Regulatory T cells (Tregs) may restrain the immune system everywhere—not just in healthy tissue, but also in tumors, where the immune system ought to have free rein. If only Tregs were more sensitive to context, they’d be less inclined to err on the side of safety and suppress antitumor activity; that is, they’d cease their secretion of anti-inflammatory factors and permit the activation of inflammation-promoting T cells.

But wait. Tregs may have unrealized potential for context-specific behavior. According to immunologists at St. Jude Children’s Research Hospital, Tregs make use of a mechanism that holds in the tumor microenvironment (TME), but not elsewhere. And interfering with this mechanism could unleash effective antitumor immune responses without inducing autoimmune toxicity.

Details appeared February 24 in Nature, in an article titled, “Lipid signaling enforces functional specialization of Treg cells in tumors.” The article presented evidence that intratumoral Treg cells “actively rewire SREBP-dependent de novo lipid biosynthesis, which acts to maintain the functional state of Treg cells in the TME.”

SREBPs, or sterol regulatory element binding proteins, are transcription factors that drive the expression of genes encoding enzymes that produce lipids. SREBPs may be important to intratumoral Tregs because cancer cells in the TME extract whatever lipids in the surroundings are available, leaving little or none for Tregs. Besides being valuable as a potential energy source, lipids such as cholesterol and fatty acids are needed for cellular signaling and the construction of cell membranes.

“We find that the activity of SREBPs is upregulated in intratumoral Treg cells,” the authors of the Nature article wrote. “Moreover, deletion of SREBP-cleavage-activating protein (SCAP)—a factor required for SREBP activity—in these cells inhibits tumor growth and boosts immunotherapy that is triggered by targeting the immune-checkpoint protein PD-1.”

The researchers showed that blocking tumor-associated Treg cell activity eliminated tumor cells in mice and sensitized the cells to cancer immunotherapy called anti-PD-1 therapy. These findings may lead to drug treatments for selectively shutting down Tregs in a tumor, rendering the tumor vulnerable to cancer immunotherapies that activate the immune system to kill the tumor.

“There has certainly been a great deal of interest in targeting regulatory T cells for cancer therapy, because they are central to keeping the immune system in check in tumors,” said corresponding author Hongbo Chi, PhD, the Robert G. Webster endowed chair, St. Jude department of immunology. “But the risk of such targeting is possibly inducing autoimmune disease because these T cells are crucial to balancing the body’s immune response.

“Our finding is exciting because we have identified a metabolic pathway that tumors use to independently reprogram Tregs. Thus, we believe there is the potential for inhibiting regulatory T-cell activation in tumors to unleash effective antitumor immune responses without triggering autoimmune toxicity.”

Chi and colleagues discovered the pathway by challenging mice with melanoma cells and then analyzing which genes were switched on in Tregs. Most important, the investigators compared tumor-infiltrating Tregs with Tregs in other tissues to assess differences in gene activation. It was this work that revealed the importance of the SREBP-mediated gene-expression pathway to intratumoral Tregs.

“We were surprised to find this context-dependent pathway functioning selectively in the tumor microenvironment,” Chi said. Seon Ah Lim, PhD, a first author of the study, added, “It is incredible we can target metabolic pathways in Tregs for cancer immunotherapy while maintaining immune homeostasis.”

The researchers determined that the tumor-specific regulatory T cell pathway was switched on in a range of cancers—melanoma, breast cancer, and head and neck cancer. The tumor-specific pathway was not switched on in animal models of inflammation or autoimmune disease.

“Mechanistically, signaling through SCAP and SREBPs coordinates cellular programs for lipid synthesis and inhibitory receptor signaling in these cells,” the Nature article’s authors detailed. “First, de novo fatty-acid synthesis mediated by fatty-acid synthase (FASN) contributes to functional maturation of Treg cells, and loss of FASN from Treg cells inhibits tumor growth. Second, Treg cells in tumors show enhanced expression of the PD-1 gene, through a process that depends on SREBP activity and signals via mevalonate metabolism to protein geranylgeranylation.”

Genetically blocking the SREBP pathway selectively in regulatory T cells led to rapid clearance of tumor cells in mice with melanoma and colon adenocarcinoma. Targeting the pathway also reduced tumor growth in mice with established tumors. Blocking the pathway had no effect on the proliferation of regulatory T cells or their overall function in the body.

Blocking the SREBP pathway also unleashed a potent antitumor response in mice with melanoma treated with immunotherapy called anti-PD-1. Anti-PD-1 treatment alone was otherwise ineffective in the mice. This form of immunotherapy inhibits the biochemical switch known as programmed cell death protein 1, or PD-1. PD-1 is a checkpoint switch that protects tumors by suppressing the immune response to them.

“Anti-PD-1 therapy currently works in only about 20% of cancer patients, although when it works, the response is durable in those cases,” Chi said. “Many pediatric cancers are not responsive to anti-PD-1. Our experiments showed that blocking this lipid pathway had quite a remarkable effect in sensitizing mice to the therapy.

“While we still have a long research path ahead of us, these findings suggest that if we can develop drugs to control this context-specific regulatory T-cell pathway in cancer patients, we can make them even more responsive to immunological checkpoint therapies.”