Nature Nanotechnology Academician Comments!

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Type I interferon (IFN) with impaired iNature may cause tumor immunodeficiency
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Current supplementary IFN therapy partially restores anti-cancer immunity, but at the same time induces immune evasion by up-regulating multiple immune checkpoints
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On September 27, 2021, Li Yaping and Zhang Pengcheng, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (Shanghai Institute of Materia Medica, PhD student Zhai Yihui and Shanghai Jiaotong University Renji Hospital Ph.
D.
student Wang Jin are named co-first authors of the paper), a joint communication was published online in Nature Nanotechnology A research paper titled "T lymphocyte membrane-decorated epigenetic nanoinducer of interferons for cancer immunotherapy", the research created a T lymphocyte membrane-decorated epigenetic nanoinducer of interferons for cancer immunotherapy (called OPEN), which uses procedures Sex cell death protein 1 (PD1) is designed to deliver the IFN inducer ORY-1001
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OPEN increases IFN and blocks the upregulation of immune checkpoints induced by IFN
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OPEN also targets tumors that recognize and express programmed cell death ligand 1 (PDL1) through PDL1/PD1, which then triggers the internalization of OPEN and immune checkpoint proteins
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After intravenous injection, OPEN can specifically target tumors, efficiently induce IFN secretion in tumors, up-regulate the expression of tumor cells PDL1 and major histocompatibility complex-I (MHC-I), and further promote the uptake of OPEN.
The self-enhancing effect increases the cytotoxic T cell infiltration in tumors by 29 times, significantly reduces the immune side effects of ORY-1001, and effectively inhibits the growth of triple-negative breast cancer, melanoma or colon cancer in animal models
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This epigenetic nanoinducer modified by T lymphocyte membrane provides a scalable platform to improve anti-tumor immunity
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Type I IFN is a pleiotropic cytokine, which can act as a central coordinator of tumor-immune system interaction and has strong anti-tumor activity
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Impaired interferon signaling leads to reduced antigen presentation, defective activation of cytotoxic T lymphocytes (CTL), and expansion of tumor-associated regulatory T (Treg) cells, and is therefore associated with advanced breast cancer, especially triple negative breast cancer (TNBC)
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By up-regulating downstream interferon-stimulating genes (ISG), interferon-induced or interferon-based therapies can partially rescue harmful results
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However, IFN-based treatments have only achieved limited clinical success due to their dose-limiting toxicity and immune evasion induced by IFN through upregulation of multiple immune checkpoints
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In order to reduce the off-target toxicity of interferon, strategies such as molecular engineering of interferon and in situ interferon production in tumors have been explored
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Fusion with antibodies can achieve the cell specificity of IFN, but a low-affinity mutant of IFN (about 100 times lower activity than natural IFN) must be used
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Immuno-oncology is exploring the use of epigenetic modulators for intratumoral upregulation of IFN
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It has been found that the consumption of lysine-specific histone demethylase 1 (LSD1) has been found to stimulate IFN and ISG
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However, given the widespread expression of these drug targets, severe extra-tumor toxicity is still a challenge for epigenetic regulators
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It is worth noting that all these treatments can trigger anti-tumor immunity and proto-tumor immunity
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Interferon-induced immune checkpoint block (ICB) polygenic resistance program is still a major obstacle to cancer immunotherapy
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IFN-induced polygenic resistance to ICB is mediated by the connection of an immune checkpoint ligand (ICL; for example, PDL1) and its receptor (ICR; for example, PD1) on T cells
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Inspired by the fact that cancer cell-derived exosomes PDL1 can specifically target and inhibit effective T cells, it is hypothesized that artificial exosomes derived from T lymphocyte membranes that overexpress PD1 can block a variety of ICLs and act as IFN inducers (Such as ORY) tumor targeting vector-1001 (a potent and selective LSD1 inhibitor)
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The article pattern (picture from Nature Nanotechnology) artificial exosomes can be constructed by disguising core nanoparticles with functional cell membranes
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Therefore, the study created an epigenetic nanoinducer (OPEN) loaded with ORY-1001 and overexpressing PD1 T lymphocyte membrane modification as an epigenetic immune modulator
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It is expected that OPEN will recognize and be internalized by PDL1, and then up-regulate intratumoral IFN and ISG, such as major histocompatibility complex I (MHC-I) and PDL1
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The study predicts that MHC-I can enhance the presentation of neoantigens
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At the same time, supplemented PDL1 will promote tumor-specific accumulation and subsequent uptake of OPEN, thereby blocking PDL1
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This study proves that OPEN supplements IFN in tumors and blocks its immunosuppressive activity, thereby increasing the recruitment, proliferation and activity of tumor infiltrating lymphocytes (TIL), thereby in a variety of tumor models including TNBC, melanoma and colon cancer Produce significant anti-tumor efficacy
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Academician Comments Zhao Yuliang, academician of the Chinese Academy of Sciences and director of the National Center for Nanoscience, believes that the research results reported for the first time that the Nano Drug Delivery System (NDDS) carries epigenetic drugs and is combined with immunotherapy to overcome immune tolerance and improve epigenetics.
The specificity of regulation and the effect of immunotherapy have remarkable originality and uniqueness
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"Successfully solved the two-sided problem of epigenetic drugs.
It is a new milestone in the use of NDDS to improve the effectiveness and safety of cancer immunotherapy
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" Combined with immunotherapy, it has realized the tumor-targeted delivery of epigenetic drugs and the blocking effect of immune checkpoints, and successfully solved the two key problems of poor specificity and dual effects of epigenetic therapy.
A major advance in the effective combination of immunotherapy in the treatment of tumors
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