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Immunosuppression of the cold tumor microenvironment improves the molecular mechanism of tumor immunotherapy effect

 Last Update: 2022-09-14
 Source: Internet
 Author: User

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role immune system

cell activator

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In addition to the distinction between "good and evil", tumors are also divided into "hot and cold"

According to the spatial distribution of immune cells in the tumor microenvironment, tumors are divided into three basic immunophenotes: immune-inflammed, immune-excluded, and immune-desert phenotype

Immuno-inflammatory tumors are "hot tumors" characterized by high T cell infiltration, elevated interferon-γ signaling pathways, PD-L1 expression, and high burden of tumor mutations (TMB: the higher the TMB, the more neoantigens that may be produced, and the higher the tumor immunogenicity

Figure 1.

Immunosuppressive mechanisms in the cold tumor microenvironment: in addition to poor T cell infiltration, T cell initiation may be inhibited in the TME of cold tumors, in addition, deposition of extracellular matrix in lesions and hypoxia induced by the "stiff" matrix establish physical and chemical barriers to hinder T cell infiltration

Figure 2.

When a "hot and cold" tumor hits an immune checkpoint

Turning a cold tumor into a hot tumor?

■ Drive T cells into cold tumors and "ignite" cold tumors to improve ICI efficacy

STING agonists, oncolytic viruses, photothermal and photodynamic therapy, chemotherapy and radiation therapy all induce immunogenic cell death (ICD) to promote T cell priming and activation

Take interferon gene-stimulating factor (STING), for example, which induces the secretion of cytokines such as interferons (IFNs) and activates T-cell-mediated innate immune responses.

In the article "Breakthrough of Potent Immune Modulators Targeting Stimulator of Interferon Genes Receptor", STING agonist 4c significantly reduced the tumor volume of the CT26 mouse colorectal cancer model and effectively inhibited the growth

Figure 3: STING-mediated immunoactivation enables cancer immunotherapy ^[3].

■ Increase the abundance of immune checkpoints, promote the effective infiltration of T cells into the tumor, and "help" the cold tumor become hot

In March this year, the latest achievement of Professor Zhang Jinfang's research group at Wuhan University in the field of tumor immunotherapy was "USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy"

The results show that inhibiting USP8 in vitro enhances ubiquitination modifications linked to PD-L1 K63 and upregulates protein levels

Figure 4: USP8 Remodeling the Tumor Immune Microenvironment (TME)^[4].

■ Nanoparticle-based treatment methods

Figure 5: Nanoparticle-based treatments to make cold tumors hot^[5]

DUB-IN-2

It is a potent deubiquitinase inhibitor that inhibits the activity of USP8 with an_IC50 value of 0.
28 μM
.

ML364

Is a ubiquitin protein-specific peptidase (USP2) inhibitor that binds directly to USP2 (Kd=5.
2 μM).

ML364 has antiproliferative activity
.

P 22077

Is a ubiquitin protein-specific protease (USP7) inhibitor with an_EC50 value of 8.
01 μM and inhibition of USP47 with an_EC50 value of 8.
74 μM
.

LUT

Is a specific Usp14 inhibitor that inhibits the catalytic activity
of proteasome-related Usp14 in vitro.

PR-619

A DUB inhibitor acting on USP4, USP8, USP7, USP2, and USP5,_EC50 is 3.
93, 4.
9, 6.
86, 7.
2, and 8.
61 μM
, respectively.

MSA-2

is a non-nucleotide STING agonist with oral activity that binds
to STING in a non-covalent dimer form with nanomolar affinity.
MSA-2 works synergistically with anti-PD-1 to increase anti-tumor immunity
.

ADU-S100 disodium salt

It is an activator (STING) of interferon gene stimulators with potent antitumor and immune activity
.

Library of ubiquitinated compounds

200+ bioactive compounds that can be used in ubiquitination studies, target key enzymes in the ubiquitination pathway, and are a useful tool
for studying ubiquitination regulation and related diseases.

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3,600+ immuno-inflammatory related products for immuno-inflammatory research and drug development
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References

1.
Yuan-Tong Liu, Zhi-Jun Sun.
Turning cold tumors into hot tumors by improving T-cell infiltration.
Theranostics.
2021 Mar 11; 11(11):5365-5386.

2.
Qinjun Chen, Tao Sun, Chen Jiang, et al.
Recent Advancements in Nanomedicine for 'Cold' Tumor Immunotherapy.
Nanomicro Lett.
2021 Mar 16; 13(1):92.

3.
Min Jae Jeon, Hyelim Lee, Jeehee Lee.
Development of Potent Immune Modulators Targeting Stimulator of Interferon Genes Receptor.
J Med Chem.
2022 Apr 14; 65(7):5407-5432.

4.
Wenjun Xiong, Xueliang Gao, et al.
USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy.
Nat Commun.
2022 Mar 31; 13(1):1700.

5.
Giulio Giustarini, Andrea Pavesi, Giulia Adriani.
Nanoparticle-Based Therapies for Turning Cold Tumors Hot: How to Treat an Immunosuppressive Tumor Microenvironment.
Front Bioeng Biotechnol.
2021 Jun 2; 9:689245.

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