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    Home > Medical News > Medical World News > Nature: Bypassing immunocheckpoint IL-18BP limits the re-development of IL-18 immunotherapy.

    Nature: Bypassing immunocheckpoint IL-18BP limits the re-development of IL-18 immunotherapy.

    • Last Update: 2020-07-24
    • Source: Internet
    • Author: User
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    Cytokine is a secreted protein that can be used in immunotherapy for tumorsHowever, because the specificity of its treatment is not ideal, and may produce toxicity, so clinical application is limitedIL-18 is a member of the IL-1 cytokine family that activates congenital lymphocytes and T cellsIts role in anti-tumor has been widely studied in recent years because il-18 can induce the proliferation and enhance its activity in immune cellsJune 24, 2020, Aaron MRing of Yale University School of Medicine published a research paper entitled "IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunorapythe" online in NatureThe study found that IL-18BP produced in the tumor microenvironment (TME) can be used as a "secreting immunology checkpoint" to limit the efficacy of IL-18 immunotherapyAs a result, the authors designed an IL-18 (decoy-resistant IL-18, DR-18) that would not be suppressed by IL-18BP, with significant anti-tumor effectsThe researchers found that IL-18R and IL-18BP were commonly expressed in TMETo study its function, they transplanted THE MC38 tumor into wild C57BL/6 mice or Il18bp-/--mice and treated it with mIL-18 or vectormIL-18 had no effect on tumor growth in wild mice, but significantly inhibited tumor growth in Il18bp-//-miceTherefore, the author thinks that IL-18BP can block il-18 function as an immune checkpointbased on this, the researchers designed more than 250 million mIL-18 mutants, using yeast surface display technology, using IL-18BP and IL-18R alpha for their targeted selection and anti-selection, and finally obtained only combined with IL-18R alpha and il-18 BP affinity very low mutants, namely DR-18The results of the mouse colon cancer and melanoma modelshowed that the tumor inhibition of DR-18 was better than that of IL-18 and PD-1 antibodiesThe DR-18 is the best in combination with PD-1, allowing most mouse tumors to completely subsideHowever, DR-18 did not affect tumor growth in IL-18R knockout mice, how does DR-18 work in tumor immunotherapy? The researchers conducted an antibody-mediated depletion studyThe results showed that in mouse colon cancer and melanoma tumor models, CD8-T cells and/or CD4-T cell depletion inhibited the effects of DR-18Therefore, the anti-tumor effect of DR-18 is mediated by T cellsTo further study the effects of DR-18 on TME, the researchers sequenced single-cellRNA in the modelThe results showed that after DR-18 treatment, the transcription levels of the effect molecules (Ifng, Prf1 and Gzmb) in CD8-T cells increased, while the CD8-T cells were shown as depleted T cells (TEX) after mIL-18 or PBS treatmentIn addition, DR-18 can effectively improve the number of stem cell-like CD8-T cells inside and outside the tumor, and thus play a lasting and effective immunotherapy roleIn addition, the analysis of NK1.1 plus cell groups showed an increase in the number of NK cells after DR-18 treatmentIn general, DR-18 can reshape TME, enhance the function of T cells, promote The proliferation of T cells, and promote the maturation and versatility of anti-tumor NK cellsthe author team designed the human source DR-18 (hDR-18) in the same wayThe results show that hDR-18 is also closely bound to IL-18R alpha (rather than IL-18BP) and can stimulate the transduction of NF-B signal without being inhibited by IL-18BPAnd in human and macaque peripheral blood mononucleocells, hDR-18 both cause the production of IFN-stomaoverall, this study demonstrates that IL-18BP plays a key role in tumor immunity, limiting the efficacy of IL-18 as a secretiating immune checkpointThe researchers designed the DR-18, which has the ability to act on CD8-TEFF cells, stem cell-like TCF1-CD8-T cells, and NK cells, provides a strong basis for the clinical development of DR-18 and other IL-18 receptor agonists.
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