Nat Nanotechnol: construction of T lymphocyte membrane modified interferon epigenetic nanoinducer

On September 27, 2021, Beijing time, Li Yaping's research group from Shanghai Institute of Materia Medica, Chinese Academy of Sciences published an online publication of engineered T lymphocyte membrane modification in the top international journal Nature Nanotechnology with the title "T lymphocyte membrane-decorated epigenetic nanoinducer of interferons for cancer immunotherapy" The latest research results of interferon (IFN) epigenetic nanoinducers to improve tumor immunotherapy
.

The team creatively designed and constructed a kind of "precise delivery + intelligent drug release integration" bionic nanovesicles, revealed the mechanism of action of the nano drug delivery system, and achieved tumor-specific IFN induction and at the same time overcoming immune tolerance.

Immunotherapy is a revolutionary development in the field of tumor treatment.
The level of type I IFN in tumors is closely related to the prognosis of many tumors including colon cancer, melanoma and triple-negative breast cancer
.

Although recombinant human IFN can be injected clinically to increase its intratumoral level, its tumor targeting is poor, the curative effect is low, and it is prone to obvious systemic immune toxicity

In response to the above-mentioned major clinical needs, the team of researcher Zhang Pengcheng and researcher Li Yaping of Shanghai Institute of Medicine first constructed T cells with high expression of programmed death receptor-1 (PD1) through genetic engineering technology, and obtained the membrane vesicles of the engineered cells; It encapsulates albumin nanoparticles loaded with lysine-specific histone demethylase 1 (LSD1) inhibitor ORY-1001; finally, it is surface-modified with reduction-sensitive penetrating peptide M70 to obtain epigenetic regulation nanocapsules Bubble (OPEN) (Figure 1A)
.

After intravenous injection, OPEN actively targets and delivers ORY-1001 to tumor cells expressing PDL1 by being recognized by the ligand (PD1/PDL1), and rapidly releases ORY-1001 under the action of intracellular glutathione (GSH), which is upregulated IFN expression promotes the activation of antigen presenting cells (APCs) and antigen presentation, activates cytotoxic T lymphocytes (CTLs), increases T cell infiltration in the tumor microenvironment, and blocks the original and IFN up-regulated multiple immune checkpoint arrangements Body-mediated immune escape (Figure 1B)

Research data shows that 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 enhanced effect increased the infiltration of CTLs in tumors by 29 times, significantly reduced the immune side effects of ORY-1001 (Figure 1C), and effectively inhibited the growth of triple-negative breast cancer, melanoma or colon cancer in animal models (Figure 1D)
.

This research opens up new directions for precision delivery + intelligent drug release integrated technology to regulate epigenetics, overcome immune tolerance, and improve tumor immunotherapy.

Zhai Yihui, a doctoral student at Shanghai Institute of Materia Medica, and Wang Jin, a doctoral student at Renji Hospital of Shanghai Jiaotong University, are the first authors of the paper.
Researchers Li Yaping and Zhang Pengcheng from Shanghai Institute of Materia Medica are the co-corresponding authors of the paper
.

Researcher Zhu He of Shanghai Jiaotong University, Researcher Yu Yang and Engineer Wang Yanke of National Center for Protein Science (Shanghai), Dr.

　　

Figure 1: (A).
Construction of PD1 overexpressing CTLL-2 cells and preparation of ORY-1001 nanovesicles (OPEN)
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(B).

　　Original link: https://doi.
org/10.
1038/s41565-021-00972-7

Expert Comment 1:  Hao Xishan 

Academician of Chinese Academy of Engineering,  Oncology Therapeutics Expert

 

　　Epigenetic imbalance is one of the key factors that induce tumorigenesis and development, but its mechanism of action is still not very clear
.

Recent studies have shown that the activation of reverse transcription factors in the genome is an important mechanism for epigenetic regulators to exert anti-tumor activity.

　　Recently, Li Yaping’s team from Shanghai Institute of Materia Medica, Chinese Academy of Sciences reported a new strategy for combining epigenetics and immunotherapy: They constructed a genetically engineered T lymphocyte membrane-encapsulated biomimetic epigenetic regulation nanoparticle, which significantly improved the appearance.
The specificity of genetic medicine
.

They incorporated an inhibitor of LSD1 (ORY-1001) into T lymphocyte membrane vesicles overexpressing PD1 to obtain a biomimetic nano drug delivery system (OPEN).

