Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Abstract

The power of immunotherapy in the battle of Multiple Myeloma (MM) started with allogeneic stem cell transplantation, and was rediscovered with immunomodulatory drugs and extended with the outstanding results achieved with targeted antibodies. Today, next to powerful antibodies Elotuzumab and Daratumumab, several T-cell-based immunotherapeutic approaches, such as bispecific antibodies and chimeric antigen receptor-transduced T-cells (CAR T-cells) are making their successful entry in the immunotherapy arena with highly promising results in clinical trials. Nonetheless, similar to what is observed in chemotherapy, MM appears capable to escape from immunotherapy, especially through tight interactions with the cells of the bone marrow microenvironment (BM-ME). This review will outline our current understanding on how BM-ME protects MM-cells from immunotherapy through immunosuppression and through induction of intrinsic resistance against cytotoxic effector mechanisms of T- and NK-cells.

Keywords: CAR T-cells; apoptosis resistance; drug resistance; immune resistance; immunosuppression; immunotherapy; microenvironment; monoclonal antibodies; multiple myeloma.

Figure 1

Bone marrow (BM) microenvironment-mediated mechanisms of immune evasion. In the BM, the cells of microenvironment mediate the escape of MM cells from immune system via three major mechanisms: immune suppression, immune exhaustion and immune resistance. Regulatory T- and B-cells (Tregs and Bregs), myeloid derived suppressor cells (MDSCs), Tumor associate Macrophages (TAMs), dysfunctional dendritic cells (pDCs) as well as mesenchymal stromal cells (MSCs) and osteoclasts generate a highly immune suppressive environment to suppress T- and NK-cells. Immune exhaustion is the result of the upregulation of immune checkpoints such as PD1, TIGIT on immune cells and their ligands on MM cells. The third mechanism of immune escape is the development of resistance against cytotoxic killer mechanisms of immune effector cells mediated by soluble factors and especially by cell–cell contacts between MSCs and MM-cells.

Figure 2

Caspase-dependent and -independent apoptosis pathways utilized by cytotoxic T-cells (CTLs) and NK-cells and mechanisms of bone marrow microenvironment-mediated immune resistance. Apoptosis, the programmed cell death that is a consequence of DNA damage in the nucleus, occurs through caspase-dependent and -independent mechanisms. Cytotoxic immune cells such as CTLs and NK-cells (not depicted) utilize both mechanisms to kill cancer cells. The most important elements of both caspase-dependent and -independent pathways are depicted with green backgrounds. The molecules depicted with red backgrounds are the negative regulators of these pathways. Green arrows depict the activation, red arrows depict the inhibition/inactivation of the indicated molecules/processes. In caspase-dependent apoptosis, the DNA-fragmentation is executed by caspase-3 and -7, which are activated through two main pathways: i) the Extrinsic Pathway that is initiated by triggering of death-cell receptors and is mediated by caspase-8, and ii) the Intrinsic pathway that involves mitochondrial destabilization and is initiated by activation of BIM/BID by caspase-8 and granzyme-B. CTLs and NK-cells mediate the caspase-independent apoptosis mainly by granzyme-A, which causes the release of ROS through activation of the mitochondrial Complex I Protein Ndufs3. In this pathway, the enzyme NM23-H1 ultimately causes single stranded DNA damage by making DNA nicks. The indicated soluble factors produced by MSCs and osteoclasts, but mainly the stroma-MM cell interactions via integrins and NOTCH can significantly upregulate the negative regulators of apoptosis via the activation of the indicated survival/proliferation pathways. The final result of these interactions between MM- and accessory-cells is the development of resistance against the cytotoxic machinery of immune killer cells, in a similar fashion how drug resistance is induced.