Immunomodulatory Drugs in the Context of Autologous Hematopoietic Stem Cell Transplantation Associate With Reduced Pro-tumor T Cell Subsets in Multiple Myeloma.

Giulia Di Lullo,Silvia Heltai,Fabio Ciceri,Anna Maria Paganoni,Cristina Tresoldi,Maria Pia Protti,Magda Marcatti,Claudio Bordignon

doi:10.3389/fimmu.2018.03171

Abstract

Immunomodulatory drugs (IMiDs) are effective therapeutics for multiple myeloma (MM), where in different clinical settings they exert their function both directly on MM cells and indirectly by modulating immune cell subsets, although with not completely defined mechanisms. Here we studied the role of IMiDs in the context of autologous hematopoietic stem cell transplantation on the T cell subset distribution in the bone marrow of newly diagnosed MM patients. We found that after transplantation pro-tumor Th17-Th1 and Th22 cells and their related cytokines were lower in patients treated with IMiDs during induction chemotherapy compared to untreated patients. Of note, lower levels of IL-17, IL-22, and related IL-6, TNF-α, IL-1β, and IL-23 in the bone marrow sera correlated with treatment with IMiDs and favorable clinical outcome. Collectively, our results suggest a novel anti-inflammatory role for IMiDs in MM.

Highlights

Multiple Myeloma (MM) is a plasma cell neoplastic disorder primarily localized in the bone marrow (BM), where interactions between neoplastic cells and cells within the tumor microenvironment mediate disease development and progression [1,2,3].Th cells play fundamental regulatory function in adaptive immune responses and in antitumor immunity being, according to their secretory cytokine profile, either anti-tumor or pro-tumor [4]
We found that T cells secreting Th1 (i.e., IFN-γ and TNF-α) and Th2 (i.e., IL-13, IL-4, and IL-5) cytokines were significantly increased after autologous hematopoietic stem cell transplantation (ASCT) compared to those at diagnosis as well as T cells coproducing IL-17 and IFN-γ, whereas T cells secreting IL-17, IL-22, and T regulatory cell (Treg) (CD4+CD127−CD25+FoxP3+) were not (Figure 2)
To evaluate the impact of IMiDs used in the induction regimen, we focused on the frequency of the T cell subsets in the post-ASCT time point and performed analyses in patients grouped based on the absence or the presence of IMiDs in the induction chemotherapy

Summary

Introduction

Multiple Myeloma (MM) is a plasma cell neoplastic disorder primarily localized in the bone marrow (BM), where interactions between neoplastic cells and cells within the tumor microenvironment (i.e., mesenchymal stromal cells, endothelial cells, osteoblasts, osteoclasts, and immune cells) mediate disease development and progression [1,2,3].Th cells play fundamental regulatory function in adaptive immune responses and in antitumor immunity being, according to their secretory cytokine profile, either anti-tumor or pro-tumor [4]. In MM, in addition to anti-proliferative and pro-apoptotic effects on malignant cells, IMiDs exert immune regulatory function and interfere with tumor microenvironment interactions [7]. In vivo lenalidomide augmented (i) vaccine responses and endogenous anti-tumor immunity [12], (ii) the number of central and effector memory CD8+ T cells, Tregs and CD14+CD15+ myeloid derived suppressor cells in patients that received lenalidomide as monotherapy or in combination with other treatments [13], (iii) the number of Tregs in patients in consolidation/maintenance therapy [14, 15], (iv) anti-myeloma specific T cell responses in patients that received lenalidomide as consolidation therapy after ASCT [16], and (v) the number of IFN-γ and IL-21 producing cells in the setting of maintenance therapy [17]. Treatment with lenalidomide was associated with impaired longterm thymic reconstitution and decreased number of CD4+ and CD8+ effector terminally differentiated T cells [14, 15] and reduced PD-1 expression on T cells in the maintenance setting [18]

Methods

Results

Conclusion