　　This work is the first time that epigenetic drugs are bionic nanotechnology and combined with immunotherapy, which realizes the tumor-targeted delivery of epigenetic drugs and immune checkpoint blocking effect, and successfully solves the poor specificity and effect of epigenetic therapy.
The two key problems of duality are a major progress in the effective combination of epigenetic therapy and immunotherapy in the treatment of tumors
.

　　Comment on the original link: http:// Comment 2: Zhao Yuliang

 

Academician of the Chinese Academy of  Sciences, Director of the National Nanoscience Center, Chief Editor of  Nano Today

　　Immune checkpoint blockade (ICB) and adoptive cellular immunotherapy are revolutionary advances in the field of cancer treatment.
They have great clinical value in inhibiting tumor growth and preventing recurrence.
However, cancer immunotherapy still faces several major challenges, such as response The low rate and less infiltration of tumor T lymphocytes can easily lead to serious immune-related adverse reactions
.
Nano-drug delivery systems have attracted widespread attention in the biomedical field due to their targeted delivery, co-delivery, and time and space controllable drug release characteristics
.

　　The Li Yaping team of Shanghai Institute of Materia Medica, Chinese Academy of Sciences has long been committed to the research of nano-drug delivery system (NDDS) in the field of cancer immunotherapy.
They proposed a new concept of carrier design integrating precise delivery + intelligent drug delivery and achieved many pioneering results.
The combination of nano-antibodies and phototherapy improves the effectiveness and safety of ICB therapy; constructing a hydrogel vaccine co-carrying BRD4 inhibitors and photosensitizers can effectively inhibit cancer recurrence and metastasis
.

　　Recently, they have constructed a new epigenetic nanoinducer and made a major breakthrough in cancer immunotherapy
.
The loss of LSD1 will lead to the up-regulation of type I IFN and interferon-stimulating genes (ISG), which in turn activates innate and acquired immunity
.
However, the activation of IFN pathway leads to the up-regulation of multiple immune checkpoints and tumor immune tolerance is still a major problem facing cancer immunotherapy
.
Li Yaping and his collaborators encapsulated the LSD1 inhibitor (ORY-1001) into the engineered T lymphocyte membrane vesicles overexpressing PD1, and constructed a new type of epigenetic immune nanomodulator OPEN
.
After intravenous injection, OPEN can be actively recognized and endocytosed by tumor cells overexpressing PDL1.
Under the action of intracellular GSH, ORY-1001 is quickly released and activated IFN signaling pathway, up-regulating MHC-I and PDL1, and promoting tumor cell antigen display and DC antigen presentation increases the intratumoral infiltration of cytotoxic T lymphocytes.
The up-regulated PDL1 can enhance the recognition and endocytosis of OPEN, and further promote the secretion of IFN while blocking the inhibitory effect of multiple immune checkpoints
.
Experimental results show that OPEN can increase tumor infiltration cytotoxic T lymphocytes by 29 times, and has a good inhibitory effect on the growth of triple-negative breast cancer, melanoma, colon cancer and other tumors in animal models
.

　　This research work reported for the first time that NDDS carries epigenetic drugs and combines them with immunotherapy to overcome immune tolerance and improve the specificity of epigenetic regulation and the effect of immunotherapy.
It has significant originality and uniqueness: first, due to The targets of epigenetic modulators are ubiquitous in the body.
Free forms of epigenetic modulators often have systemic side effects (such as bone marrow suppression, central nervous system toxicity, etc.
).
OPEN significantly improves the specificity of epigenetic therapy and increases The enrichment of intratumoral drugs reduces the side effects of drugs; secondly, the T lymphocyte membrane constructed by genetic engineering methods overexpresses a variety of immune checkpoint receptors.
While improving the targeting of OPEN, it also reduces the activation of IFN signaling pathways.
In addition, OPEN can automatically replenish multiple immune checkpoint ligands such as PDL1 on tumor cells to avoid desensitization caused by its consumption and enable OPEN to achieve sustainable specific accumulation
.
The research skillfully transformed the side effects of epigenetic drugs that promote the expression of multiple immune checkpoints into tumor-specific targets, successfully solved the dual-sided problems of epigenetic drugs, and used NDDS to improve the effectiveness and safety of cancer immunotherapy A new milestone in progress
.

　　Link to the original review: https://doi.
org/10.
1007/s11426-021-1108-0

(Contributor: Preparation Research Center; Contributor: Zhang Pengcheng)