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

Gal1 promotes tumor growth and metastases in a HNC model by causing immune suppression.

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Gal1 promotes tumor growth and metastases in a HNC model by causing immu...
(A) Kaplan-Meier analysis of overall survival of patients with HNSCC according to Gal1 gene expression (n = 518 patients, TCGA data set). P = 0.0016. (B) ELISA results for secreted levels of Gal1 in murine HNSCC cells (MOC1, MEERL, and MOC2) after 24 hours of normoxia or hypoxia (0.5% O2). (C) Immunoblots show Gal1 deletion with CRISPR/Cas9 in MOC1, MOC2, and MEERL cells and stable lentiviral overexpression of Gal1 in MOC1 (MOC1 + Gal1) cells. (D) Tumor growth curves for C57BL/6 mice subcutaneously implanted with 1 × 106 MOC1 vector control cells (MOC1-Vec) or MOC1 Gal1-overexpressing cells (MOC1-Gal1) (n = 5 mice). (E) Tumor growth curves for C57BL/6 mice subcutaneously implanted with 2.5 × 105 MOC2 Gal1 WT or Gal1-KO cells (n = 5 mice). (F) Tumor growth curves for C57BL/6 mice subcutaneously implanted with 1 × 106 MEERL Gal1 WT or Gal1-KO cells (n = 5 mice/group). (G) Quantification of lung metastases foci after subcutaneous implantation of each cell line. The number of nodules per lung area was quantified by H&E staining (scale bars: 500 μm). In the graph, each dot represents 1 mouse, and the bar indicates the mean. (H) Quantification of LN metastases in mice bearing either MOC2 Gal1 WT or Gal1-KO tumors. (I) Quantification and representative histologic images of metastatic foci in lungs after subcutaneous implantation of MOC2 Gal1 WT or Gal1-KO cells, measured at comparable primary tumor sizes. Scale bars: 250 μm. (J) Quantification of CD4+ and CD8+ T cells in MOC2 Gal1 WT and Gal1-KO tumors at sizes of approximately 100 mm3 and 300 mm3, after enzymatic dissociation and flow cytometric analyses. (K) Flow cytometric analyses of CD44 and CD62L markers on CD3+ T cells from MOC2 Gal1 WT and Gal1-KO tumors. **P < 0.01 and ***P < 0.001. Overall survival was summarized using Kaplan-Meier curves, and groups were compared using log-rank tests (A); repeated-measures ANOVA was used for tumor growth measurement over time (D–F); and a 2-tailed Student’s t test was used for comparisons of single treatment with the control (B, G, and I–K).