T细胞免疫治疗 z-bo 2020-09-30 343

　　The immune system monitors our body, looking for things that do not belong to us, such as bacteria and viruses. Cancer cells are abnormal cells that cause uncontrolled proliferation of cells, but they are good at avoiding detection by the immune system. T cell immunotherapy uses the body's own T cells, but reprograms them to target cancer cells. It is currently believed that three different signal transduction pathways are essential for regulating T cell function. The cytokine interleukin 15 (IL-15) stimulates the production of central memory-like T cells (memory-like T cells, Tcm) that can kill excessive memory. Cells; transforming growth factor Beta (transforming growth factor Beta, TGF-β) differentiates T cells into T regulatory cell subsets; peroxisome proliferator activated receptor γ (peroxisome proliferator activated receptor Orgamma , PPARγ) are T cells that regulate lipid metabolism and provide energy. However, the mechanisms by which these pathways determine T cell function remain unclear.

　　Two collaborative research teams of the School of Medicine of South Carolina (Medical School of South Carolina, MUSC) are studying lipid signaling in the context of cancer biology and cancer immunology. The results of a recently published study indicate that these three seem to be unrelated. These methods are interrelated. Two groups of scientists worked together to study the role of lipid sphingosine-1-phosphate (S1P) produced by sphingosine kinase 1 (SphK1) in regulating T cell differentiation. The results of their research were recently published in Cell Reports. The results of the study showed that the loss of SphK1 and the decrease of S1P levels in T cells promoted the maintenance of Tcm phenotype and inhibited the differentiation into Treg. Ultimately, this signaling pathway improves the effectiveness of T cell-mediated immunotherapy.

　　Shikhar Mehrotra, a researcher at Hollins Cancer Center (HCC), said: "We are already familiar with the role of SphK1 in tumors, but little is known about how SphK1 regulates T cell function. Associate Professor said. This research is from the MUSC Cell Therapy Department. Co-author and deputy director. To evaluate the SphK1 pair

　　The role of T cells, researchers used genes and chemicals to block the function of SphK1. They found that inhibiting SphK1 and thereby reducing S1P levels can lead to Tcm phenotypes, reduce tumor size and reduce mortality in preclinical cancer models. Dr. Besim Ogretmen said: "Inhibiting S1P produced by SphK1 can make these T cells more active and kill tumors. "I think this is the first time we have found that lipid signaling in the body plays an important role in regulating the function of T cells against cancer cells. effect. "

　　Next, they discovered that SphK1 is a T cell phenotype. I studied the mechanism of how it affects people. Loss of S1P levels increases the activity of transcription factors that can activate genes related to memory phenotypes. In addition, removal of S1P reduces the activity of PPARγ. This has two consequences. Decreased PPARγ activity prevents T cells from dividing into Treg subgroups. Decreased PPARγ activity leads to increased lipid utilization to produce energy. Generally, the multiple effects of S1P deletion lead to the formation of Tcm phenotype T cells. Mehrotra said: "This is an upstream molecule that regulates T cells in many ways." The details of these molecules explain the various previously known effects of T cell regulation. IL-15 induces Tcm phenotype by inhibiting SphK1 and S1P. In contrast, TGF-β promotes the activation of the SphK1Treg phenotype. In addition, these different pathways influence each other and complexly control the fate of T cells.

　　Merotra said: "Everything needs to be balanced until the immune response is overkill and the infection increases the signal. After that, Tregs need to tolerate the immune system and prevent autoimmunity, but cancer cells. In order to fight, this resistance must be very active, because T cells Must be very active. I will. Chemotherapy not only kills cancer cells, but also immune cells. When SphK1 is used as a target, immune cells can attach and target and kill cancer cells. In addition, Mehrotra and Ogretmen are in preclinical models It proved that the combination of a drug called PD1 and a compound that inhibits SphK1 can improve the therapeutic effect. Ogreitman said: “There is a lot of communication between cancer cells and immune cells in the human body. "We don't really understand this kind of communication, and we don't know whether cancer cells will signal T cells to increase S1P levels and make them more inactive. "

　　Interestingly, cancer cells have high S1P levels. High, it enables them to survive better. This also affects the ability of T cells to target cancer cells. This new study shows that the loss of S1P may have two meanings. One is to inhibit the survival of cancer cells, and the other is to promote the activity of T cells.

　　"This opens up many interesting areas for further research," Merotra said. "We have found that simply regulating the internal levels of S1P can produce T cells with different phenotypes."

　　"Understanding how this pathway regulates T cell function and differentiation mechanisms." It is important to do this," Ogretmen added. This work paves the way for the calibration of cancer T cell immunotherapy by inhibiting the accumulation of S1P. Future work The focus will be on validating this approach in several preclinical cancer models. The mechanism of action between different model systems should remain the same, but this is an important next step in bringing this therapy into the clinic. In addition, Mehrotra and Ogretmen believe This method may regulate autoimmune diseases such as multiple sclerosis, lupus and colitis.