MiR155 Sensitized B-Lymphoma Cells to PD-L1 Blockade Via PD-1/PD-L1-Mediated Lymphoma Cell Interaction with CD8+T Cells

Diffuse large B-cell lymphoma (DLBCL) represents the most common neoplastic disorder of B-lymphocytes. Besides genetic aberration of lymphoma cells themselves, dysfunction in immune cells can lead to lymphoma cell resistance to immunochemotherapy. Immune checkpoint inhibitors have emerged as successful treatment strategies for DLBCL. However, the underlying mechanisms that lymphoma cells escape from anti-tumor immune responses need to be further investigated.

MiR155 was assessed by quantitative RT-PCR in a large cohort of patients with newly diagnosed DLBCL. Serum miR155 was significantly elevated, correlated with tumor miR155, and indicated poor prognosis. In peripheral blood, miR155 overexpression was associated with decreased CD8+T cells, reduced IFN-γ level and inhibition of T-cell receptor signaling. RNA sequencing was performed on blood samples of 82 DLBCL patients, which indicated that 73 genes closely related with lymphoma were differentially expressed between high miR155 group and low miR155 group. Above genes were plotted by heatmap. Dysregulation of multiple signaling pathway enriched by KEGG pathway analysis. Gene set enrichment analysis (GSEA) analysis manifested that miR155 is closely related with T cell receptor signaling pathway, cell cycle pathway and cytokine-cytokine receptor interaction pathway.

In co-culture systems of B-lymphoma cells with immune cells, miR155 modulated Fas-mediated apoptosis of CD8+T cells, which was targeted by PD-1 and PD-L1 antibodies. As mechanism of action, miR155 enhanced lymphoma cell PD-L1 expression, recruited CD8+T cells via PD-1/PD-L1 interaction, and inhibited AKT/ERK phosphorylation of CD8+T cells. Moreover, EBV-positive patients showed higher serum miR155 than EBV-negative patients. In vivo in a murine xenograft model established with subcutaneous injection of A20 cells, PD-L1 blockade particularly retarded the growth of miR155-overexpressing tumors, consistent with AKT/ERK phosphorylation and CD8+T cell persistence.

Taken together, as a serum oncogenic biomarker of DLBCL, miR155 indicated the sensitivity of B-lymphoma cells to PD-L1 antibody via PD-1/PD-L1-mediated interaction with CD8+T cells. Persistence of CD8+T cells could be an alternative target of action of PD-L1 antibody in treating B-lymphoid malignancies.