Tumor-specific T cell-mediated upregulation of PD-L1 in myelodysplastic syndrome cells does not affect T-cell killing

• Published in: Frontiers in oncology Vol. 12; p. 915629
• Main Authors: Ferrari, Valentina, Tarke, Alison, Fields, Hannah, Tanaka, Tiffany N., Searles, Stephen, Zanetti, Maurizio
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 05.08.2022
• Subjects: adoptive cell transfer (ACT); immune check inhibitor (ICI); myelodyslastic syndromes; neoantigens (neoAgs); Oncology; unfolded protein response (UPR)
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2022.915629

The PD-1:PD-L1 axis is a binary interaction that delivers inhibitory signals to T cells, impeding both immune surveillance and response to immunotherapy. Here we analyzed a phenomenon whereby tumor-specific T cells induce PD-L1 upregulation in autologous MDS cells in short-term culture, through a mechanism that is cell-contact-independent and partially IFNγ-dependent. After investigating a panel of small-molecule inhibitors, we determined that PD-L1 upregulation was attributed to the PKR-like ER kinase (PERK) branch of the unfolded protein response. Interestingly, we found that the cytotoxic capacity of tumor-specific T cells was not impaired by the expression of PD-L1 on MDS target cells. These results highlight a little appreciated aspect of PD-1:PD-L1 regulation in hematologic cancers and indicate that this phenomenon, while likely to hinder autochthonous immune surveillance, may not be an obstacle to immunotherapies such as personalized adoptive T-cell therapy.