senior scientist Biomedical Research Center/Cancer Research Institute SAS, United States
Introduction: The tumor microenvironment is considered essential to maintain tumor cell survival and growth, subclonal evolution, and stage of the disease. Interactions between tumor cells and immune cells form immunosuppressive tumor-supporting niche by regulating of immune cell responses either by reducing the antitumoral activity of immune cells, expanding of immune-suppressive cells or specific mechanisms of tumor-promoting cell polarization and activation. Therefore, revealing insights into the immune myeloma microenvironment will enhance our understanding of the pathogenesis of multiple myeloma (MM).
Methods: Our pipeline has been designed for profiling of the complex immune landscape of the adaptive and innate immune bone marrow microenvironment during MM evolution and progression in BM samples from patients with MGUS, smoldering MM (SMM), and active MM by mass cytometry analysis (CyTOF).
Results: Our data showed that both naïve and effector cytotoxic T cells, g/d T cells, immature and mature B cells were reduced in both premalignant and active myeloma stages. In addition, downregulation of immature T cells, naïve and effector memory T helper cells was showed in active MM, revealing profound adaptive immune-suppression in myeloma microenvironment. Profiling of the innate immune microenvironment, an increase in myeloblasts, non-canonical monocytes, erythroblasts, and platelets, and a decrease in pro-monocytes was observed in both premalignant and active MM conditions. Importantly, the transformation from MGUS to SMM was associated with alterations in central/effector memory T helper cells and/or effector cytotoxic T cells, as well as increases in monocytic and neutrophil subsets. Evaluation of myeloma B lymphopoiesis revealed a decrease in B cell progenies, immature and transitional B, and unswitched memory B cells, but an increase in switched memory B cells and plasmablasts along with PC subsets in SMM and active MM stages. In addition, modulation by immune checkpoints, including PD-1/PD-L1, TIGIT/PVR, CD137/CD137-L, CTLA-4, BTLA and KIR expression, was indicated in innate and adaptive immune subsets of myeloma microenvironment. Corresponding analysis of immune subsets of each patient revealed stratification of MM patients with high frequencies of plasma cell subsets, plasmablasts, switched memory B cells, and myelocytes that were associated with poor clinical outcomes.
Conclusions: In conclusion, exploring the immune tumor microenvironment revealed profound adaptive immune-suppression and extensive innate immune-infiltration in both premalignant and active MM stages. Therefore, our in-depth characterization of the immune ecosystem at various stages of MM demonstrates the utility of CyTOF technology for defining disease heterogeneity and prognosis in patients with MM.
This study was supported by R01-50947 and P50-100707; 609427-SASPRO 0064/01/02; TRS-2015-00000170; 2019/14-BMCSAV-9; APVV-16-0484; APVV-20-0183; and APVV-19-0212.
