Immune hematology

The study find that The immune system surveils our body looking for things that don’t belong, often bacteria and viruses. While cancer cells are abnormal cells that undergo unregulated cell growth; therefore they are good at evading detection by the immune system. T cell immunotherapy uses the body’s own T cells but reprograms them to target cancer cells. Three different signaling pathways are know to be important for regulating T cell function.

Immune system surveils

The cytokine interleukin-15 (IL-15) promotes a central memory-like T cell (Tcm) phenotype that can kill unwanted cells, transforming growth factor beta (TGF-β) pushes T cells to differentiate into T regulatory cells (Tregs); and peroxisome proliferator-activated receptor gamma (PPARγ) regulates lipid metabolism; which is important for providing energy to T cells. The mechanism by which these pathways determine T cell function; however; remains unknown.

In recent work published by two collaborative research groups at the Medical University of South Carolina (MUSC) who study lipid signaling in the context of cancer biology and cancer immunology; these three seemingly disparate pathways have been linked. Because The two groups collaborated to examine the role of sphingosine 1-phosphate (S1P); a lipid generated by sphingosine kinase 1 (SphK1), in regulating T cell differentiation.

Cancer biology and cancer

Their results, published online on August 13, 2019 by Cell Reports, showed that loss of SphK1 from T cells and the resulting decrease in S1P levels foster the maintenance of a Tcm phenotype and inhibits their differentiation into Tregs. Ultimately, this signaling pathway improves T cell-mediated immunotherapy. “A lot of information is known about SphK1 in tumors, but there is little known about how SphK1 regulates T cell function,” says Shikhar Mehrotra, Ph.D., co-senior author, Hollings Cancer Center (HCC) researcher; but associate director of the Cell Therapy Unit; and associate professor at MUSC.

To evaluate the impact of SphK1 on T cells, SphK1 function was inhibited both genetically and by using a chemical drug. They found that inhibition of SphK1; and therefore reduced S1P levels ; led to a Tcm phenotype that reduced tumor size and decreased mortality in preclinical cancer models. Because “When we inhibit S1P; generated by SphK1, we can make these T cells more active for killing tumors,” says Besim Ogretmen, Ph.D., co-senior author, HCC researcher, program coleader of HCC’s Developmental  Cancer Therapeutics Research Program; professor and SmartState endowed chair of biochemistry and molecular biology at MUSC.

Developmental  Cancer Therapeutics

“They think this was the first discovery that internal lipid signaling can play an important role in regulating the function of T cells against cancer cells.” They next worked out the mechanism of how SphK1 influences the T cell phenotype. Depletion of S1P levels increased the activity of a transcription factor that turns on genes associated with the memory phenotype. Additionally, loss of S1P reduced the activity of PPARγ, with two consequences: