AUTHOR=Lopes Raquel , Caetano Joana , Barahona Filipa , Pestana Carolina , Ferreira Bruna Velosa , Lourenço Diana , Queirós Ana C. , Bilreiro Carlos , Shemesh Noam , Beck Hans Christian , Carvalho Ana Sofia , Matthiesen Rune , Bogen Bjarne , Costa-Silva Bruno , Serre Karine , Carneiro Emilie Arnault , João Cristina TITLE=Multiple Myeloma-Derived Extracellular Vesicles Modulate the Bone Marrow Immune Microenvironment JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.909880 DOI=10.3389/fimmu.2022.909880 ISSN=1664-3224 ABSTRACT=

Multiple myeloma (MM), the third most frequent hematological cancer worldwide, is characterized by the proliferation of neoplastic plasma cells in the bone marrow (BM). One of the hallmarks of MM is a permissive BM microenvironment. Increasing evidence suggests that cell-to-cell communication between myeloma and immune cells via tumor cell-derived extracellular vesicles (EV) plays a key role in the pathogenesis of MM. Hence, we aimed to explore BM immune alterations induced by MM-derived EV. For this, we inoculated immunocompetent BALB/cByJ mice with a myeloma cell line, MOPC315.BM, inducing a MM phenotype. Upon tumor establishment, characterization of the BM microenvironment revealed the expression of both activation and suppressive markers by lymphocytes, such as granzyme B and PD-1, respectively. In addition, conditioning of the animals with MOPC315.BM-derived EV, before transplantation of the MOPC315.BM tumor cells, did not anticipate the disease phenotype. However, it induced features of suppression in the BM milieu, such as an increase in PD-1 expression by CD4+ T cells. Overall, our findings reveal the involvement of MOPC315.BM-derived EV protein content as promoters of immune niche remodeling, strengthening the importance of assessing the mechanisms by which MM may impact the immune microenvironment.