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Glioma-derived galectin-1 regulates innate and adaptive antitumor immunity

Significance Statement

High-grade gliomas (HGG) are the most common primary tumors in the central nervous system in adults. The current treatment pillars consist of maximal safe resection of the tumor mass followed by chemo- and radiotherapy. Unfortunately, despite state-of-the-art oncological treatment, HGG remains among the most devastating and deadliest of all human cancers. The highly malignant behavior of HGG is attributed to extensive angiogenesis, tumor-induced immune evasion, brain invasion and consequent resistance to cytotoxic therapies. As a consequence, residual tumor cells give rise to a recurrent tumor in virtually every treated patient. Hence, there is an urgent need for new therapies that reverse treatment resistance and that limit angiogenesis and invasion.

Recent data from our research group and collaborators have demonstrated that galectin-1, a hypoxia-sensitive glycan-binding protein, may serve as a critical “molecular key-hub” linking multiple pathways involved in treatment resistance and disease recurrence. Galectin-1 has been demonstrated to enhance glioma cell migration, to stimulate angiogenesis and to protect malignant glioma cells against chemo- and radiotherapy. Moreover, in this paper we demonstrated that glioma-derived galectin-1 is also capable of modulating both innate and adaptive anti-glioma immune responses and that the targeting of glioma-derived galectin-1 prolongs the survival of glioma-bearing mice both in the absence and in the presence of dendritic cell-based immunotherapy.

The diverse role of galectin-1 in HGG supports the development and clinical assessment of galectin-1-targeting molecules. With respect to HGG, the ideal galectin-1-targeting drug is specific for galectin-1 and targets both its extracellular, carbohydrate-dependent functions as well as its intracellular functions which are predominantly mediated through protein-protein interactions. Among all of the different approaches that could be used to interfere with the function of galectin-1 within the tumor microenvironment, approaches that are based on RNA interference have gained our interest. These approaches work at the post-transcriptional level and rely on the cellular uptake of synthetic siRNA molecules and the subsequent degradation of the target mRNA (1;2). Early proof-of-principle studies in animal models have strengthened the usefulness of these small synthetic siRNA molecules as specific and powerful inhibitors of gene expression without significant toxicity. These synthetic siRNA molecules have a broad range of clinical applications as theoretically siRNA molecules can be designed to silence almost any gene in a sequence-specific manner. To date, 32 clinical trials are registered at ‘http://www.clinicaltrials.gov’ in which the usefulness and safety of several siRNA molecules are explored in many kinds of diseases. Interestingly, among these reported trials, 12 explore the usefulness of siRNA in cancer therapy. Although many hurdles remain for applying these technologies in the treatment of cancer, these early clinical results demonstrate that the clinical application of synthetic siRNA is feasible and safe and has real potential as a genetic-based therapy, especially when combined with a synthetic non-viral carrier. With respect to HGG, the intranasal (rather than intraventricular) delivery of such nanoparticles is currently being explored in our laboratory as a non-invasive and promising route that can bypass the blood-brain-barrier and which has limited systemic side effects (3).

Reference List

(1)    Davidson BL, McCray PB, Jr. Current prospects for RNA interference-based therapies. Nat Rev Genet 2011 May;12(5):329-40.

(2)    Pecot CV, Calin GA, Coleman RL, Lopez-Berestein G, Sood AK. RNA interference in the clinic: challenges and future directions. Nat Rev Cancer 2011 Jan;11(1):59-67.

(3)    Van WM, Wauthoz N, Rosiere R, Amighi K, Mathieu V, Lefranc F, Van Gool SW, De VS. Formulations for Intranasal Delivery of Pharmacological Agents to Combat Brain Disease: A New Opportunity to Tackle GBM? Cancers (Basel) 2013;5(3):1020-48.

Verschuere T, Toelen J, Maes W, Poirier F, Boon L, Tousseyn T, Mathivet T, Gerhardt H, Mathieu V, Kiss R, Lefranc F, Van Gool SW, De Vleeschouwer S.

Int J Cancer. 2014 Feb 15;134(4):873-84.

Department of Neurosciences, Laboratory of Experimental Neurosurgery and Neuroanatomy, KU Leuven, Leuven, Belgium.

Abstract

Galectin-1 is a glycan-binding protein, which is involved in the aggressiveness of glioblastoma (GBM) in part by stimulating angiogenesis. In different cancer models, galectin-1 has also been demonstrated to play a pivotal role in tumor-mediated immune evasion especially by modulating cells of the adaptive immune system. It is yet unknown whether the absence or presence of galectin-1 within the glioma microenvironment also causes qualitative or quantitative differences in innate and/or adaptive antitumor immune responses. All experiments were performed in the orthotopic GL261 mouse high-grade glioma model. Stable galectin-1 knockdown was achieved via transduction of parental GL261 tumor cells with a lentiviral vector encoding a galectin-1-targeting miRNA. We demonstrated that the absence of tumor-derived but not of host-derived galectin-1 significantly prolonged the survival of glioma-bearing mice as such and in combination with dendritic cell (DC)-based immunotherapy. Both flow cytometric and pathological analysis revealed that the silencing ofglioma-derived galectin-1 significantly decreased the amount of brain-infiltrating macrophages and myeloid-derived suppressor cells (MDSC) in tumor-bearing mice. Additionally, we revealed a pro-angiogenic role for galectin-1 within the glioma microenvironment. The data provided in this study reveal a pivotal role for glioma-derived galectin-1 in the regulation of myeloid cell accumulation within the glioma microenvironment, the most abundant immune cell population in high-grade gliomas. Furthermore, the prolonged survival observed in untreated and DC-vaccinated glioma-bearing mice upon the silencing of tumor-derived galectin-1 strongly suggest that the in vivo targeting of tumor-derived galectin-1 might offer a promising and realistic adjuvant treatment modality in patients diagnosed with GBM.

© 2013 UICC.

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