Study Finds Inhibiting Lipid Can Improve Immunotherapy Function

Three seemingly disparate pathways that have been found to be important for regulating T cell function, known as cytokine interleukin-15 (IL-15), transforming growth factor beta (TGF- β), and peroxisome proliferator-activated receptor gamma (PPARγ), have been linked in a way that could lead to promising new targeted cancer treatments.

A new study published in Cell Reports by 2 collaborative research groups at the Medical University of South Carolina examined the role of spihingosine 1-phosphate (S1P), a lipid generated by sphingosine kinase 1 (SphK1), in regulating T cell differentiation. The study showed that the 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 regulatory T cells (Tregs). This signaling pathway improves T cell-mediated immunotherapy, according to the study.

Although there is evidence from prior research on SphK1 in tumors, there is little known about how SphK1 regulates T cell function. In order to evaluate the impact of SphK1 on T cells, researchers inhibited SphK1 function both genetically and by using a chemical drug. From this process, they found that inhibition of SphK1, and a subsequent decrease in S1P levels, led to a Tcm phenotype that reduced tumor size and decreased mortality in preclinical cancer models.

The study authors then evaluated the mechanism that leads to SphK1’s influence on 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 2 consequences: reduced PPARγ activity prevented T cells from differentiating into Tregs and reduced PPARγ activity led to an increase in lipid use for energy production. Cumulatively, the multiple impacts of S1P depletion led to the Tcm phenotype.

These molecular details explain the different impacts of T cell regulation that were known previously, according to the study. IL-15 leads to a Tcm phenotype by inhibiting SphK1 and S1P; conversely, TGF-β pushes cells towards the Treg phenotype by activating SphK1. Furthermore, these different pathways influence each other to intricately control T cell fate.

Targeting treatments such as these are important, since many current chemotherapy treatments also kill vital immune cells that could potentially help in attacking cancer cells. The study authors have found that combination therapy using a drug called PD1 mixed with compounds that inhibit SphK1 increased the efficacy of treatment in preclinical models.

According to the study authors, this research will lead to other work in calibrating T cell immunotherapy for cancer by dampening the accumulation of S1P. Future work will be aimed at validating this pathway in several preclinical cancer models. Although the mechanism of action should not change across the various model systems, this is an important next step in bringing this therapy to the clinic. Furthermore, the study authors think this pathway has the potential to modulate autoimmune diseases such as multiple sclerosis, lupus, and colitis.

Reference

• Chakraborty P, Vaena S, Thyagarajan K, et al. Pro-Survival Lipid Sphingosine-1-Phosphate Metabolically Programs T Cells to Limit Anti-tumor Activity. Cell Reports, 2019; 28 (7): 1879 DOI: 10.1016/j.celrep.2019.07.044. https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30941-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124719309416%3Fshowall%3Dtrue. Accessed August 23, 2019.