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 5

Gal1 inhibition reverses PD1 blockade resistance in a HNC model.

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Gal1 inhibition reverses PD1 blockade resistance in a HNC model. Tumor g...
Tumor growth curves in C57BL/6 mice subcutaneously implanted with (A) MOC2 Gal1 WT or Gal1-KO tumor cells (2.5 × 105) or (B) MEERL Gal1 WT or Gal1-KO tumor cells (1 × 106). Following tumor establishment (~75 mm3), mice were treated with either isotype IgG or anti-PD1 antibody (200 μg i.p. every 4 days) for 4 weeks. (C) Quantification of lung metastatic foci at the end of treatment in mice bearing MOC2 tumors. (D) Number of inguinal (left and right) and axillary (left and right) nodal metastases in each mouse for each treatment group. Each dot represents 1 mouse (n = 5). (E) C57BL/6 mice were implanted with 4 × 104 MOC2 Gal1 WT cells in the buccal cavity (orthotopic), followed by treatment with isotype IgG or anti-Gal1 antibody (150 μg, i.p.) and/or anti-PD1 antibody (200 μg, i.p.) every 4 days. Tumor growth was measured at regular intervals using a caliper (n = 5–8 mice/group). (F) Representative images and quantification of lung metastatic foci after treatment in the MOC2 orthotopic model (n = 5 mice/group). Scale bars: 250 μm. (G) Quantification of CD8+ T cells in orthotopically implanted tumors after treatment. (H) Representative images showing immunohistochemical staining for Gal1 in biopsy samples from patients with HNSCC prior to immunotherapy treatment. Stainings were used for the grading of high or low Gal1 expression levels. Scale bar: 100 μm. (I) Kaplan-Meier analysis showing survival probability based on the expression of Gal1 protein in the tumor cells and tumor stroma of patients (n = 33 patients) with recurrent/metastatic HNC treated with immune checkpoint therapy. High Gal1 (high Gal1 levels in either the tumor or stroma); low Gal1 (low Gal1 levels in both the tumor and stroma). Data are presented as the mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001. A 1-way ANOVA with Tukey’s adjustment was used for comparison of multiple treatments (C, D, F, and G); a repeated-measures ANOVA was used for measurement of tumor growth over time (A, B, and E). Overall survival was summarized using Kaplan-Meier curves, and the groups were compared using log-rank tests (I). The rates of response to immunotherapy and distribution of Gal1 staining were analyzed using a χ2 test (I).