Treatment With a Fusion Protein of the Extracellular Domains of NKG2D to IL-15 Retards Colon Cancer Growth in Mice

Xia, Yan; Chen, Bei; Shao, Xiaorong; Xiao, Weiming; Li, Qian; Ding, Yanbing; Ming-chun, JI; Gong, Weijuan

doi:10.1097/cji.0000000000000033

Cited by 14 publications

(16 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Human dsNKG2D-IL-15 fusion protein can bind to MICA of B16BL16-MICA cells, through double NKG2D extracellular domains, and stimulate mouse NK and CD8 þ T cells through the IL-15 domain as shown previously [14]. Human NKG2D only binds to MICA or other human ligands but not murine ligands [22].…”

Section: Discussionmentioning

confidence: 74%

“…The addition of exogenous dsNKG2D-IL-15 protein did not downregulate functions of NK and CD8 þ T cells but promoted their activation through IL-15 [24]. Moreover, treatment with recombinant dsNKG2D-IL-15 protein displayed suppression of tumor growth and elongation of survival in tumor-bearing mice [14].…”

Section: Discussionmentioning

confidence: 98%

“…The recombinant pQE3.1-dsNKG2D-IL-15 plasmid was previously generated [14]. Taq DNA polymerase, restriction endonucleases, T4 DNA ligase, PCR product purification, and DNA recovery kits were all obtained from Takara Bio (Dalian, China).…”

Section: Plasmids Cell Lines and Reagentsmentioning

confidence: 99%

“…Exogenous IL-15 has been evaluated for tumor therapy in mice and clinical studies [12,13]. We previously generated two recombinant fusion proteins, namely, human dsNKG2DeIL-15 (hdsNKG2D-IL-15) and mouse dsNKG2D-IL-15 (mdsNKG2D-IL- 15), in which two identical NKG2D extracellular domains were fused to IL-15 [14]. DsNKG2D-IL-15 binds to NKG2D ligand-positive tumor cells through double NKG2D extracellular domain and activates NK or CD8 þ T cells via the IL-15 moiety, Abbreviations: MICA, major histocompatibility complex class I chain-related protein A; DD, degree of deacetylation; PBS, phosphate buffer saline; NP, nanoparticle; DLS, dynamic light scattering; ELISA, enzyme-linked immunosorbent assay.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Delivery of human NKG2D-IL-15 fusion gene by chitosan nanoparticles to enhance antitumor immunity

Chen

Leng

Wang

et al. 2015

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 98%

Section: Plasmids Cell Lines and Reagentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Delivery of human NKG2D-IL-15 fusion gene by chitosan nanoparticles to enhance antitumor immunity

Chen

Leng

Wang

et al. 2015

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

“…Last, we explored thermal control to expand CAR T recognition of tumor-associated antigens to include NKG2D ligands (NKG2DLs), which are upregulated on a wide range of cancers as well as suppressor cells [61][62][63][64] . Targeting NKG2DLs is limited by their expression in healthy cells such as intestinal epithelial cells and bone marrow stromal cells 65 .…”

Section: Thermal Control Of Car T Cell Functionsmentioning

confidence: 99%

Remote control of CAR T cell therapies by thermal targeting

Miller

Sun

Harris

et al. 2020

Preprint

View full text Add to dashboard Cite

The limited ability to control anti-tumor activity within tumor sites contributes to poor CAR T cell responses against solid malignancies. Systemic delivery of biologic drugs such as cytokines can augment CAR T cell activity despite off-target toxicity in healthy tissues that narrow their therapeutic window. Here we develop a platform for remote control of CAR T therapies by thermal targeting. To enable CAR T cells to respond to heat, we construct synthetic thermal gene switches that trigger expression of transgenes in response to mild elevations in local temperature (40-42 °C) but not to orthogonal cellular stresses such as hypoxia. We show that short pulses of heat (15-30 min) lead to more than 60-fold increases in gene expression without affecting key T cell functions including proliferation, migration, and cytotoxicity. We demonstrate thermal control of broad classes of immunostimulatory agents including CARs, Bispecific T cell Engagers (BiTEs), and cytokine superagonists to enhance proliferation and cell targeting. In mouse models of adoptive transfer, photothermal targeting of intratumoral CAR T cells to control the production of an IL-15 superagonist significantly enhances anti-tumor activity and overall survival. We envision that thermal targeting could improve the safety and efficacy of next-generation therapies by allowing remote control of CAR T cell activity.

show abstract

Human fused NKG2D–IL-15 protein controls xenografted human gastric cancer through the recruitment and activation of NK cells

Chen

Yang

et al. 2015

Cell Mol Immunol

Self Cite

View full text Add to dashboard Cite

Interleukin (IL)-15 plays an important role in natural killer (NK) and CD8+ T-cell proliferation and function and is more effective than IL-2 for tumor immunotherapy. The trans-presentation of IL-15 by neighboring cells is more effective for NK cell activation than its soluble IL-15. In this study, the fusion protein dsNKG2D-IL-15, which consisted of two identical extracellular domains of human NKG2D coupled to human IL-15 via a linker, was engineered in Escherichia coli. DsNKG2D-IL-15 could efficiently bind to major histocompatibility complex class I chain-related protein A (MICA) of human tumor cells with the two NKG2D domains and trans-present IL-15 to NK or CD8+ T cells. We transplanted human gastric cancer (SGC-7901) cells into nude mice and mouse melanoma cells with ectopic expression of MICA (B16BL6-MICA) into C57BL/6 mice. Then, we studied the anti-tumor effects mediated by dsNKG2D-IL-15 in the two xenografted tumor models. Human dsNKG2D-IL-15 exhibited higher efficiency than IL-15 in suppressing gastric cancer growth. Exogenous human dsNKG2D-IL-15 was centrally distributed in the mouse tumor tissues based on in vivo live imaging. The frequencies of human CD56+ cells infiltrated into the tumor tissues following the injection of peripheral blood mononuclear cells into nude mice bearing human gastric cancer were significantly increased by human dsNKG2D-IL-15 treatment. Human dsNKG2D-IL-15 also delayed the growth of transplanted melanoma (B16BL6-MICA) by activating and recruiting mouse NK and CD8+ T cells. The anti-melanoma effect of human dsNKG2D-IL-15 in C57BL/6 mice was mostly decreased by the in vivo depletion of mouse NK cells. These data highlight the potential use of human dsNKG2D-IL-15 for tumor therapy.Cellular& Molecular Immunology advance online publication, 14 September 2015; doi:10.1038/cmi.2015.81.

show abstract

Treatment With a Fusion Protein of the Extracellular Domains of NKG2D to IL-15 Retards Colon Cancer Growth in Mice

Cited by 14 publications

References 0 publications

Delivery of human NKG2D-IL-15 fusion gene by chitosan nanoparticles to enhance antitumor immunity

Delivery of human NKG2D-IL-15 fusion gene by chitosan nanoparticles to enhance antitumor immunity

Remote control of CAR T cell therapies by thermal targeting

Human fused NKG2D–IL-15 protein controls xenografted human gastric cancer through the recruitment and activation of NK cells

Contact Info

Product

Resources

About