T Cells Expressing Checkpoint Receptor TIGIT Are Enriched in Follicular Lymphoma Tumors and Characterized by Reversible Suppression of T-cell Receptor Signaling

• Published in: Clinical cancer research 2018-02, Vol.24 (4), p.870-881
• Main Authors: Josefsson, Sarah E, Huse, Kanutte, Kolstad, Arne, Beiske, Klaus, Pende, Daniela, Steen, Chloé B, Inderberg, Else Marit, Lingjærde, Ole Christian, Østenstad, Bjørn, Smeland, Erlend B, Levy, Ronald, Irish, Jonathan M, Myklebust, June H
• Format: Article
• Language: English
• Subjects: Cancer; CD8 antigen; Cell culture; Computer memory; Cytometry; Dendritic cells; Effector cells; Exhaustion; Experimental design; Flow cytometry; Immune checkpoint; Immunohistochemistry; Immunosuppression; Immunotherapy; Ligands; Lymph nodes; Lymphocytes; Lymphocytes T; Lymphoma; Memory cells; PD-1 protein; Peripheral blood; Phosphorylation; Receptor mechanisms; Receptors; Signaling; T cell receptors; Tumors; γ-Interferon
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-2337

T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing coinhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets. Surface expression of 9 coinhibitory receptors governing T-cell function was characterized in T-cell subsets from FL lymph node tumors and from healthy donor tonsils and peripheral blood samples, using high-dimensional flow cytometry. The results were integrated with T-cell receptor (TCR)-induced signaling and cytokine production. Expression of T-cell immunoglobulin and ITIM domain (TIGIT) ligands was detected by immunohistochemistry. TIGIT was a frequently expressed coinhibitory receptor in FL, expressed by the majority of CD8 T effector memory cells, which commonly coexpressed exhaustion markers such as PD-1 and CD244. CD8 FL T cells demonstrated highly reduced TCR-induced phosphorylation (p) of ERK and reduced production of IFNγ, while TCR proximal signaling (p-CD3ζ, p-SLP76) was not affected. The TIGIT ligands CD112 and CD155 were expressed by follicular dendritic cells in the tumor microenvironment. Dysfunctional TCR signaling correlated with TIGIT expression in FL CD8 T cells and could be fully restored upon culture. The costimulatory receptor CD226 was downregulated in TIGIT compared with TIGIT CD8 FL T cells, further skewing the balance toward immunosuppression. TIGIT blockade is a relevant strategy for improved immunotherapy in FL. A deeper understanding of the interplay between coinhibitory receptors and key T-cell signaling events can further assist in engineering immunotherapeutic regimens to improve clinical outcomes of cancer patients. .