Circulating myeloid-derived suppressor cells and regulatory T cells as immunological biomarkers in refractory/relapsed diffuse large B-cell lymphoma: translational results from the R2-GDP-GOTEL trial

Abstract

BackgroundThe search for immunological markers with ability of predicting clinical outcome is a priority in lymphomas, and in cancer in general. It is well known that some immunomodulatory cells, such as myeloid derived suppressor cells (MDSCs) or regulatory T cells (Tregs), are recruited by tumors, jeopardizing antitumor immunosurveillance. In this work, we have studied blood levels of these immunosuppressive cells in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), prior to and along the course of the experimental rituximab, gemcitabine, dexamethasone, and cisplatin (R2-GDP) schedule, as a translational substudy of the R2-GDP-GOTEL trial (EudraCT Number: 2014-001620-29), which included lenalidomide as an immunomodulator.MethodsBlood samples were taken before treatment, at cycle 3 and end of induction. Samples were analyzed by flow cytometry. Non-parametric tests were used. Mann-Whitney U test was used to compare basal cells distributions, and Wilcoxon test was considered to compare cells distribution at different times. Spearman test was performed to measure the degree of association between cell populations.ResultsIn this study, MDSC and Treg circulating concentration was found increased in all patients compared with a healthy control group and decreased after treatment only in patients with longest overall survival (>24 months), reaching the levels of the healthy group. Likewise, the number of inhibited T lymphocytes expressing Programmed Death-1 (PD-1) were increased in peripheral blood from patients and decreased on the treatment, whereas activated T lymphocytes increased after therapy in those with better overall survival.ConclusionsIn conclusion, blood concentration of MDSCs and Treg cells may be good prognostic markers for overall survival after 2 years in R/R DLBCL. These results point to a possible role of these elements in the immunosuppression of these patients, as assessed by the circulating activated and inhibited T lymphocytes, and therefore, they may be considered as therapeutic targets in DLBCL.

Lower Survival and Increased Circulating Suppressor Cells in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma with Deficit of Vitamin D Levels Using R-GDP Plus Lenalidomide (R2-GDP): Results from the R2-GDP-GOTEL Trial

“…Nevertheless, it is also important to consider the role of immune response suppressor cells or immune checkpoint pathways as targets to overcome the tumor-induced immunosuppression, such as MDSCs [47], Tregs [48], or both PD-1 and CTLA-4 pathways [49,50]. In this regard, our group previously reported the depletion of MDSCs, Tregs and inhibitory PD-1+OX40− T cells, as well as the increase in activated OX40+PD-1− T cells in R/R DLBCL patients with OS > 24 months from the R2-GDP-GOTEL trial [26].…”

“…That is why we wanted to check the vitamin D levels in the patients with R/R DLBCL included in an intervention trial (the R2-GDP-GOTEL trial), using lenalidomide as immunomodulator. Our results were oriented in the same direction and we observed significant low levels of serum vitamin D in R/R DLBCL patients compared with age-matched healthy subjects, as well as a better OS after 24 months in patients with vitamin D levels higher than 15 ng/mL before treatment, which means that vitamin D deficiency could play a key role in the immunosuppression of the disease but, once the R2-GDP schedule began, could contribute to a worse long-term clinical outcome, considering the advanced age of the patients from the R2-GDP-GOTEL trial [26]. The lower vitamin D levels in patients compared with controls should be expected since these patients may not have as many open-air activities as healthy controls.…”

“…In R/R DLBCL, rituximab combined with lenalidomide (R2) has been used alone [22] or combined with GDP (gemcitabine, cisplatin, and dexamethasone) [23], obtaining promising responses. In the same line, R2-GDP was used as an alternative schedule in R/R DLBCL patients from the study "Phase II clinical trial to evaluate the combination of lenalidomide with R-GDP in patients diagnosed with R/R DLBCL not candidates for high-dose chemotherapy and hematopoietic progenitor cell transplantation" (EudraCT Number: 2014-001620-29), performed by the Spanish Lymphoma Oncology Group (GOTEL), reporting promising objective response rates (ORR) [24,25] and the depletion of immune suppressor cells in patients with an overall survival (OS) longer than 24 months [26].…”

Low Levels of Granulocytic Myeloid-Derived Suppressor Cells May Be a Good Marker of Survival in the Follow-Up of Patients With Severe COVID-19

“…M-MDSCs were gated as CD45 + CD11b + CD33 + HLA-DR low/− CD14 + CD15 − , G-MDSCs as CD45 + CD11b + CD33 + HLA-DR low/− CD14 − CD15 + , Tregs as CD4 + CD25 high CD127 low/− , activated T cells as CD3 + CD4 + OX40 + PD-1 − and CD3 + CD8 + OX40 + PD-1 − , and exhausted T cells as CD3 + CD4 + PD-1 + OX40 − and CD3 + CD8 + PD-1 + OX40 − , as previously described (6,21). Total T, B, and NK cells were gated as CD3 + , CD19 + , and CD16 + CD56 + , respectively.…”

Tumor Immune Microenvironment in Lymphoma: Focus on Epigenetics

“…Besides, there are two different subpopulations of MDSCs that can either express CD14 or CD15: monocytic MDSCs (M-MDSCs), which express CD14 and may differentiate into monocytes (such as macrophages and dendritic cells), and granulocytic MDSCs (G-MDSCs), which express CD15 and may differentiate into granulocytes (polymorphonuclear leukocytes) [90][91][92]. MDSCs mainly inhibit T cell immune responses by using different mechanisms, such as reactive oxygen species or nitrogen oxide production [93] and Tregs induction, which contributes to tumor dissemination [94]. Through the production of angiogenic factors and proteases, MDSCs also promote angiogenesis [95].…”