Reprogramming T cells to overcome tumor challenges

Solid tumors often provide a challenging environment for the T cells of our immune system. By reprogramming the metabolism of T cells, scientists at the VIB-KU Leuven Center for Cancer Biology and their collaborators demonstrated a remarkable ability to boost the immune system's fight against cancer, showing promise for improving patient outcomes in difficult-to-treat malignancies. Their work appears in Nature Metabolism.

Tumors and immune cells

Over the past few decades, immune therapies such as checkpoint inhibitor therapy have revolutionized cancer treatment by 'teaching' the immune system to attack tumors. However, these therapies often fall short in solid tumors, where a hostile tumor microenvironment (TME) hinders the activity of immune cells. For example, in high-mortality cancers like pancreatic cancer, the TME can harm the immune cells with nutrient deprivation, acidity, and low oxygen levels, leading to T cell exhaustion.

But what if we can reprogram T cells so that they can use a different nutrient?

"We turned to the metabolic pathways that govern T cell functioning," says Dr. Samantha Pretto (VIB-KU Leuven), first author of the study, "to identify mechanisms that can help them thrive in challenging conditions. If we could reprogram T cells to use another food source, they might survive for longer inside tumors and be more effective in fighting cancer."

A metabolic maneuver

Using several research methods, such as single-cell RNA sequencing, single-cell gene perturbation screenings, and gene knockouts, the scientists homed in on the enzyme Elovl1 as a target to reprogram T cells. By blocking Elovl1, T cells could harness fatty acid oxidation — an efficient energy source — over glucose metabolism, which is often compromised in tumor-saturated environments.

Prof. Max Mazzone (VIB-KU Leuven) says, "This study offers a genetic analysis of multiple metabolic pathways at the primary tumor and metastatic site, disclosing which T phenotype is enabled by the perturbation of each of these pathways. Specifically, targeting Elovl1 not only enhanced the T cells' energy efficiency but also empowered them to maintain higher rates of proliferation and robust antitumor activity. T cells that underwent this metabolic reprogramming survived for longer and remained active and effective in combating cancer cells."

In a compelling demonstration of the potential of this approach, the researchers showed that blocking Elovl1 in conjunction with providing immune checkpoint therapies significantly improves T cell responses in experimental models of melanoma and pancreatic cancer. These stronger anti-tumor responses outsmart the cancer's defenses and increase the likelihood of successful treatment outcomes.

"By shifting the metabolic approach to T cell therapy, we open exciting new avenues for cancer treatment, particularly for patients who have limited options," says Mazzone. "Our findings suggest that modifying T cell metabolism not only helps these cells to combat cancer more effectively but also enhances the overall efficacy of existing immunotherapies."

As the quest for more effective cancer treatments continues, this innovative study marks a significant stride forward in empowering T cells to overcome the obstacles posed by solid tumors.

Funding

This work was supported by FWO, Stichting Tegen Kanker, NIH, Deutsche Forschungsgemeinschaft, Melanoma Research Alliance, and ERC.