Targeting legumain-mediated cell-cell interaction sensitizes glioblastoma to immunotherapy in preclinical models
Lizhi Pang, Songlin Guo, Yuyun Huang, Fatima Khan, Yang Liu, Fei Zhou, Justin D. Lathia, Peiwen Chen
Lizhi Pang, Songlin Guo, Yuyun Huang, Fatima Khan, Yang Liu, Fei Zhou, Justin D. Lathia, Peiwen Chen
View: Text | PDF
Research Article Immunology Oncology

Targeting legumain-mediated cell-cell interaction sensitizes glioblastoma to immunotherapy in preclinical models

Abstract

Tumor-associated macrophages (TAMs) are the most prominent immune cell population in the glioblastoma (GBM) tumor microenvironment and play critical roles in promoting tumor progression and immunosuppression. Here we identified that TAM-derived legumain (LGMN) exhibited a dual role in regulating the biology of TAMs and GBM cells. LGMN promoted macrophage infiltration in a cell-autonomous manner by activating the GSK3β/STAT3 pathway. Moreover, TAM-derived LGMN activated integrin αv/AKT/p65 signaling to drive GBM cell proliferation and survival. Targeting of LGMN-directed macrophage (inhibiting GSK3β and STAT3) and GBM cell (inhibiting integrin αv) mechanisms resulted in an antitumor effect in immunocompetent GBM mouse models that was further enhanced by combination with anti–PD-1 therapy. Our study reveals a paracrine and autocrine mechanism of TAM-derived LGMN that promotes GBM progression and immunosuppression, providing effective therapeutic targets to improve immunotherapy in GBM.

Authors

Lizhi Pang, Songlin Guo, Yuyun Huang, Fatima Khan, Yang Liu, Fei Zhou, Justin D. Lathia, Peiwen Chen

×

Figure 6

Combined inhibition of integrin αv and GSK3β or STAT3 activates antitumor immunity.

Options: View larger image (or click on image) Download as PowerPoint
Combined inhibition of integrin αv and GSK3β or STAT3 activates antitumo...
(A) Survival curves of C57BL/6 mice implanted with CT2A cells. Mice were treated with integrin αv inhibitor cilengitide (30 mg/kg, i.p., daily), STAT3 inhibitor WP1066 (30 mg/kg, i.p., daily), and GSK3β inhibitor AR-A014418 (30 mg/kg, i.p., daily). For T cell depletion, anti-CD8 (Bio X Cell, BE0061, clone 2.43) or anti-CD4 (Bio X Cell, BE003-1, clone GK1.5) antibodies were injected intraperitoneally (300 mg per mouse) starting on day 2 after tumor injection for 3 consecutive days and every 5 days thereafter. n = 6–8 mice per group. (B and C) Representative images and quantification of flow cytometry for percentage of CD45+CD3+CD4+CD69+ cells (B) and CD45+CD3+CD8+CD69+ cells (C) in tumor tissues from size-matched CT2A tumor–bearing C57BL/6 mice. n = 3 independent samples. (D) Representative images and quantification of IF analysis for CD4+CD69+ and CD8+CD69+ cells in size-matched CT2A tumors from C57BL/6 mice. n = 4 independent samples. Scale bars: 25 μm. Log-rank test (A); 1-way ANOVA test (B–D). *P < 0.05, **P < 0.01, ***P < 0.001.