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Control of triple-negative breast cancer using ex vivo self-enriched, costimulated NKG2D CAR T cells.

ABSTRACT: BACKGROUND:Triple-negative breast cancer (TNBC) is an aggressive disease that currently lacks effective targeted therapy. NKG2D ligands (NKG2DLs) are expressed on various tumor types and immunosuppressive cells within tumor microenvironments, providing suitable targets for cancer therapy. METHODS:We applied a chimeric antigen receptor (CAR) approach for the targeting of NKG2DLs expressed on human TNBCs. Lentiviral vectors were used to express the extracellular domain of human NKG2D that binds various NKG2DLs, fused to signaling domains derived from T cell receptor CD3 zeta alone or with CD27 or 4-1BB (CD137) costimulatory domain. RESULTS:Interleukin-2 (IL-2) promoted the expansion and self-enrichment of NKG2D-redirected CAR T cells in vitro. High CD25 expression on first-generation NKG2D CAR T cells was essential for the self-enrichment effect in the presence of IL-2, but not for CARs containing CD27 or 4-1BB domains. Importantly, self-enriched NKG2D CAR T cells effectively recognized and eliminated TNBC cell lines in vitro, and adoptive transfer of T cells expressing NKG2D CARs with CD27 or 4-1BB specifically enhanced NKG2D CAR surface expression, T cell persistence, and the regression of established MDA-MB-231 TNBC in vivo. NKG2D-z CAR T cells lacking costimulatory domains were less effective, highlighting the need for costimulatory signals. CONCLUSIONS:These results demonstrate that CD27 or 4-1BB costimulated, self-enriched NKG2D CAR-redirected T cells mediate anti-tumor activity against TNBC tumor, which represent a promising immunotherapeutic approach to TNBC treatment.

SUBMITTER: Han Y

PROVIDER: S-EPMC6035420 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Control of triple-negative breast cancer using ex vivo self-enriched, costimulated NKG2D CAR T cells.

Han Yali Y Xie Wei W Song De-Gang DG Powell Daniel J DJ

Journal of hematology & oncology 20180706 1

<h4>Background</h4>Triple-negative breast cancer (TNBC) is an aggressive disease that currently lacks effective targeted therapy. NKG2D ligands (NKG2DLs) are expressed on various tumor types and immunosuppressive cells within tumor microenvironments, providing suitable targets for cancer therapy.<h4>Methods</h4>We applied a chimeric antigen receptor (CAR) approach for the targeting of NKG2DLs expressed on human TNBCs. Lentiviral vectors were used to express the extracellular domain of human NKG2 ...[more]

PMID: 29980239

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Project description:Introduction:Ex vivo-expanded natural killer (NK) cells are a potential candidate for cancer immunotherapy based on high cytotoxicity against malignant tumor cells. However, a limited understanding of the migration of activated NK cells toward solid tumors is a critical dilemma in the development of effective and adoptive NK cell-based immunotherapy. Methods:Ex vivo-expanded NK cells from healthy donors were stained with near-infrared fluorophores at different concentrations. NK cell proliferation and cytotoxicity were assessed using a WST-8 assay, while the expression levels of surface molecules were analyzed by flow cytometry. To investigate the biodistribution of NK cells in both normal and tumor-bearing NSG mice, NK cells labeled with ESNF13 were subjected to NIR fluorescence imaging using the Mini-FLARE imaging system. Finally, mice were sacrificed and histopathological tests were performed in resected organs. Results:The signal intensity of ESNF-stained NK cells was long-lasting at 72 h using concentrations as low as 0.04 µM. At a low dose range, ESNF13 did not affect NK cell purity, expression levels of surface receptors, or cytotoxic functions against MDA-MB-231 cancer cells. Ex vivo-expanded NK cells labeled with ESNF13 had a 4-h biodistribution in non-tumor-bearing NSG mice that mainly localized to the lungs immediately after injection and then fully migrated to the kidney after 4 h. In an MDA-MB-231 tumor-bearing NSG mice with extensive metastasis in both lungs, the fluorescence signal was dominant in both lungs and steady at 1, 2, and 4 h post-injection. In a early phase of tumor progression, administered NK cell migrated to the lungs and tumor sites within 30 min post-injection, the signal dominated the tumor site after 1 h, and remained steady at 4 h. Conclusion:Optical imaging with NIR fluorophore ESNF13 is a highly sensitive, applicable, and inexpensive method for the real-time tracking of ex vivo-expanded NK cells both in vitro and in vivo. Administered NK cells had different patterns of NK cell distribution and accumulation to the tumor site according to tumor progression in triple-negative breast cancer xenograft models.

Dataset Information

Control of triple-negative breast cancer using ex vivo self-enriched, costimulated NKG2D CAR T cells.

Publications

Control of triple-negative breast cancer using ex vivo self-enriched, costimulated NKG2D CAR T cells.

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