Galectin-1–driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance
Dhanya K. Nambiar, … , Amato Giaccia, Quynh Thu Le
Dhanya K. Nambiar, … , Amato Giaccia, Quynh Thu Le
Published November 11, 2019
Citation Information: J Clin Invest. 2019;129(12):5553-5567. https://doi.org/10.1172/JCI129025.
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Research Article Oncology

Galectin-1–driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance

Abstract

Immune checkpoint inhibitors (ICIs), although promising, have variable benefit in head and neck cancer (HNC). We noted that tumor galectin-1 (Gal1) levels were inversely correlated with treatment response and survival in patients with HNC who were treated with ICIs. Using multiple HNC mouse models, we show that tumor-secreted Gal1 mediates immune evasion by preventing T cell migration into the tumor. Mechanistically, Gal1 reprograms the tumor endothelium to upregulate cell-surface programmed death ligand 1 (PD-L1) and galectin-9. Using genetic and pharmacological approaches, we show that Gal1 blockade increases intratumoral T cell infiltration, leading to a better response to anti-PD1 therapy with or without radiotherapy. Our study reveals the function of Gal1 in transforming the tumor endothelium into an immune-suppressive barrier and that its inhibition synergizes with ICIs.

Authors

Dhanya K. Nambiar, Todd Aguilera, Hongbin Cao, Shirley Kwok, Christina Kong, Joshua Bloomstein, Zemin Wang, Vangipuram S. Rangan, Dadi Jiang, Rie von Eyben, Rachel Liang, Sonya Agarwal, A. Dimitrios Colevas, Alan Korman, Clint T. Allen, Ravindra Uppaluri, Albert C. Koong, Amato Giaccia, Quynh Thu Le

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Figure 3

Gal1 preconditioning upregulates STAT1 activation on ECs.

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Gal1 preconditioning upregulates STAT1 activation on ECs. (A) Images sho...
(A) Images showing vessel normalization as measured by costaining of CD31 (red) and α-SMA (green) in MOC2 Gal1 WT and MOC2 Gal1-KO tumor sections (~100 mm3 in size). Scale bars: 100 μm. (B) Images showing vessel perfusion in vivo using intravenous injection of Hoechst 33258 (blue) and rhodamine dextran (red) dyes into Gal1 WT or Gal1-KO tumor–bearing mice at comparable volumes. Data are presented as the mean ± SD (n = 3). Scale bars: 25 μm. (C) Transendothelial migration of T cells across NECs or TECs isolated from MOC2 Gal1 WT (TECs – Gal1 WT) or Gal1-KO (TECs – Gal1-KO) tumors. (D) Representative histogram and quantification of PD-L1 expression on lung NECs and TECs (CD31+CD45–) and tumor cells (CD31–CD45–) isolated from MOC2 Gal1 WT or Gal1-KO tumors. Each dot represents 1 mouse (n = 3). (E) Immunoblots of pSTAT1 and total STAT1 in C166 mouse ECs treated with CM from MOC2 Gal1 WT cells, with or without anti-Gal1 antibody, or Gal1-KO cells or HUVECs treated with different concentrations of rGal1 for 3 hours. (F) Immunoblots of pSTAT1, pJAK2, and JAK2 in C166 mouse ECs treated with CM from MOC2 Gal1 WT cells, with or without anti-Gal1 antibody (10 μg/mL) or JAK inhibitor (100 nM), or from Gal1-KO cells treated for 24 hours in 1% serum-containing media. The numbers below the immunoblots in E and F show the relative quantitation of band intensities calculated using ImageJ (NIH). **P < 0.01; ***P < 0.001. A 2-tailed Student’s t test was used for comparison of the single treatment with the control (D); a 1-way ANOVA with Tukey’s adjustment was used for comparison of multiple treatments (C and D).