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Memory-like natural killer cells facilitate effector functions of daratumumab in multiple myeloma

ABSTRACT: Natural killer (NK) cells support the anti-myeloma activity of daratumumab via antibody-dependent cellular cytotoxicity (ADCC) in multiple myeloma (MM). However, the different roles of heterogeneous NK cell subpopulations have not been elucidated in MM. Here, we delineate memory-like NK cells in the bone marrow (BM) of newly diagnosed MM (NDMM) patients using single-cell RNA sequencing, and further characterize their distinct immunophenotypic features and functions by multicolor flow cytometry. Memory-like NK cells exert robust daratumumab-mediated effector functions ex vivo, including cytokine production and degranulation, compared to conventional NK cells. The composition of memory-like NK cells in BM determines the daratumumab-mediated ex vivo functional activity of BM NK cells in NDMM patients. Unlike conventional NK cells, sorted memory-like NK cells from the BM of NDMM patients exert substantial cytotoxic activity against myeloma cells in the presence of daratumumab. Our findings indicate that memory-like NK cells are an important mediator of daratumumab-dependent effector functions in MM and support direct future efforts to better predict and improve the clinical efficacy of therapeutic antibodies by selectively employing memory-like NK cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155795 | GEO | 2021/08/01

REPOSITORIES: GEO

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Project description:Tumor immune microenvironmental alterations occur early in multiple myeloma (MM) development. In this study, we aim to systematically characterize the tumor immune microenvironment (TME) and the tumor-immune interactions from precursor stages, i.e., monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), to newly diagnosed MM, comparing these to healthy donors. CIBERSORT analysis revealed proportions of 27 cell types, including 10 innate immune cells (monocytes, M0/M1/M2 macrophages, resting/activated dendritic cells, resting/activated mast cells, eosinophils, and neutrophils), 7 T cell subsets (CD8+ T cells, naive CD4+ T cells, resting/activated memory CD4+ T cells, follicular helper T cells, regulatory T cells, and gamma delta T cells), resting/activated NK cells, naive B cells, memory B cells, plasma cells, myeloma plasma cells, memory plasma cells, osteoblasts, osteoclasts and adipocytes. We removed plasma cells (PC) from the 100% total cell proportions to avoid bias resulting from different tumor burdens. We found that the proportions of neutrophils, mast cells, and monocytes account for the majority of innate immune cells and were decreased in NDMM and its precursor stages when compared with NBM. We noticed a significant abundance of M2 macrophages in NDMM, but not in the precursor stages. The proportion of CD8+ T cells was increased at the SMM and MM stages, and the proportion of activated memory CD4+ T cells continued to decrease from NBM to MGUS, SMM, and MM. We performed correlation analysis of immune cell proportions with the time of progression of MGUS and SMM patients. We observed neutrophil proportions were negatively correlated with the time to progression in SMM patients, indicating more neutrophils predict inferior outcomes for SMM patients. However, in NDMM patients, we observed that the neutrophil percentage was decreased in patients with high-risk status based on the 70-gene Prognostic Risk Score (GEP-70) or at stage III of International Staging System (ISS), and patients with high proportions of neutrophils had a significantly superior overall survival (OS) and event-free survival (EFS). For T cell populations, we observed that the proportions of CD8+ T cells were negatively correlated with the time of progression in SMM patients and the γδ T cells were positively correlated. We observed the proportions of γδ T cells were also positively correlated with the time of progression in MGUS patients. Consistent with the time-to-progression data, high-risk SMM patients showed higher proportions of CD8+ T cells and lower proportions of naïve CD4+ T cells and γδ T cells.

Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients Eight healthy donor and eight myeloma patients were used in the study. Non-expanded natural killer (NK) cells were isolated from PBMCs of healthy donors and myeloma patients. Expanded natural killer (ENK) cells were generated from same set of samples as mentioned in expansion protocol. All ENK and NK cells were used for gene expression profiling.

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Memory-like natural killer cells facilitate effector functions of daratumumab in multiple myeloma

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