Cell Rep: a new lipid signaling target may improve T cell immunotherapy

August 26, 2019 / BIOON / - the immune system monitors our bodies for things that don't belong to us, such as bacteria and viruses Although cancer cells are abnormal cells, experiencing uncontrolled cell growth, they are good at avoiding the detection of the immune system T cell immunotherapy uses the body's own T cells, but reprogrammes them to target cancer cells At present, it is believed that three different signaling pathways are essential to regulate the function of T cells: interleukin-15 (IL-15) promotes the production of memory like T cells, which can kill redundant cells; transforming growth factor β (transforming growth factor Beta, TGF - β) differentiated T cells into t-regulated subsets, peroxisome proliferator activated receptor gamma (PPAR γ) regulated lipid metabolism and provided energy for T cells However, the mechanism of these pathways determining T cell function is not clear Photo source: two cooperative research groups of cell reports Medical University of South Carolina (musc) study lipid signals in the context of cancer biology and cancer immunology Their recently published research results show that the three seemingly unrelated pathways are interrelated Two groups of scientists cooperated to study the role of sphingosine-1-phosphate (S1P) produced by sphingosine kinase 1 (SphK1) in regulating T cell differentiation Their results were published in cell reports recently The results showed that the deletion of SphK1 in T cells and the resulting decrease of S1P level promoted the maintenance of TCM phenotype and inhibited their differentiation to Treg Ultimately, this signaling pathway improves the efficacy of T-cell-mediated immunotherapy "We already know a lot about the role of SphK1 in cancer, but we don't know much about how SphK1 regulates T cell function," said Dr shikhar Mehrotra, associate professor, researcher at the Hollins Cancer Center (HCC), co-author of the study and deputy director of the musc cell therapy unit To assess the effect of SphK1 on T cells, researchers used genes and chemicals to inhibit the function of SphK1 They found that inhibition of SphK1, which reduces the level of S1P, leads to a TCM phenotype, reduces tumor size, and reduces the mortality of preclinical cancer models "When we inhibit S1P produced by SphK1, we can make these T cells more active in killing tumors," Dr besim ogletmen said "I think this is the first time that lipid signaling in the body can play an important role in regulating the function of T cells against cancer cells "Next they looked at how SphK1 affects the phenotype of T cells Loss of S1P level increases the activity of a transcription factor that activates genes associated with memory phenotypes In addition, the loss of S1P reduced the activity of PPAR γ, resulting in two consequences: the decrease of PPAR γ activity prevented T cells from differentiating into Treg subsets; the decrease of PPAR γ activity led to the increase of lipid utilization for energy production In general, the multiple effects of S1P deficiency lead to the formation of T cells in the TCM phenotype "It's an upstream molecule that regulates T cells in many different ways," Mehrotra said These molecular details explain the different effects of previously known T cell regulation IL-15 results in the TCM phenotype by inhibiting SphK1 and S1P; on the contrary, TGF - β promotes the activation of SphK1 Treg phenotype In addition, these different pathways interact with each other and control the fate of T cells intricately "Everything has to be balanced until infection increases the signal when the immune response is hyperactive," Mehrotra said Tregs then need to tolerate our immune system and prevent autoimmunity However, in order to fight cancer cells, we need to break this tolerance, because we need T cells to become hyperactive "Chemotherapy is usually the center of common cancer treatment Chemotherapy can not only kill cancer cells, but also kill immune cells Using SphK1 as a target can make immune cells adhere to the surrounding, aiming at and killing cancer cells In addition, Mehrotra and ogletmen have shown that in preclinical models, the use of a drug called PD1 in combination with a compound that inhibits SphK1 can improve the therapeutic effect "There's a lot of communication between cancer cells and immune cells in the body," ogretman said "We don't really understand this communication, and we don't know if cancer cells are signaling to T cells to increase their S1P levels and make them less active "Interestingly, the high levels of S1P in cancer cells allow them to survive better This may also affect the ability of T cells to target cancer cells This new study suggests that the loss of S1P may have two effects, one is to inhibit the survival of cancer cells, the other is to promote the activity of T cells "This opens up many interesting areas for further research," Mehrotra said "Now we know that T cells with different phenotypes can be produced only by regulating the intrinsic level of S1P "The key is to understand how this pathway regulates T cell function and the mechanism of differentiation," ogretman added This work paves the way to calibrate T cell immunotherapy for cancer by inhibiting the accumulation of S1P Future work will focus on validating this approach in several preclinical cancer models Although the mechanism of action between different model systems should not be changed, it is an important next step to introduce the therapy into clinical practice In addition, Mehrotra and ogletmen believe that this pathway may regulate autoimmune diseases such as multiple sclerosis, lupus and colitis Reference: paramita Chakraborty et al, pro survival limited sphingosine-1-photosphate metallic programs T cells to limit anti tumor activity, cell reports (2019) Doi: 10.1016/j.cellep.2019.07.044