[Nature Sub-Journal] Opening the "black box" of immune checkpoint LAG3 - developing blocking therapies to treat cancer and autoimmune diseases

This article was originally written by Translational Medicine.
Please indicate the source Author: Ashley Introduction: Although LAG3 has been extensively studied as a potential immunomodulatory target, not much is known about how it works
.

This is really a black box
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Recent studies have pinpointed how LAG3 regulates T cell activity, providing important insights into the development of other LAG3-blocking therapies to treat cancer and autoimmune diseases
.

This is a landmark study because we finally know how LAG3 works
.

This will facilitate the development of new LAG3-targeted therapeutics
.

Fighting cancer and chronic disease is exhausting work for the immune system
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When T cells engage in this lengthy battle, they become exhausted or unable to function properly
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Federal regulators recently approved an immunotherapy that revives these cells by blocking an immune checkpoint protein called LAG3
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But exactly how LAG3 works has remained a mystery — until now
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A new study, "LAG3 associates with TCR–CD3 complexes and suppresses signaling by driving co-receptor–Lck dissociation," published today in Nature Immunology, identifies how LAG3 modulates T cell activity, and could be useful for the development of other LAG3 blockade therapies.
Provides important insights into the treatment of cancer and autoimmune diseases
.

https:// "Although LAG3 has been extensively studied as a potential immunomodulatory target, not much is known about how it works
.

This It's really a black box," said co-senior author Dario aaVignali, PhD, Distinguished Professor and Vice Chair of Immunology at the University of Pittsburgh School of Medicine
.

"I believe this is a landmark study because we finally know how LAG3 works
.

This will help in the development of new LAG3-targeted therapeutics
.

" T cells protect the body by eliminating threats such as cancer, infection, etc.

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Molecules known as cancer cell and pathogen antigens are recognized by T cell receptors, activating these immune cells to fight
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But exhausted T cells don't make normal contact with antigen-presenting cells because immune checkpoint proteins slow down the immune response like the brakes on a car
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Research on two immune checkpoints called PD-1 and CTLA-4 led to the development of breakthrough drugs called immune checkpoint inhibitors more than a decade ago
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These therapies work by releasing the brakes on the immune system and accelerating T cell function
.

In March 2022, the U.
S.
Food and Drug Administration approved the first LAG3 inhibitor for advanced melanoma, and 18 other LAG3 inhibitors are in clinical trials — although the mechanism by which this checkpoint inhibits T-cell function is unclear
.

To investigate the mechanism by which LAG3 inhibits T cell function, Vignali worked with first author Clifford Guy, Ph.
D.
, then a postdoc in his lab, and co-senior author Creg Workman, Ph.
D.
, at St.
Jude Children's research Hospital started this research
.

When T cells bind to antigen-presenting cells, they form a point of contact called the immune synapse, which is overwhelmed by T cell receptors
.

"We found that LAG3 binds to T-cell receptors, but it doesn't directly inhibit them," explains Workman
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"Instead, LAG3 uses T-cell receptors to hitch a ride to the immune synapse
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" Using special dyes that measure acidity, the team found that LAG3's accumulation in synapses creates acidic conditions that disrupt the coreceptors CD4 or CD4 on helper T cells.
The association between CD8 on killer T cells and a signaling enzyme called Lck thwarts a key requirement for T cell activation and signaling
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Current LAG3-blocking drugs target the interaction between LAG3 and so-called MHC class II molecules, which are thought to be critical for LAG3 function
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But new research has found that LAG3's suppression of T-cell activity occurs with or without these molecules
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"This study calls into question the design of LAG-blocking therapeutics in development," Vignali said.
"
They
clearly work, but do they work optimally? They are designed to block class II interactions, but this study showed that LAG3 can function in the absence of class II
.

" "Now that we know that LAG3 binds to the T cell receptor, we may be able to generate the best blockers that target this interaction," he added.

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Beyond cancer, Vignali said the research could lead to new treatments for autoimmune and inflammatory diseases
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Because these diseases are caused by an overactive immune response, potential drugs could enhance -- rather than block, LAG3 activity
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"To help the body fight cancer, you want to release the brakes on the immune system
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But with autoimmunity, you want to hit the brakes harder, " explains Vignali
.

Reference: https://medicalxpress.
com/news/2022-04 -illumination-immune-checkpoint-lag3-black.
html Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment plans
.

For health guidance, please go to a regular hospital for treatment
.

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