Progress of immune senescence in multiple myeloma treatment resistance

Abstract

Multiple myeloma has become the second most common hematologic malignancy threatening human health with the increasing incidence in the population, and the emergence of drug resistance in its treatment has become a problem that needs to be solved urgently. Recent studies have shown that the immune system is closely related to the development of multiple myeloma, and immune senescence plays an extremely critical role in MM treatment resistance. In this paper, we review the connection between immune senescence and the development of MM and its possible role in the drug resistance of MM treatment, to provide new research ideas for the in-depth study of the mechanism of immune senescence and the search for new immunotherapeutic targets to overcome the phenomenon of drug resistance in the immunotherapy of MM patients.

Keywords: Drug resistance; Immunosenescence; Multiple myeloma; Therapy.

Fig. 1

The development process of cellular senescence and MM therapy resistance. 1. Normal cells in the body are subjected to various injuries or stimuli, some cells undergo pre-deterioration changes and secrete senescence-related secretory phenotypes, and the body's immune cells play a normal role in monitoring and recognizing thereby removing senescent cells; 2. When the body's immune function is senescent, it is unable to remove the persistent injuries of senescence and the oncogenic pressure from the malignant cells promptly, which leads to senescent cell accumulation—the point of cancer initiation. Abnormal cells continue to develop and eventually malignant cell migration and invasion, immune escape, and malignant enhancement of tumor cells

Fig. 2

Mechanisms of immunotherapy in multiple myeloma. IMiD immunomodulatory, mAb monoclonal antibody, BiTE bispecific T cell splicer, CAR chimeric antigen receptor, T T lymphocyte, NK natural killer cell, MM MM cell, DC lymph dendritic cell, Tregs regulatory T cell, CD4T helper T lymphocyte, CD8T Cytotoxic T lymphocytes. 1.IMiD therapeutic mechanism: (1) Trigger T cells to produce cytokines IFN-γ, IL-2, IL-10, etc. to drive T cell clonal expansion and NK cell activation (2) Induce an increase in antigen presentation by DC cells, thus activating CD4 and CD8 T cells to promote immune recognition and killing of MM cells. It also acts synergistically with immune checkpoint blockade to reduce MM immune tolerance. 2. Therapeutic mechanism of mAb: FCγR-mediated cross-linking stimulation of T cells, NK cells, and Tregs cells regulation, thus binding to CD38, SLAMF7 on the surface of MM cells and exerting therapeutic effects. 3. BiTE: Bispecific T-cell splicer binds to MM cell surface antigens (e.g., CD19, CD33, or BCMA) at one end, and binds to T-cell surface receptors (e.g., CD3) at the other end to recruit T-cells to the vicinity of the tumor cells, so that the T-cells are not restricted by the histocompatibility complex but are directly activated, releasing perforins and granzymes that lead to the tumor cells' lysis.CAR-T therapy Directed regulation of B cell maturation and differentiation into plasma cells by binding to MM cell surface antigens such as CD19 supports the survival of long-lived cells and prompts immune cells to kill MM cells in a targeted manner. 4. Cytotoxic drugs work through PD-1 and PD-L1 to ultimately recognize and kill MM cells