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

doi:10.1172/JCI129025

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

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71 Scopus citations

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.

Original language	English (US)
Pages (from-to)	5553-5567
Number of pages	15
Journal	Journal of Clinical Investigation
Volume	129
Issue number	12
DOIs	https://doi.org/10.1172/JCI129025
State	Published - Dec 2 2019

ASJC Scopus subject areas

Medicine(all)

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10.1172/JCI129025

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Nambiar, D. K., Aguilera, T., Cao, H., Kwok, S., Kong, C., Bloomstein, J., Wang, Z., Rangan, V. S., Jiang, D., Von Eyben, R., Liang, R., Agarwal, S., Dimitrios Colevas, A., Korman, A., Allen, C. T., Uppaluri, R., Koong, A. C., Giaccia, A., & Le, Q. T. (2019). Galectin-1-driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance. Journal of Clinical Investigation, 129(12), 5553-5567. https://doi.org/10.1172/JCI129025

Nambiar, DK, Aguilera, T, Cao, H, Kwok, S, Kong, C, Bloomstein, J, Wang, Z, Rangan, VS, Jiang, D, Von Eyben, R, Liang, R, Agarwal, S, Dimitrios Colevas, A, Korman, A, Allen, CT, Uppaluri, R, Koong, AC, Giaccia, A & Le, QT 2019, 'Galectin-1-driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance', Journal of Clinical Investigation, vol. 129, no. 12, pp. 5553-5567. https://doi.org/10.1172/JCI129025

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title = "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.",

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

note = "Funding Information: We thank William Spanos for the HPV+ cell lines. We acknowledge support form the NIH (R01CA161585-03 and P01CA067166). We thank Colleen and Rick Pouliot for their support of the project. We also acknowledge Manish Chamoli for the exchange of ideas and provision of reagents for the project. Publisher Copyright: Copyright: {\textcopyright} 2019, American Society for Clinical Investigation.",

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doi = "10.1172/JCI129025",

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AU - Nambiar, Dhanya K.

AU - Aguilera, Todd

AU - Cao, Hongbin

AU - Kwok, Shirley

AU - Kong, Christina

AU - Bloomstein, Joshua

AU - Wang, Zemin

AU - Rangan, Vangipuram S.

AU - Jiang, Dadi

AU - Von Eyben, Rie

AU - Liang, Rachel

AU - Agarwal, Sonya

AU - Dimitrios Colevas, A.

AU - Korman, Alan

AU - Allen, Clint T.

AU - Uppaluri, Ravindra

AU - Koong, Albert C.

AU - Giaccia, Amato

AU - Le, Quynh Thu

N1 - Funding Information: We thank William Spanos for the HPV+ cell lines. We acknowledge support form the NIH (R01CA161585-03 and P01CA067166). We thank Colleen and Rick Pouliot for their support of the project. We also acknowledge Manish Chamoli for the exchange of ideas and provision of reagents for the project. Publisher Copyright: Copyright: © 2019, American Society for Clinical Investigation.

PY - 2019/12/2

Y1 - 2019/12/2

N2 - 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.

AB - 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.

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

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