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CD73 Immune Checkpoint Defines Inducible Regulatory NK cells in the Tumor Microenvironment

ABSTRACT: High levels of ecto-5'-nucleotidase (CD73) have been implicated in immune suppression and tumor progression. Elevated levels of CD73 has also been observed in patients who progress on anti–PD-1 immunotherapy. While regulatory T cells can express CD73 and inhibit T cell responses via the production of adenosine, less is known if conventional T cells and natural killer (NK) cells can express CD73. We found that the expression of CD73 is restricted to tumor-infiltrating NK cells and the frequency of these cells correlate with larger tumor size in patients with breast cancer. In addition, the expression of other immune checkpoint receptors including LAG-3 and VISTA was significantly higher in CD73 positive NK cells than on CD73 negative NK cells. Furthermore, the prognostic value of CD73 gene expression was influenced by NK cell signature expressed in patients with breast cancer and sarcoma. Mechanistically, upon engagement of 4-1BBL on tumor cells, NK cells transport CD73 in intracellular vesicles to the cell surface and extracellular space via actin polymerization-dependent exocytosis. These CD73 positive NK cells undergo transcriptional reprogramming and upregulate IL10 production via STAT3 transcriptional activity and suppress CD4 T cell activity. Altogether, our results support that tumors can hijack NK cells as a means to escape immunity and that CD73 expression defines an inducible population of NK cells with immune regulatory properties within the tumor microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125119 | GEO | 2020/06/10

REPOSITORIES: GEO

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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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CD73 Immune Checkpoint Defines Inducible Regulatory NK cells in the Tumor Microenvironment

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