Dataset Information

The nuclear export protein XPO1 provides a peptide ligand for natural killer cells

ABSTRACT: XPO1 is a nuclear export protein that is frequently overexpressed in cancer and functions as a driver of oncogenesis. Currently small molecules that target XPO1 are being used in the clinic as anti-cancer agents. We identify XPO1 as a target for natural killer (NK) cells. Using immunopeptidomics we have identified a peptide derived from XPO1 that can be recognized by the activating NK cell receptor KIR2DS2 in the context of HLA-C. The peptide can be endogenously processed and presented to activate NK cells specifically through this receptor. Although high XPO1 expression in cancer is commonly associated with a poor prognosis, we show that the outcome of specific cancers, such as hepatocellular carcinoma, can be substantially improved if there is concomitant evidence of NK cell infiltration. We thus identify XPO1 as a bona fide tumor antigen recognised by NK cells, that offers an opportunity for a personalized approach to NK cell therapy for solid tumors.

INSTRUMENT(S): Orbitrap Fusion, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

SUBMITTER: Ralf Schittenhelm

LAB HEAD: Salim Khakoo

PROVIDER: PXD053264 | Pride | 2024-10-17

REPOSITORIES: Pride

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			Action	DRS
	C1RS20160323_SK_Huh7_Cw1_Rep_W632_1.raw	Raw
	C1RS20160323_SK_Huh7_Cw1_Rep_W632_2.raw	Raw
	C1RS20160323_SK_Huh7_Cw1_Rep_W632_3.raw	Raw
	C1RS20160323_SK_Huh7_Cw1_Rep_W632_4.raw	Raw
	C1RS20160323_SK_Huh7_Cw1_Rep_W632_5.raw	Raw

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The nuclear export protein XPO1 provides a peptide ligand for natural killer cells.

Blunt Matthew D MD Fisher Hayden H Schittenhelm Ralf B RB Mbiribindi Berenice B Fulton Rebecca R Khan Sajida S Espana-Serrano Laura L Graham Lara V LV Bastidas-Legarda Leidy L Burns Daniel D Khakoo Sophie M S SMS Mansour Salah S Essex Jonathan W JW Ayala Rochelle R Das Jayajit J Purcell Anthony W AW Khakoo Salim I SI

Science advances 20240823 34

XPO1 (Exportin-1/CRM1) is a nuclear export protein that is frequently overexpressed in cancer and functions as a driver of oncogenesis. Currently small molecules that target XPO1 are being used in the clinic as anticancer agents. We identify XPO1 as a target for natural killer (NK) cells. Using immunopeptidomics, we have identified a peptide derived from XPO1 that can be recognized by the activating NK cell receptor KIR2DS2 in the context of human leukocyte antigen-C. The peptide can be endogeno ...[more]

PMID: 39178254

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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.