PD-L1-PD-1 Pathway in the Pathophysiology of Multiple Myeloma.

Hideto Tamura,Koiti Inokuchi,Mariko Ishibashi,Mika Sunakawa-Kii

doi:10.3390/cancers12040924

Abstract

PD-L1 expressed on tumor cells contributes to disease progression with evasion from tumor immunity. Plasma cells from multiple myeloma (MM) patients expressed higher levels of PD-L1 compared with healthy volunteers and monoclonal gammopathy of undetermined significance (MGUS) patients, and its expression is significantly upregulated in relapsed/refractory patients. Furthermore, high PD-L1 expression is induced by the myeloma microenvironment and PD-L1+ patients with MGUS and asymptomatic MM tend to show disease progression. PD-L1 expression on myeloma cells was associated with more proliferative potential and resistance to antimyeloma agents because of activation of the Akt pathway through PD-1-bound PD-L1 in MM cells. Those data suggest that PD-L1 plays a crucial role in the disease progression of MM.

Highlights

Multiple myeloma (MM) remains an incurable disease even with new treatment strategies using proteasome inhibitors, immunomodulatory drugs (IMiDs) and monoclonal antibodies
B7-1 (CD80) and PD-1 were identified as receptors of PD-L1, and PD-1, a 55-KDa transmembrane protein belonging to the CD28/CTLA-4 family, has an immunoreceptor tyrosine-based inhibitory motif in its intracellular domain
We found that PD-L1-expressing myeloma cells exhibit growth, anti-apoptosis and drug resistance in MM cells

Summary

Introduction

Multiple myeloma (MM) remains an incurable disease even with new treatment strategies using proteasome inhibitors, immunomodulatory drugs (IMiDs) and monoclonal antibodies. PD-L1+ patients with diffuse large B cell lymphoma had shorter overall survival [23] Immune checkpoint inhibitors, such as anti-PD-1 and anti-PD-L1 antibodies, recovered tumor immune surveillance by tumor-specific CTLs and achieved 12–28% overall response rates, resulting in the improvement of survival in refractory cancer patients with melanoma, renal cell carcinoma and non-small cell lung cancer [24,25]. These results demonstrate the emergence of a promising new immunotherapeutic approach for treatment-refractory cancer patients. This review describes the expression and function of the PD-1–PD-L1 pathway in MGUS and MM, and the possibility of immunotherapy through the blockade of this pathway

Expression of PD-L1 in MGUS and MM

Induction of PD-L1 Expression in MGUS and MM

Functions of but PD-L1

Soluble Form of PD-L1 in MM Patients

Findings

Conclusions