Human colorectal cancer: upregulation of the adaptor protein Rai in TILs leads to cell dysfunction by sustaining GSK-3 activation and PD-1 expression.
Cancer Immunol Immunother
; 73(1): 2, 2024 Jan 04.
Article
em En
| MEDLINE
| ID: mdl-38175205
ABSTRACT
BACKGROUND:
The immunosuppressive tumor microenvironment (TME) of colorectal cancer (CRC) is a major hurdle for immune checkpoint inhibitor-based therapies. Hence characterization of the signaling pathways driving T cell exhaustion within TME is a critical need for the discovery of novel therapeutic targets and the development of effective therapies. We previously showed that (i) the adaptor protein Rai is a negative regulator of T cell receptor signaling and T helper 1 (Th1)/Th17 cell differentiation; and (ii) Rai deficiency is implicated in the hyperactive phenotype of T cells in autoimmune diseases.METHODS:
The expression level of Rai was measured by qRT-PCR in paired peripheral blood T cells and T cells infiltrating tumor tissue and the normal adjacent tissue in CRC patients. The impact of hypoxia-inducible factor (HIF)-1α on Rai expression was evaluated in T cells exposed to hypoxia and by performing chromatin immunoprecipitation assays and RNA interference assays. The mechanism by which upregulation of Rai in T cells promotes T cell exhaustion were evaluated by flow cytometric, qRT-PCR and western blot analyses.RESULTS:
We show that Rai is a novel HIF-1α-responsive gene that is upregulated in tumor infiltrating lymphocytes of CRC patients compared to patient-matched circulating T cells. Rai upregulation in T cells promoted Programmed cell Death protein (PD)-1 expression and impaired antigen-dependent degranulation of CD8+ T cells by inhibiting phospho-inactivation of glycogen synthase kinase (GSK)-3, a central regulator of PD-1 expression and T cell-mediated anti-tumor immunity.CONCLUSIONS:
Our data identify Rai as a hitherto unknown regulator of the TME-induced exhausted phenotype of human T cells.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
/
Quinase 3 da Glicogênio Sintase
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article