PD-L1/PD-1 Pattern of Expression Within the Bone Marrow Immune Microenvironment in Smoldering Myeloma and Active Multiple Myeloma Patients

Abstract

BackgroundThe PD-1/PD-L1 axis has recently emerged as an immune checkpoint that controls antitumor immune responses also in hematological malignancies. However, the use of anti-PD-L1/PD-1 antibodies in multiple myeloma (MM) patients still remains debated, at least in part because of discordant literature data on PD-L1/PD-1 expression by MM cells and bone marrow (BM) microenvironment cells. The unmet need to identify patients which could benefit from this therapeutic approach prompts us to evaluate the BM expression profile of PD-L1/PD-1 axis across the different stages of the monoclonal gammopathies.MethodsThe PD-L1/PD-1 axis was evaluated by flow cytometry in the BM samples of a total cohort of 141 patients with monoclonal gammopathies including 24 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), 38 patients with smoldering MM (SMM), and 79 patients with active MM, including either newly diagnosed or relapsed-refractory patients. Then, data were correlated with the main immunological and clinical features of the patients.ResultsFirst, we did not find any significant difference between MM and SMM patients in terms of PD-L1/PD-1 expression, on both BM myeloid (CD14+) and lymphoid subsets. On the other hand, PD-L1 expression by CD138+ MM cells was higher in both SMM and MM as compared to MGUS patients. Second, the analysis on the total cohort of MM and SMM patients revealed that PD-L1 is expressed at higher level in CD14+CD16+ non-classical monocytes compared with classical CD14+CD16− cells, independently from the stage of disease. Moreover, PD-L1 expression on CD14+ cells was inversely correlated with BM serum levels of the anti-tumoral cytokine, IL-27. Interestingly, relapsed MM patients showed an inverted CD4+/CD8+ ratio along with high levels of pro-tumoral IL-6 and a positive correlation between %CD14+PD-L1+ and %CD8+PD-1+ cells as compared to both SMM and newly diagnosed MM patients suggesting a highly compromised immune-compartment with low amount of CD4+ effector cells.ConclusionsOur data indicate that SMM and active MM patients share a similar PD-L1/PD-1 BM immune profile, suggesting that SMM patients could be an interesting target for PD-L1/PD-1 inhibition therapy, in light of their less compromised and more responsive immune-compartment.

Immune response to SARS-CoV-2 mRNA vaccination and booster dose in patients with multiple myeloma and monoclonal gammopathies: impact of Omicron variant on the humoral response

“…MM patients are known to have a deep reduction of CD4 + T cells with an inverted CD4 + /CD8 + ratio compared to precursors stages of the disease. 35 In fact, CD4 + T cells are closely associated with B cell differentiation into IgG-producing plasma cells and with the development of an adequate humoral immune response.…”

Impact of Omicron variant on the response to SARS-CoV-2 mRNA Vaccination in multiple myeloma

“…MM patients are known to have a deep reduction of CD4 + T cells with an inverted CD4 + /CD8 + ratio compared to precursors stages of the disease. 28 In fact, CD4 + T cells are closely associated with B cell differentiation into IgG-producing plasma cells and with the development of an adequate humoral immune response.…”

The yin–yang effects of immunity: From monoclonal gammopathy of undetermined significance to multiple myeloma

“…Moreover, there was an inversion of the CD4+/CD8+ ratio in patients with relapsed MM, followed by increased levels of IL-6 expression. There was a remarkable positive correlation between %CD14+PD-L1+ and %CD8+PD-1+ cells in relapsed patients compared to the patients with SMM and newly diagnosed MM (NDMM) ( 30 ). Therefore, MGUS and MM obviously exhibit the immune yin-yang effects.…”

“…found that as tumor load increases, the quantity of CD16+CD14 dim monocytes has been shown to increase ( 73 ). Meanwhile, another study found that in MM and SMM patients, PD-L1 was expressed at higher levels in CD14+CD16+ monocytes than CD14+CD16- cells, independent of disease stage ( 30 ). Therefore, other types of cells also play an important role in MM progression ( Figure 2 , Table 1 ).…”