Tumor is a systemic disease, and its treatment process requires long-term planning, like a marathon, but due to the long confrontation in this tug-of-war, the T cells that fight tumors are unable to do what they want
Therefore, in order to become a winner on the track and avoid the phenomenon of "T cell exhaustion", it is imperative to improve the defense power of cells on the road to slowly fighting cancer
Recently, scientists at the La Jolla Institute for Immunology (LJI) have found a breakthrough to solve this problem
They found that the basic leucine zipper transcription factor "BATF" cooperates with the interferon regulatory factor 4 "IRF4" to effectively combat T cell depletion in mouse tumor models
Related research BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells was published in Nature Immunology magazine
As the most important immune cell in the human immune system, T cells play an indispensable role in resisting bacterial viruses and other foreign pathogens and killing cancer cells
A large number of studies have found that the activation of CD8+ T cells requires the TCR-CD3 complex to receive the antigen information presented by the antigen-presenting cells, and it also requires costimulatory signals provided by a variety of accessory molecules to clear pathogen-infected cells and tumor cells.
On the contrary, if the costimulatory signal is lacking, the CD8+ T cells that infiltrate the tumor tissue for a long time will enter a state of "exhaustion or dysfunction", resulting in symptoms of immune incompetence and loss of anti-tumor ability
Therefore, even the most cutting-edge cancer immunotherapy "CAR-T therapy", there will be T cell failure
In fact, CD8+ T cell effects and depletion responses are both initiated by T cell receptor (TCR) signals, and nuclear factor of activated T cells (NFAT) is a type of transcription factor with multidirectional regulatory functions.
Both play an important role
Therefore, in order to determine which transcription factor is more effective against cell failure, researchers transferred three NFAT-AP-1 active transcription factors "JUN, MAFF and BATF" into mouse models of melanoma and colorectal cancer, respectively.
As a result, it was found that controlling the overexpression of BATF by CAR-T cells is beneficial to eliminate tumors without causing T cell exhaustion, and the long-term survival rate of mice has also been significantly improved
BATF-transduced CAR T cells exhibit enhanced tumor rejectionBATF-transduced CAR T cells exhibit enhanced tumor rejection BATF-transduced CAR T cells exhibit enhanced tumor rejection
Previous studies have shown that T cell depletion usually prevents T cells from producing a strong memory response to recurrent cancer.
However, surprisingly, this latest study reverses the traditional view.
The study pointed out that BATF-transduced CAR-T The cells will continue to exist after the tumor subsides and become the umbrella for the same tumor to attack the human body again
BATF-transduced CAR T cells persist after tumor regressionBATF-transduced CAR T cells persist after tumor regression, BATF-transduced CAR T cells persist after tumor regression
In order to more effectively combat the T cell exhaustion program, the researchers found in further experiments that the combination of BATF and interferon regulatory factor 4 (IRF4) has a better effect.
It is well known that IRF4 is a transcription factor protein that is found in B cells, T cells and macrophages play an important role in the functions of macrophages.
Studies have found that the combination of the two can not only improve the ability of T cells to fight fatigue, but also effectively improve the ability of T cells to fight tumors
BATF-IRF4 interaction is essential for anti-tumor responseBATF-IRF4 interaction is critical for anti-tumor response BATF-IRF4 interaction is critical for anti-tumor response
Hogan of the La Jolla Institute for Immunology (LJI), one of the authors of the study, said: "Cell therapy currently only shows extraordinary efficacy in blood diseases, while the development of solid tumors is still difficult
And BATF overexpression The law is a promising way to improve CAR-T therapy and combat solid tumors
Original source:Original source:
, González-Avalos, E.
, Zhang, W.
BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells .
Nat Immunol (2021).
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