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

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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

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Follicular Lymphoma
T-Cell Antigen Receptor
T-Lymphocytes
Neoplasms
Costimulatory and Inhibitory T-Cell Receptors
T-Lymphocyte Subsets
Follicular Dendritic Cells
Ligands
Tumor Microenvironment
Palatine Tonsil
Immunotherapy
Immunosuppression
Flow Cytometry
Down-Regulation
Lymph Nodes
Immunohistochemistry
Phosphorylation
Tissue Donors
Cytokines

Keywords

  • Journal Article

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

In: Clinical Cancer Research, 07.12.2017.

Research output: Contribution to journalArticle

Josefsson, SE, Huse, K, Kolstad, A, Beiske, K, Pende, D, Steen, CB, Inderberg, EM, Lingjærde, OC, Østenstad, B, Smeland, EB, Levy, R, Irish, JM & Myklebust, JH 2017, 'T cells expressing checkpoint receptor TIGIT are enriched in follicular lymphoma tumors and characterized by reversible suppression of T-cell receptor signaling', Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-17-2337
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. / T cells expressing checkpoint receptor TIGIT are enriched in follicular lymphoma tumors and characterized by reversible suppression of T-cell receptor signaling. In: Clinical Cancer Research. 2017.
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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.",
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T1 - T cells expressing checkpoint receptor TIGIT are enriched in follicular lymphoma tumors and characterized by reversible suppression of T-cell receptor signaling

AU - Josefsson, Sarah E

AU - Huse, Kanutte

AU - Kolstad, Arne

AU - Beiske, Klaus

AU - Pende, Daniela

AU - Steen, Chloé B

AU - Inderberg, Else Marit

AU - Lingjærde, Ole Christian

AU - Østenstad, Bjørn

AU - Smeland, Erlend B

AU - Levy, Ronald

AU - Irish, Jonathan M

AU - Myklebust, June H

N1 - Copyright ©2017, American Association for Cancer Research.

PY - 2017/12/7

Y1 - 2017/12/7

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1158/1078-0432.CCR-17-2337

DO - 10.1158/1078-0432.CCR-17-2337

M3 - Article

C2 - 29217528

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

ER -