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Author: Mia
Introduction : The hope of cancer immunotherapy is to enhance our own immune cells through specific methods to prevent cancer cells from evading the immune system . Although great progress has been made, immunotherapy is not always effective. Recently, a research team speculated that one of the reasons why immunotherapy is ineffective is that T cells produce a stress response once they penetrate into solid cancers.
Recently, Dr. Jessica Thaxton's team from the Immunotherapy Group at the University of North Carolina Lineberger Comprehensive Cancer Center published a study titled "Stress-Mediated Attenuation of Translation Undermines T-cell Activity in Cancer" in the journal Cancer Research, describing in detail how the stress response of T cells renders them unable to block tumor growth.
Thaxton's team found that T cells exposed to solid cancers develop a natural response to stress that shuts down their function and weakens their ability to kill tumors. By controlling the multiple proteins in the stress response pathway within T cells, Thaxton's team showed that it is possible to overcome the innate T cell stress response and thereby enable the immune system to stop cancer growth.
https://doi.org/10.1158/0008-5472.CAN-22-1744
PERK mediates T cell stress response
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At the center of this study is a protein called PERK (PKR-like ER kinase), which is the major HT6 stress sensor HT7 in all cell types including T cells, has not been well studied in the context of HT6 immunity. The researchers found that when T cells are stressed, such as when faced with a hostile environment created by cancer cells, PERK responds to the stress by causing the T cells to stop secreting proteins to help the T cells survive. Professor Thaxton, senior author of
, said stopping protein translation has a protective effect in most cells and is part of the T cell stress response. Everything in the scientific literature suggests that the acute part of the PERK-mediated stress response is designed to protect cells in harsh environments.
But Thaxton's group believes that in the context of tumor suppression, this natural T cell stress response would be detrimental to effective tumor immunotherapy . T cells are one of the most secretory cells in the human body. When activated to fight foreign invaders, they produce approximately 800,000 proteins per minute. For immunotherapy to be effective, T cells must secrete substances such as cytotoxic cytokines to kill tumor cells.
Molecular mechanism of inhibiting T cell protein secretion
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In 2019, Thaxton's laboratory created PERK-deficient T cells and injected these cells into tumor-bearing hosts and found that T cells unable to experience stress responses through PERK were very good at controlling tumor growth. In animal models, the research team improved the efficacy of clinically used immunotherapies by adding PERK inhibition, further demonstrating that PERK impairs effective immunotherapy .
Because proteins in cells need to operate through a series of complex interactions, the research team conducted further experiments to determine whether PERK itself was responsible for poor T cell tumor control, or whether other substances in , the signaling pathway initiated by PERK, inhibited protein secretion in T cells.
The researchers discovered that modification of a molecule called p-eIF2 alpha when PERK is activated causes T cells to temporarily stop protein synthesis during a stress response. When p-eIF2α was forced to cease its natural function, the T cells continued to synthesize the protein, controlling tumor growth in mice .
Research Significance
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Thaxton said this work is part of an effort to explore the PERK axis to understand the role this stress sensor plays in coordinating T cell function in cancer. The research team aims to discover the most effective therapeutic targets in the PERK cascade to develop unique pathways to improve the efficacy of immunotherapy.
In summary, this study shows that it is very possible to tweak T cells genetically or pharmacologically to enhance their ability to fight cancer tumor cells.This work also demonstrates the importance of studying the fundamental cell biology and bioenergetics of cells at the forefront of cancer therapy.
Reference:
https://www.eurekalert.org/news-releases/974913
https://doi.org/10.1158/0008-5472.CAN-22-1744
Note: This article is intended to introduce the progress of medical research and cannot be used as a reference for treatment plans. If you need health guidance, please go to a regular hospital.
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