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CD226 opposes TIGIT to disrupt Tregs in melanoma
Julien Fourcade, … , Alan J. Korman, Hassane M. Zarour
Julien Fourcade, … , Alan J. Korman, Hassane M. Zarour
Published July 25, 2018
Citation Information: JCI Insight. 2018;3(14):e121157. https://doi.org/10.1172/jci.insight.121157.
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Research Article Immunology Oncology

CD226 opposes TIGIT to disrupt Tregs in melanoma

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Abstract

CD4+ Tregs impede T cell responses to tumors. They express multiple inhibitory receptors that support their suppressive functions, including T cell Ig and ITIM domain (TIGIT). In melanoma patients, we show that Tregs exhibit increased TIGIT expression and decreased expression of its competing costimulatory receptor CD226 as compared with CD4+ effector T cells, resulting in an increased TIGIT/CD226 ratio. Tregs failed to upregulate CD226 upon T cell activation. TIGIT+ Tregs are highly suppressive, stable, and enriched in tumors. TIGIT and CD226 oppose each other to augment or disrupt, respectively, Treg suppression and stability. A high TIGIT/CD226 ratio in Tregs correlates with increased Treg frequencies in tumors and poor clinical outcome upon immune checkpoint blockade. Altogether, our findings show that a high TIGIT/CD226 ratio in Tregs regulates their suppressive function and stability in melanoma. They provide the rationale for novel immunotherapies to activate CD226 in Tregs together with TIGIT blockade to counteract Treg suppression in cancer patients.

Authors

Julien Fourcade, Zhaojun Sun, Joe-Marc Chauvin, Mignane Ka, Diwakar Davar, Ornella Pagliano, Hong Wang, Sofiane Saada, Carmine Menna, Rada Amin, Cindy Sander, John M. Kirkwood, Alan J. Korman, Hassane M. Zarour

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Figure 1

Tregs exhibit a high ratio of TIGIT/CD226 expression in the periphery and at tumor sites of melanoma patients.

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Tregs exhibit a high ratio of TIGIT/CD226 expression in the periphery an...
(A and B) Dot plots from 3 representative donors (A) and summary data (B) showing ex vivo percentages and mean fluorescence intensity (MFI) of TIGIT expression by CD25hiFoxp3+CD4+ Tregs (gated among total CD4+ T cells, as shown in A, with frequencies on the left), CD25– and CD25+Foxp3–CD4+ T effector cells (Teffs), and total CD4+ T cells in PBMCs of healthy donors (HDs) and melanoma patients (MPs) and in metastatic melanoma (MM) tumor-infiltrating lymphocytes (TILs). n = 20. (C and D) Dot plots from 3 representative donors (C) and summary data (D) showing ex vivo percentages and MFI of CD226 expression by CD25– or CD25+Foxp3–CD4+ Teffs, CD25hiFoxp3+ Tregs, and total CD4+ T cells in PBMCs of HDs and MPs and in MM TILs. n = 20. (E) Summary data showing the ratio of TIGIT to CD226 ex vivo expression (percentage and MFI) by CD25– or CD25+Foxp3–CD4+ Teffs and CD25hiFoxp3+ Tregs in PBMCs of HDs and MPs and in MM TILs. n = 20. Results represent the mean of independent experiments. P values were obtained by 1-way ANOVA and repeated-measures ANOVA followed by Tukey’s test (B and D) or by Kruskal-Wallis test and Friedman’s test followed by Dunn’s test (E). Horizontal bars depict mean values. Error bars indicate SEM. *P < 0.05; **P < 0.01; ***P < 0.001.

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