Human colorectal cancer: upregulation of the adaptor protein Rai in TILs leads to cell dysfunction by sustaining GSK-3 activation and PD-1 expression.
- Resource Type
- Article
- Authors
- Montecchi, Tommaso; Nannini, Giulia; De Tommaso, Domiziana; Cassioli, Chiara; Coppola, Federica; Ringressi, Maria Novella; Carraro, Fabio; Naldini, Antonella; Taddei, Antonio; Marotta, Giuseppe; Amedei, Amedeo; Baldari, Cosima T.; Ulivieri, Cristina
- Source
- Cancer Immunology, Immunotherapy. Jan2024, Vol. 73 Issue 1, p1-12. 12p.
- Subject
- *GENE expression
*ADAPTOR proteins
*T-cell exhaustion
*COLORECTAL cancer
*GLYCOGEN synthase kinase
*T cell receptors
*IPILIMUMAB
- Language
- ISSN
- 0340-7004
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. [ABSTRACT FROM AUTHOR]