Human colorectal cancer: upregulation of the adaptor protein Rai in TILs leads to cell dysfunction by sustaining GSK-3 activation and PD-1 expression.

Autor: Montecchi T; Department of Life Sciences, University of Siena, Siena, 53100, Italy., Nannini G; Department of Experimental and Clinical Medicine, University of Florence, Florence, 50134, Italy., De Tommaso D; Department of Life Sciences, University of Siena, Siena, 53100, Italy., Cassioli C; Department of Life Sciences, University of Siena, Siena, 53100, Italy., Coppola F; Department of Molecular and Developmental Medicine, University of Siena, Siena, 53100, Italy., Ringressi MN; Department of Experimental and Clinical Medicine, University of Florence, Florence, 50134, Italy., Carraro F; Department of Medical Biotechnologies, University of Siena, Siena, 53100, Italy., Naldini A; Department of Molecular and Developmental Medicine, University of Siena, Siena, 53100, Italy., Taddei A; Department of Experimental and Clinical Medicine, University of Florence, Florence, 50134, Italy., Marotta G; Siena University Hospital, Siena, Italy., Amedei A; Department of Experimental and Clinical Medicine, University of Florence, Florence, 50134, Italy. amedeo.amedei@unifi.it., Baldari CT; Department of Life Sciences, University of Siena, Siena, 53100, Italy. cosima.baldari@unisi.it., Ulivieri C; Department of Life Sciences, University of Siena, Siena, 53100, Italy. cristina.ulivieri@unisi.it.
Jazyk: angličtina
Zdroj: Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2024 Jan 04; Vol. 73 (1), pp. 2. Date of Electronic Publication: 2024 Jan 04.
DOI: 10.1007/s00262-023-03614-0
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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