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

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.

Bone Marrow Immune Microenvironment in Myelodysplastic Syndromes

“…Secreted factors in the microenvironment, such as IFN-γ and TNF-α, upregulate PD-L1 expression [ 142 , 143 ] and recently, the role of S100A9, a central molecule in the MDS pathophysiology, as an inducer of PD-1 and PD-L1, has been detected [ 144 ]. Contrary to former knowledge, recently, Ferrari et al did not observe an inhibition of cytotoxicity after de novo PD-L1 expression on MDS cells [ 145 ]. Additional inhibitory signals originating from the innate immune system may interfere with anti-tumor immunity.…”