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Author: Sophia
Summary: Tumor-infiltrating T cells enter a state of depletion or dysfunction, which limits anti-tumor immunity. Among the exhausted T cells, a subset of cells with progenitor or stem-cell-like characteristics has been identified as TCF1 CD8 T cells that respond to immunotherapy. Contrary to the discovery that TCF1 controls epigenetic and transcriptional reprogramming in tumor-infiltrating stem cell-like T cells, little is known about the regulation of TCF1. New data suggest that elevated body mass index is associated with outcomes of immunotherapy. However, this mechanism has not yet been clarified.
Recently, Peixiang Lan, Gang Chen, and Zhishui Chen from Tongji Medical College jointly published a paper titled "LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 phosphorylation, enhancing anti-PD1 immunotherapy" in the Journal for Immuno Therapy of Cancer In this article, by using a tumor-bearing mouse model, we found LDL-induced tumor infiltration TCF1PD1CD8 T cells. Using a cell-based chimeric receptor screening system, we found that LRP11 interacts with LDL and activates TCF1. LRP11 activation enhances TCF1PD1CD8 T cell-mediated anti-tumor immunity, which is consistent with LRP11 blocking impaired T cell function. Mechanistically, LRP11 activation induces MAPK13 activation. MAPK13 then phosphorylates TCF1, resulting in an increase in stem cell-like T cells.
https://jitc.bmj.com/content/12/1/e008367
Background:
01
In the tumor microenvironment, immune cells, especially T cells, enter a state of exhaustion or dysfunction, cytokine production decreases, and inhibitory receptor expression continues to increase, such as programmed cell death protein 1 (PD1) (encoded by Pdcd1) and TIM3 (encoded by Havcr2), limiting immunotherapy, including adoptive cell therapy of autologous T cells or chimeric antigen receptor (CAR) T cells and blockade of inhibitory receptors, which has achieved remarkable success in clinical cancer therapy.
Stem cell-like or progenitor Tex cells in tumors are associated with long-term maintenance of T cell responses and better patient outcomes after immunotherapy. Although depleted and dysfunctional signals, such as sustained antigen exposure, highly inhibitory ligands, and cytokines, are enriched in tumors that promote CD8 T cell depletion, stem cell-like Tex cells maintain proportions and responses to PD1 blockade. Importantly, TCF1 acts as a major regulator of T cell fate and development. New data suggest that TCF1 CD8 T cells exist in specific tissue niches of tumor or viral infection. How TCF1 CD8 T cells receive signals in the niche is not well understood.
Interestingly, clinical and experimental data suggest that an elevated body mass index (BMI) is associated with a good outcome in patients receiving immunotherapy. Although high levels of PD1 expression are thought to contribute to these outcomes, the mechanism of enhancing anti-tumor immunity in people with elevated BMI remains unknown.
Findings:
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Recent advances have highlighted the critical role of TCF1 in stem cell-like T cells in tumor tissues and chronic viral infections. The regulation of TCF1 located in the nucleus is poorly understood compared to the detailed characterization of TCF1 that controls transcriptional reprogramming in tumor-infiltrating stem cell-like T cells. Here, we found that LRP11, a membrane receptor, acts as a sensor to receive extracellular signals and activate TCF1. LRP11 activation enhances TCF1 CD8 T cell-mediated anti-tumor immunity and enhances the anti-tumor ability of PD1-blocking immunotherapy. Mechanistically, LRP11 activation induces MAPK13 activation. MAPK13 then phosphorylates TCF1. This leads to increased proliferation and cytotoxicity of CD8 T cells and prolongs the duration of their effector function in tumors. It also increases the proportion of tumor-infiltrating stem cell-like T cells, thereby enhancing anti-tumor immunity (Figure 7).
Summary plot of the LRP11-MAPK13-TCF1 axis in stem cell-like TCF1CD8 T cells. Activation of the MAPK13 signaling pathway is achieved by binding of LDL to the membrane receptor LRP11. Once phosphorylated, MAPK13 enters the nucleus and phosphorylates TCF1, thereby promoting transcription of stemness-related genes and enhancing ICB therapy.
Conclusions of the study
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In conclusion, we found that low-density lipoprotein (LDL) associated with high-fat diet-induced obesity promotes CD8 T cell proliferation and TCF1 expression through LRP11. Similarly, LRP11 agonistic antibodies show strong anti-tumor capabilities. LRP11 blockade limits TCF1 CD8 T cells during PD1 blockade immunotherapy. Notably, LRP11 activation induces phosphorylation and transport of MAPK13 into the nucleus, where MAPK13 functions as a kinase and promotes TCF1 phosphorylation, leading to transcriptional reprogramming in CD8 T cells and enhancing PD1 blockade immunotherapy. Thus, the LRP11-MAPK13 axis promotes stem cell-like TCF1 CD8 T cells through transcriptional reprogramming, enhancing anti-PD1 immunotherapy.
Resources:
https://jitc.bmj.com/content/12/1/e008367
Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment options. If you need health guidance, please visit a regular hospital.
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