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

Valentina Ferrari; Alison Tarke; Hannah Fields; Tiffany N Tanaka; Stephen Searles; Maurizio Zanetti

doi:10.3389/fonc.2022.915629

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

Front Oncol. 2022 Aug 5:12:915629. doi: 10.3389/fonc.2022.915629. eCollection 2022.

Authors

Valentina Ferrari¹, Alison Tarke¹, Hannah Fields¹, Tiffany N Tanaka², Stephen Searles³, Maurizio Zanetti³

Affiliations

¹ PersImmune, Inc., San Diego, CA, United States.
² Moores Cancer Center, Department of Hematology and Oncology, University of California San Diego, La Jolla, CA, United States.
³ The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California San Diego, La Jolla, CA, United States.

Abstract

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.

Keywords: adoptive cell transfer (ACT); immune check inhibitor (ICI); myelodyslastic syndromes; neoantigens (neoAgs); unfolded protein response (UPR).