Myeloma cells act as tolerogenic antigen-presenting cells and induce regulatory T cells in vitro

Regulatory T cells (Tregs) are essential for maintenance of self-tolerance; however, tumor cells can exploit the tolerance to escape the immune system. We investigated the Tregs frequency in patients with multiple myeloma (MM) and in those with monoclonal gammopathy of undetermined significance (MGUS), and found that CD4(+)FoxP3(+) and CD8(+)FoxP3(+) Tregs were significantly increased in patients with MM and correlated with the active phase. Both Tregs subsets were expanded in cocultures of CD3(+) lymphocytes and fresh CD138(+) MM plasma cells or RPMI8226 and U266 cell lines and functioned as natural (n) and inducible (i) Tregs insofar as they inhibited the proliferation of stimulated CD3 lymphocytes via contact-dependent and contact-independent pathways. Induction of Tregs by MM plasma cells required a contact-dependent pathway, implying antigen recognition by T cells. MM plasma cells acted as immature and tolerogenic antigen-presenting cells (APCs), in that they displayed low CD80/CD86 expression associated with a phagocytic activity. By acting as immature APCs, MM plasma cells plausibly expand (n)Tregs and (i)Tregs both through conversion of CD3(+)FoxP3(-) into CD3(+)FoxP3(+) T cells and proliferation of CD3(+)FoxP3(+) T cells, which may suppress the anti-MM immune response.