Sensitization of glioblastoma tumor micro-environment to chemo- and immunotherapy by Galectin-1 intranasal knock-down strategy

Abstract

In this study, we evaluated the consequences of reducing Galectin-1 (Gal-1) in the tumor micro-environment (TME) of glioblastoma multiforme (GBM), via nose-to-brain transport. Gal-1 is overexpressed in GBM and drives chemo- and immunotherapy resistance. To promote nose-to-brain transport, we designed siRNA targeting Gal-1 (siGal-1) loaded chitosan nanoparticles that silence Gal-1 in the TME. Intranasal siGal-1 delivery induces a remarkable switch in the TME composition, with reduced myeloid suppressor cells and regulatory T cells, and increased CD4+ and CD8+ T cells. Gal-1 knock-down reduces macrophages’ polarization switch from M1 (pro-inflammatory) to M2 (anti-inflammatory) during GBM progression. These changes are accompanied by normalization of the tumor vasculature and increased survival for tumor bearing mice. The combination of siGal-1 treatment with temozolomide or immunotherapy (dendritic cell vaccination and PD-1 blocking) displays synergistic effects, increasing the survival of tumor bearing mice. Moreover, we could confirm the role of Gal-1 on lymphocytes in GBM patients by matching the Gal-1 expression and their T cell signatures. These findings indicate that intranasal siGal-1 nanoparticle delivery could be a valuable adjuvant treatment to increase the efficiency of immune-checkpoint blockade and chemotherapy.

Lack of galectin‐1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model

“…The marked up-regulation of Gal1 in the liver, its protumorigenic effects, and its broad anti-inflammatory activity in a wide variety of pathologic settings prompted us to investigate the role of this glycan-binding protein in CLIdriven HCC development. Targeted inhibition of Lgals1 expression in a variety of tumors, including melanoma cells, Hodgkin lymphoma, lung adenocarcinoma, pancreatic adenocarcinoma, breast adenocarcinoma and glioblastoma, resulted in unleashed antitumor immunity, leading to inhibition of tumor growth and metastasis in syngeneic mice (26)(27)(28)(29)(30). From an immunologic standpoint, this lectin impairs CD8, T h 1, and T h 17; deactivates antigen-presenting cells; inhibits NK cells; and promotes expansion of regulatory T cells (7,29,(31)(32)(33).…”

An Integrated Meta-Analysis of Secretome and Proteome Identify Potential Biomarkers of Pancreatic Ductal Adenocarcinoma

“…Among our protein pool, we found Galectin-1 (LGALS1), a glycan-binding protein that is highly expressed in PDAC stroma, and a significant contributor to pancreatic cancer progression [148]. Increased LGALS1 expression in cancer cells such as lung, liver, ovarian, glioblastoma, and lymphoma has been associated with drug resistance (temozolomide, sorafenib, rituximab, and cisplatin) [149][150][151][152][153][154][155][156]. Proteins with increased expression in cancers identified here, such as Galectin-3 (LGALS3), Peptidyl-prolyl cis-trans isomerase A (PPIA), Alpha-enolase (ENO1), L-lactate dehydrogenase A chain (LDHA), Protein/nucleic acid deglycase DJ-1 (PARK7), and Cathepsin D (CTSD), also confer resistance to chemotherapy [157][158][159][160][161][162][163][164][165].…”

Intranasal delivery of stem cell-based therapies for the treatment of brain malignancies

“…The inherent ability of stem cells to migrate to the tumor may offer benefits when delivered intranasally that not conferred by other therapeutic vectors, namely viruses or NPs, without further modification. However, both viral [39–41] and NP [42] systems have demonstrated therapeutic benefit against glioma when delivered via the intranasal route. While there is limited literature available directly comparing the various techniques, we have demonstrated the significant survival benefit to irradiated mice after delivering oncolytic virus in NSCs cultured in hypoxic conditions in comparison to oncolytic viruses alone [5].…”