Immune checkpoint blockade has emerged as a promising approach to treat cancer by restoring T cell effector function and breaking a tumor-permissive microenvironment. Remarkable clinical efficacy, durable response, and low toxicity of PD-1 checkpoint blockade have been observed in various malignancies including hematological cancers. However, in a phase 1 study of nivolumab (anti-PD-1 antibody; BMS-936558), none of 27 patients with multiple myeloma (MM) experienced a partial or complete response, whereas objective responses were observed in about 40% of patients with follicular lymphoma or diffuse large B cell lymphoma. As we and others have shown that MM cells express high levels of PD-L1, that bone marrow (BM)-infiltrating T cells are largely PD-1 positive, and more importantly MM cells carry somatic mutations in amounts similar to as B-cell lymphomas, the absence of response to PD-1 antibody therapy for MM cannot be explained by a lack of tumor-infiltrating T cells or PD-L1 or neoantigen expression by MM cells or immune cells. We speculated that PD-1/PD-L1 checkpoint blockade alone is insufficient to break the permissive microenvironment in MM because BM-infiltrating immunosuppressive cells, such as tumor-associated M?s, myeloid-derived suppressor cells (MDSCs), and/or regulatory T cells (Tregs) could still inhibit the function of MM-specific effector T cells restored by the checkpoint blockade. Indeed, our preliminary studies showed that, similar to human MM, PD-1 mAbs had no significant therapeutic effect against established MM in murine models. However, to our surprise, in vivo depletion of M?s, but not MDSCs or Tregs, resulted in significant anti-MM effects following PD-1 checkpoint blockade. This application will test our hypothesis is that M?s, as one of the major BM-infiltrating cell types, are crucial in suppressing T-cell immunity in the tumor microenvironment, and targeting these cells will significantly improve the therapeutic efficacy of checkpoint blockade in patients with MM.
Aim 1 will determine the role and mechanism of M?s in the primary resistance to PD-1 checkpoint blockade therapy in MM.
Aim 2 will elucidate the mechanisms of M?-mediated immune suppression, and Aim 3 will determine the translational potential of combining M?-targeting and PD-1 antibodies to treat human MM. Accomplishing these aims will provide the justification and tools to clinically target BM-infiltrating M?s to sensitize MM patients to PD-1 checkpoint inhibitors. The proposed studies will also lead to a better understanding of the fundamental mechanisms underlying the primary resistance to PD-1 checkpoint blockade and could pave the way to the first substantial improvements in the treatment in MM and other hematological malignancies by way of targeting M?s and PD-1 inhibition.
PD-1 checkpoint blockade therapy activates immune responses and has been a successful treatment in several cancers but so far, not in multiple myeloma. In this project we will determine how specialized white blood cells, called macrophages, inhibit the immune responses activated by PD-1 checkpoint blockade therapy in patients with multiple myeloma. We hypothesize that macrophages are crucial to myeloma tumor resistance to this treatment, and targeting these cells will significantly improve the therapeutic efficacy of PD-1 checkpoint blockade in patients. We will examine how macrophages inhibit the immune responses and how to target these cells to enhance sensitivity to treatment in myeloma patients.
|Wang, Q; Lu, Y; Li, R et al. (2018) Therapeutic effects of CSF1R-blocking antibodies in multiple myeloma. Leukemia 32:176-183|
|Ma, Xingzhe; Bi, Enguang; Huang, Chunjian et al. (2018) Cholesterol negatively regulates IL-9-producing CD8+ T cell differentiation and antitumor activity. J Exp Med 215:1555-1569|
|Yang, Jing; Liu, Zhiqiang; Liu, Huan et al. (2017) C-reactive protein promotes bone destruction in human myeloma through the CD32-p38 MAPK-Twist axis. Sci Signal 10:|