Cargando…

TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism

T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immunosuppressive receptor expressed on the surface of immune cells, suppressing immune responses by activating the intracellular negative regulatory signals. TIGIT plays an important role in the pathogenes...

Descripción completa

Detalles Bibliográficos
Autores principales: Shao, Qi, Wang, Lei, Yuan, Maoling, Jin, Xiaohong, Chen, Zhiming, Wu, Changping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511404/
https://www.ncbi.nlm.nih.gov/pubmed/34659197
http://dx.doi.org/10.3389/fimmu.2021.688961
_version_ 1784582754284863488
author Shao, Qi
Wang, Lei
Yuan, Maoling
Jin, Xiaohong
Chen, Zhiming
Wu, Changping
author_facet Shao, Qi
Wang, Lei
Yuan, Maoling
Jin, Xiaohong
Chen, Zhiming
Wu, Changping
author_sort Shao, Qi
collection PubMed
description T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immunosuppressive receptor expressed on the surface of immune cells, suppressing immune responses by activating the intracellular negative regulatory signals. TIGIT plays an important role in the pathogenesis of various tumors, but its immune escape in colorectal cancer remains unclear. We found that the proportion of CD3(+)TIGIT(+) T cells was increased in peripheral blood and cancer tissue in colorectal cancer patients when compared with the healthy donors. These cells exhibited functional defects, low proliferative activity, impaired cytokine production and reduced glucose metabolism. A strong association was also observed between the elevated TIGIT expression and poor prognosis in this cohort. In the in vitro co-culture assays of T cells and tumor cells, the suppressed glucose metabolic activity of T cells was reversed by TIGIT blockade. In addition, this blockade induced the apoptosis and reduced G2/M transit in tumor cells. The antitumor efficacy of TIGIT Ab therapy was further demonstrated in a human colorectal xenograft mice model while co-blockers of TIGIT and PD-1 exhibited synergistic suppressing effects on tumor growth. These results suggest that while TIGIT induces CD3(+) T cell dysfunction in colorectal cancer, co-targeting TIGIT and PD-1 can lead to an effective antitumor response and may serve as a novel therapeutic strategy for colorectal patients.
format Online
Article
Text
id pubmed-8511404
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-85114042021-10-14 TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism Shao, Qi Wang, Lei Yuan, Maoling Jin, Xiaohong Chen, Zhiming Wu, Changping Front Immunol Immunology T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immunosuppressive receptor expressed on the surface of immune cells, suppressing immune responses by activating the intracellular negative regulatory signals. TIGIT plays an important role in the pathogenesis of various tumors, but its immune escape in colorectal cancer remains unclear. We found that the proportion of CD3(+)TIGIT(+) T cells was increased in peripheral blood and cancer tissue in colorectal cancer patients when compared with the healthy donors. These cells exhibited functional defects, low proliferative activity, impaired cytokine production and reduced glucose metabolism. A strong association was also observed between the elevated TIGIT expression and poor prognosis in this cohort. In the in vitro co-culture assays of T cells and tumor cells, the suppressed glucose metabolic activity of T cells was reversed by TIGIT blockade. In addition, this blockade induced the apoptosis and reduced G2/M transit in tumor cells. The antitumor efficacy of TIGIT Ab therapy was further demonstrated in a human colorectal xenograft mice model while co-blockers of TIGIT and PD-1 exhibited synergistic suppressing effects on tumor growth. These results suggest that while TIGIT induces CD3(+) T cell dysfunction in colorectal cancer, co-targeting TIGIT and PD-1 can lead to an effective antitumor response and may serve as a novel therapeutic strategy for colorectal patients. Frontiers Media S.A. 2021-09-29 /pmc/articles/PMC8511404/ /pubmed/34659197 http://dx.doi.org/10.3389/fimmu.2021.688961 Text en Copyright © 2021 Shao, Wang, Yuan, Jin, Chen and Wu https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Shao, Qi
Wang, Lei
Yuan, Maoling
Jin, Xiaohong
Chen, Zhiming
Wu, Changping
TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism
title TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism
title_full TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism
title_fullStr TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism
title_full_unstemmed TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism
title_short TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism
title_sort tigit induces (cd3+) t cell dysfunction in colorectal cancer by inhibiting glucose metabolism
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511404/
https://www.ncbi.nlm.nih.gov/pubmed/34659197
http://dx.doi.org/10.3389/fimmu.2021.688961
work_keys_str_mv AT shaoqi tigitinducescd3tcelldysfunctionincolorectalcancerbyinhibitingglucosemetabolism
AT wanglei tigitinducescd3tcelldysfunctionincolorectalcancerbyinhibitingglucosemetabolism
AT yuanmaoling tigitinducescd3tcelldysfunctionincolorectalcancerbyinhibitingglucosemetabolism
AT jinxiaohong tigitinducescd3tcelldysfunctionincolorectalcancerbyinhibitingglucosemetabolism
AT chenzhiming tigitinducescd3tcelldysfunctionincolorectalcancerbyinhibitingglucosemetabolism
AT wuchangping tigitinducescd3tcelldysfunctionincolorectalcancerbyinhibitingglucosemetabolism