Programmed Cell Death-1 and Its Ligands as Targets for Therapy of Multiple Myeloma Patients

Abstract

Agnieszka Karczmarczyk,1 Maciej Korpysz,2 Sylwia Bilska,3 Joanna Purkot,1 Marek Hus,3 Krzysztof Giannopoulos1,4 1Department of Experimental Hematooncology, Medical University of Lublin, Lublin, Poland; 2Department of Biochemical Diagnostics, Medical University of Lublin, Lublin, Poland; 3Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland; 4Department of Hematology, St. John’s Cancer Centre, Lublin, PolandCorrespondence: Krzysztof Giannopoulos, Department of Experimental Hematooncology, Medical University of Lublin, Chodzki 1, Lublin, 20-093, Poland, Tel + 48 81448 6632, Fax + 48 81448 6634, Email [email protected]: Among hematological malignancies, the expression profile of programmed cell death-1 (PD-1) and its ligands in multiple myeloma (MM) is still debated by numerous research groups. In current study, we characterized the expression of PD-1 and its ligands both on RNA and protein levels in MM patients. We have also attempted to analyze whether daratumumab therapy might overcome CD38-mediated immunosuppression that inhibits in particular CD8+ T-cell function.Patients and Methods: This study included 149 newly diagnosed MM patients and 15 relapsed/refractory MM patients before and after daratumumab treatment. The mRNA levels of PDCD1, PDCD1LG1, PDCD1LG2 and their splicing variants was assessed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Flow cytometry was used to characterize the surface expression of PD-1 and its ligands on plasma cells, B and T cells. The surface expression of PD-1 on T cells was assessed by flow cytometry before and after daratumumab treatment.Results: The mRNA expression of PDCD1LG1, PDCD1LG2 and their splicing variants were higher in plasma cells as compared to bone marrow mononuclear cells (BMMCs). Our results show that the percentage of plasma cells expressing PD-L1 was significantly higher than plasma cells expressing PD-L2 (p< 0.0001) in bone marrow (BM) of MM patients. There was no significant difference between the percentage of plasma cells expressing PD-1 and B cells expressing PD-1 in BM of MM patients (11.19% vs 8.91%). We also found that the percentage of CD8+PD-1+ T cells was significantly higher than CD4+PD-1+T cells in BM (p< 0.0001) of MM patients. Here, we observed no change in PD-1 expression on CD4+ and CD8+ T cells after the daratumumab treatment.Conclusion: The PD-1 and its ligands might represent an interesting target for MM immunotherapy, as one would target both malignant plasma cells as well as the immune cells that play a key role in tumor escape mechanisms.Keywords: PD-1, PD-L1, PD-L2, daratumumab, multiple myeloma

Keywords

• pd-1
• pd-l1
• pd-l2
• daratumumab
• multiple myeloma