growth. Moreover, chemokines (such as CCL5, secreted by glioblastoma cells) can create autocrine growth-promoting circuits in which tumor cells produce their own mitogens in a self-stimulating manner to promote cell survival (Pan et al 2017).…”

CAR T cells for brain tumors: Lessons learned and road ahead

“…This work is under further investigation in a phase I clinical trial (NCT03602157). Expressed on CD4+ but not on mature CD8+ T cells, CCR4 could be a versatile, albeit promiscuous, strategy as it recognizes the chemokines CCL2, CCL4, CCL5, CCL17, and CCL21, which have all been associated with glioma . Despite this connection, engineered chemokine receptors have not specifically been evaluated in CAR T cells for the treatment of brain tumors.…”

“…Engineering CCL17, and CCL21, which have all been associated with glioma. [208][209][210][211] Despite this connection, engineered chemokine receptors have not specifically been evaluated in CAR T cells for the treatment of brain tumors. CCL2 is also produced by the glioma microenvironment to recruit both Treg and myeloid-derived suppressor cells.…”