*For medical professionals only
Recently, Professor Zhou Dawang and Professor Chen Lanfen of Xiamen University and Professor Ye Lilin of Army Medical University have cracked the mechanism of tumor "crushing" T cells. The paper was recently published in the journal Cell [1].
It's really overwhelming in a physical sense!
They found that areas of high fibrosis with higher stiffness in tumor tissue can induce anti-tumor T cell functional depletion through mechanical stress. Mechanosensitive channel proteins on the surface of T cells can convert this foreign mechanical stress into intracellular biochemical signals, and synergistically induce the expression of transcription factor Osr2 with T cell surface receptor (TCR) signaling, reshape T cell phenotype, and promote functional exhaustion.
This study identified Osr2 as a key immune checkpoint for CD8-positive T cells in response to mechanical stress. In mouse experiments, knockout of Osr2 can greatly alleviate the problem of T cell depletion and improve the efficacy of CAR-T therapy when applied to the treatment of solid tumors.
Screenshot of the first page of the paper
During their occurrence and progression, tumors change not only biological behavior, but also physical properties.
In the case of single tumor cells, they are usually softer than non-malignant tumor cells. A 2021 paper published in Nature Biomedical Engineering has revealed that tumor cells "overcome rigidity with softness" [2], identifying the reduction of cell stiffness as a physical immune checkpoint, demonstrating that increasing stiffness by depleting cholesterol in the plasma membrane of tumor cells can weaken their resistance to T cell killing.
As for the extracellular matrix (ECM), its structural alteration and increased stiffness are typical hallmarks of cancer. These changes are primarily caused by tumor-associated fibroblasts (CAFs) and are associated with abnormal production and cross-linking of extracellular matrix proteins, resulting in solid tumor tissues that are often stiffer than normal. This "topographic" change has an impact on T cell warfare, and the mechanism by which reducing ECM stiffness can improve T cell migration and improve cancer immune checkpoint blockade (ICB) efficacy is not well understood.
This time, the research team sought to explore and understand the specific effects and potential mechanisms of ECM stiffness changes on CD8+ T cells.
Using samples from hepatocellular carcinoma patients, the research team observed that high-fibrosis areas of tumor tissue were enriched with exhausted CD8+ T cells (TEX). When constructing an in vitro model using polydimethylsiloxane (PDMS) gels of different hardnesses to mimic the tumor microenvironment, they found that increased ECM stiffness significantly promoted and enhanced the exhaustion of activated T cells, manifested by low expression of IFN-γ and TNF-α and high expression of PD-1 and TIM-3.
This means that the tumor may be able to exert a real physical strain on the T cells by using the hard ECM. (It's so stressful that I can't stop cooking)
The results of liver cancer tissue samples and in vitro experimental models showed that ECM stiffness was related to T cell depletion
To help T cells solve their problems, we must first find the "stress point" on T cells, which are mechanosensitive ion channels (MSICs) that are responsible for sensing mechanical stimuli and converting them into intracellular biochemical signals.
After in vitro and mouse experiments, the research team set their sights on the mechanosensitive ion channel protein Piezo1. They found that Piezo1 was highly expressed on the surface of activated CD8+ T cells, and Piezo1 was activated after feeling the external mechanical stress, and the structure was altered and the channels were opened, which promoted the influx of calcium ions, resulting in the depletion of CD8+ T cells.
The use of Piezo1 inhibitor or gene knockout can alleviate the depletion of CD8+ T cells in the sclerosis culture matrix or tumors, and show stronger cytotoxicity and proliferation ability. In contrast, Piezo1 activator treatment inhibits CD8+ T cell proliferation and IFN-γ production.
The next study revealed how tumor tissue uses physical attacks to crush T cells.
Mechanistically, when T cells encounter high stiffness of ECM, Piezo1 acts as a mechanosensitive ion channel to convert mechanical stress into calcium signal, activate transcription factors such as CREB in T cells, and then promote the expression of transcription factor Osr2. The upregulation of OSR2 can remodel the epigenetic state of T cells and inhibit the gene expression of T cell killing function, thereby causing and exacerbating the exhaustion state of T cells. In addition, the expression of Osr2 is not only dependent on mechanical stress, but also needs to be co-induced by T-cell receptor (TCR) signaling.
mechanism
Coincidentally, one of the major challenges faced by CAR-T cell therapy in solid tumors is the unavoidable failure of T cells. Using a mouse model of colorectal cancer, the research team explored whether knocking out the Osr2 gene could improve the efficacy of CAR-T cell therapy in the treatment of solid tumors.
The results showed that compared with CAR-T cells with normal expression of Osr2, the control of tumor growth was significantly enhanced after infusion into mice. The number of T cells proliferating increased, the number of apoptosis decreased, the proportion of effector T cells expressing cytotoxic factors increased, and the expression of depletion-related markers such as PD-1, TIM-3 and LAG-3 decreased.
In other words, Osr2 is expected to become a new intervention target for CAR-T cell failure in solid tumors, which opens up new possibilities for improving the efficacy of solid tumor immunotherapy.
Knockout of Osr2 can alleviate T cell depletion in CAR-T therapy
This study expands our understanding of tumors' use of their physical properties for immune evasion, and finds a way to help anti-tumor T cells solve problems.
Bibliography:
[1]https://www.cell.com/cell/abstract/S0092-8674(24)00448-3
[2] Lei K, Kurum A, Kaynak M, et al. Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy. Nat Biomed Eng. 2021; 5(12):1411-1425. doi:10.1038/s41551-021-00826-6
The author of this article丨Zhang Aidi