Role of the Immune Response in Disease Progression and Therapy in Multiple Myeloma.

Abstract

Multiple myeloma (MM) is a hematologic cancer derived from malignant plasma cells within the bone marrow. Unlike most solid tumors, which originate from epithelial cells, the myeloma tumor is a plasma cell derived from the lymphoid cell lineage originating from a post-germinal B-cell. As such, the MM plasma cell represents an integral component of the immune system in terms of both antibody production and antigen presentation, albeit not efficiently. This fundamental difference has significant implications when one considers the implications of immunotherapy. In the case of lymphoid malignancies such as myeloma, immune-based strategies must take into consideration this important difference, potentially necessitating immunotherapy targeted toward MM to be altered from that targeted at solid tumors. Typically, the immune system "surveys" cells within our body and is able to recognize and attack cancerous cells that may arise. However, some cancer cells are able to evade immune surveillance and continue to flourish, causing disease. The major mechanism leading to an effective tumor-specific response is one that enables effective antigen processing and presentation with subsequent T-cell activation, expansion, and effective trafficking to the tumor site. Plasma cells employ several mechanisms to escape immune surveillance which include altered interactions with T-cells, DCs, bone marrow stromal cells (BMSC's), and natural killer cells (NK Cells) that can be mediated by immunosuppressive cells such as and myeloid-derived suppressor cells (MDSC's) and cytokines such as IL-10, TGFβ, and IL-6 as well as down-regulation of the antigen processing machinery. Many therapies have been developed to reestablish a functional immune system in MM patients. These include adoptive T-cell therapies to deliver more tumor-specific T-cells, vaccines to increase the tumor-specific precursor frequency of the endogenous T-cell population, immunomodulatory agents (IMiDs) such as thalidomide and lenalidomide to enhance global endogenous immunity, immunostimulatory cytokines, and antibodies to specifically target tumor-specific cell-surface proteins or cytokines. This review will dissect these various approaches currently being explored in MM as well as highlight some future directions for myeloma-specific immune-based strategies.