PD-1 and LAG-3-positive T cells are associated with clinical outcomes of relapsed/refractory multiple myeloma patients

Abstract

Objective To investigate the frequency of PD-1 and LAG-3-positive T cells in relapsed/refractory multiple myeloma (RRMM) patients and its clinical significance. Methods This prospective observational study enrolled a total of 71 RRMM patients, as well as 70 MM patients (non-refractory) and 70 healthy individuals during January 2018 to March 2021. The frequency of circulating CD4+ and CD8+ T cells expressing PD-1 and LAG-3 was analyzed using flow cytometry. Serum cytokines of IL-6, IL-17, CRP, TNF-α and TGF-β were evaluated by enzyme linked immunosorbent assay (ELISA). Results Significant higher 1-year mortality rate was found in RRMM patients compared with the MM patients. In both CD4+ and CD8+ T cells, the frequencies of PD-1+, LAG-3+ and PD-1+/LAG-3+ T cells were markedly higher in the RRMM patients and the deceased patients, compared with the MM patients and the survival patients, respectively. All cytokines were remarkably higher in RRMM and MM patients than in the healthy control, while only serum levels of IL-6 and IL-17 were markedly higher in RRMM patients compared with the MM patients. Positive correlation was observed among the IL-6, IL-17 and the frequencies of circulating T cells in both CD4+ and CD8+ T cells in RRMM and MM patients. The frequency of CD8+PD-1+LAG-3+ T cells showed the best sensitivity 82.61% and specificity 76.06% for diagnosis of RRMM using ROC curve. Meanwhile, the frequency of CD4+PD-1+ cells showed the best sensitivity 84.00% and specificity 97.35% for prediction of patients’ mortality by ROC curve. The frequencies of CD4+PD-1+, CD8+PD-1+/LAG-3+, as well as IL-6, IL-17 and TNF-α were found as risk factors for incidence of RRMM in all MM patients. Conclusion The frequency of PD-1 and LAG-3-positive T cells is associated with the clinical severity and inflammation in RRMM patients, which may also serve as potential biomarkers for its diagnosis.

Immune checkpoint blockade in hematological malignancies: current state and future potential

“…LAG-3 has been shown to be an important immune checkpoint in the pathogenesis and progression of myeloma. PD-1/LAG-3+ T cells are significantly enriched in patients with RRMM compared to NDMM ( 98 , 99 ). Targeting the LAG-3/GAL-3 pathway has been shown to result in proliferation of MM specific T cells in combination with immunotherapy ( 100 ).…”

TGF-β: an active participant in the immune and metabolic microenvironment of multiple myeloma

“…Furthermore, Alissa Visram et al reported that marked downregulation of interferon, TGF-β, IL-6, and TNF-α signaling pathways in abnormal plasma cells from patients with triple-refractory multiple myeloma (TRMM) compared to newly diagnosed or relapsed cases, indicating lower responsiveness of TRMM to new immunotherapies [36,37]. Ming Chen et al reported that the frequency of CD4 + PD-1+, CD8 + PD-1+/LAG-3+, as well as IL-6, IL-17, and TNF-α were found as risk factors for the incidence of relapsed/refractory MM (RRMM) in all MM [38]. Particularly, IL-6 and TGF-β not only influence the treatment outcomes but also the prognosis of MM.…”

Immune checkpoint inhibitors for multiple myeloma immunotherapy

“…A currently available prospective study enrolled 71 patients with RRMM, 70 patients with MM, and 70 healthy controls. By measuring CD6 and CD17, as well as cytokines including IL-4, IL-8, TNF-α, and TGF-β, the clinical severity of patients with RRMM was found to be strongly correlated with the frequency of PD-1 and LAG-3 positive T cells, which also implies that LAG-3 and PD-1 are potential biomarkers for the diagnosis of RRMM, directly affecting the prognosis and clinical outcome of patients [ 64 ]. A phase I/II randomized trial in 2019 in patients with relapsed refractory multiple myeloma is designed to evaluate two agents, anti-LAG-3 and anti-TIGIT, for their immune effects and safety as single agents and in combination with pomalidomide and dexamethasone.…”