T cells expressing checkpoint receptor TIGIT are enriched in follicular lymphoma tumors and characterized by reversible suppression of T-cell receptor signaling

Sarah E Josefsson, Kanutte Huse, Arne Kolstad, Klaus Beiske, Daniela Pende, Chloé B Steen, Else Marit Inderberg, Ole Christian Lingjærde, Bjørn Østenstad, Erlend B Smeland, Ronald Levy, Jonathan M Irish, June H Myklebust

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE: T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing co-inhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets.

EXPERIMENTAL DESIGN: Surface expression of 9 co-inhibitory 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 TIGIT ligands were detected by immunohistochemistry.

RESULTS: TIGIT was a frequently expressed co-inhibitory receptor in FL, expressed by the majority of CD8 T effector memory cells, which commonly co-expressed 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 IFN-γ, 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 in vitro culture. The co-stimulatory receptor CD226 was downregulated in TIGIT+ compared to TIGIT-CD8 FL T cells, further skewing the balance towards immunosuppression.

CONCLUSIONS: TIGIT blockade is a relevant strategy for improved immunotherapy in FL. A deeper understanding of the interplay between co-inhibitory receptors and key T-cell signaling events can further assist in engineering immunotherapeutic regimens to improve clinical outcomes of cancer patients.

Original languageEnglish
JournalClinical Cancer Research
DOIs
Publication statusE-pub ahead of print - Dec 7 2017

Keywords

  • Journal Article

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