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 2

Gal1 mediates T cell exclusion from the tumor microenvironment by inhibiting T cell infiltration.

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Gal1 mediates T cell exclusion from the tumor microenvironment by inhibi...
(A) Schematic representation of transendothelial migration assay. (B) Quantification of T cell migration through preconditioned ECs. Mouse ECs (C166) pretreated for 24 hours with MOC2 Gal1 WT or Gal1-KO CM, with or without anti-Gal1 antibody, were seeded onto Transwell inserts. T cells (2 × 105) were seeded onto the upper chamber of the Transwell. The number of migrated cells at the bottom of the well was quantified 4 hours after transfer. (C) Schematic of adoptive T cell transfer experimental design. (D) Representative images of adoptively transferred CSFE-labeled T cells (green) and dextran rhodamine–stained vasculature (red) in MOC2 Gal1 WT or Gal1-KO tumors following cryosectioning and imaging using a ×40 objective (scale bars: 250 μm). (E) Flow cytometric plots and quantification graphs showing the percentage of adoptively transferred live CD3+ T cells in dissociated MOC2 Gal1 WT or Gal1-KO tumors and respective spleens from tumor-bearing mice. SSC-A, side scatter area. (F) Quantification of adoptively transferred T cells in MOC2 Gal1 WT tumors from mice treated for 8 days with isotype IgG or 200 μg anti-Gal1 antibody every 4 days. Each dot represents 1 mouse (n = 4–5 mice). (G) Schematic representation showing the donor and recipient mice in the adoptive transfer experiments. (H) Quantification of T cells after 48 hours in MOC2 Gal1 WT or Gal1-KO tumors from mice that received splenic T cells from donor mice bearing either MOC1 Gal1 WT or Gal1-KO tumors. *P < 0.05, **P < 0.01, and ***P < 0.001. Each dot represents 2 mice (n = 4–5 mice). Data are presented as the mean ± SD. A 1-way ANOVA with Tukey’s adjustment was used for comparison of multiple treatments (B and H); a 2-tailed Student’s t test was used for comparison of the single treatment with the control (E and F).