Targeting regulatory T cells could boost the effects of cancer immunotherapy

A Ludwig Cancer Research study has identified a mechanism by which regulatory T cells, which suppress immune responses, adapt their metabolism to thrive in the harsh microenvironment of the tumor. This mechanism, the study finds, is exclusively engaged by regulatory T cells (T_regs) that reside in tumors and could be disrupted to selectively target such T_regs and boost the effects of cancer immunotherapy.

"It has long been known that the T_regs found in tumors protect cancer cells from immune attack, so countering T_regs would be an important strategy for cancer immunotherapy," says Ping-Chih Ho, associate member of the Lausanne Branch of the Ludwig Institute for Cancer Research, who led the study. "But a major hurdle to such interventions is that the systemic suppression of T_reg activity can cause severe autoimmune reactions. We have discovered a potential approach to overcoming that problem, one that selectively targets T_regs in tumors and could therefore prevent such adverse effects."

T_regs play a critical role in healthy tissues, where they prevent autoimmune disease and aid wound-healing. But, when recruited into tumors, T_regs also thwart anti-cancer immune responses-;and immunotherapy. The current study, published in Nature Immunology, identifies a protein that drives the metabolic adaptations of intratumoral T_regs. The researchers show in a mouse model of melanoma that targeting that protein with an antibody significantly boosts the efficacy of immunotherapy without causing autoimmune side effects.

The cores of tumors are often acidic and starved of oxygen and vital nutrients, which forces resident cells to adapt their metabolism to survive. Ho and graduate student Haiping Wang suspected those adaptations might also reveal vulnerabilities unique to intratumoral T_regs. To find those vulnerabilities, they analyzed a dataset of T_reg gene expression in breast tumors and blood compiled a few years ago by the laboratory of Ludwig MSK Director Alexander Rudensky.

They found that those and other intratumoral T_regs expressed high levels of genes involved in lipid uptake and metabolism- particularly CD36, a receptor involved in lipid import. An analysis of T_regs from human melanoma patients conducted by Ludwig Memorial Sloan Kettering (MSK) researchers Taha Merghoub and Jedd Wolchok yielded similar results.

To explore the role of CD36 in intratumoral T_regs, the researchers generated mice that lacked the CD36 gene only in their T_reg cells and engrafted them with melanoma. "We found that the tumor burden was reduced in CD36-deficient mice," says Wang, "and the number and functionality of T_regs declined only within tumors, not in the other, healthy tissues of the mice."

CD36 deficiency induced in intratumoral T_regs a form of cell suicide known as apoptosis that was driven by a decline in the health and number of mitochondria-;the power generators of cells. Further study revealed that CD36 fuels the activity of PPARβ, a protein essential to the genesis and function of mitochondria.

Treating mice bearing melanoma tumors with an antibody to CD36 resulted in a decline of intratumoral T_regs that was not seen in genetically identical control mice. When this antibody was combined with an immunotherapy known as PD-1 blockade, which stimulates a T cell attack on cancer cells, tumor growth slowed significantly, prolonging the survival of the mice.

By targeting CD36 with an antibody, we don't just create trouble for intratumoral T_regs, we also createtrouble for the tumor's ability to maintain an immunosuppressive microenvironment and hamper immunotherapy."Ping-Chih Ho, associate member of the Lausanne Branch of the Ludwig Institute for Cancer Research

Ho's lab is now working to translate these findings into a potential cancer therapy while exploring how CD36-targeting might be combined with other interventions to more extensively disable T_regs selectively within tumors. They are also exploring which other types of solid tumors harbor T_regs that are dependent on CD36 for survival.
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New melanoma test may better predict recurrence and improve patient care

According to the study author Thomas Kupper, the “simple and elegant test,” which the team developed in collaboration with international colleagues, could improve current prediction models and patient care.

Generally, patients first suspect melanoma when noticing changes in the appearance of a pigmented spot such as a mole or freckle. A primary melanoma can often be cured through surgical removal, but, in some cases, the lesion can also recur and spread.

Lesion analysis has not changed significantly in the last hundred years

Analyzing the lesion post-removal provides a certain amount of information about whether it may recur. Currently, this analysis has not particularly moved on from a hundred years ago, despite the major advancements that have been made in the field of molecular cancer diagnostics.

The surprisingly simple procedure involves assessing the lesion’s thickness (thinner tends to be better) and microscopic features before assigning a cancer stage of T1 to T4, where increasing T number indicates larger tumor size, or more growth into nearby tissues.

As reported in Nature Cancer, Kupper and colleagues now present a novel, quantitative DNA sequencing technique that serves as a more sophisticated and accurate predictor of whether primary melanomas are likely to recur and spread.

New immunotherapies offer hope to patients
Kupper says that only a decade ago, the prognosis for metastatic melanoma was dismal, but that today, new immunotherapies can be offered to patients with metastatic disease and possibly to patients with primary melanoma that has not yet spread.

"Because of the advent of these new immunotherapy treatments, it's important to have a clear idea of which patients are likely to progress so that we can tailor treatment accordingly," adds Kupper.

The treatments discussed are called immune checkpoint inhibitors - agents that can reawaken T cells to launch an immune attack against cancer cells. The new therapies have radically changed patients’ options and outcomes in cases where melanoma has spread. In some patients, outcomes include long-term remission, which is essentially a cure.

An unmet need stands in the way
However, the ability to stratify patients by risk to identify who is most likely to experience disease progression remains an unmet need.

Kupper and colleagues, therefore, set out to determine whether certain features of T cells in tumors removed from patients could predict disease recurrence. Since T1 melanomas (<1mm and="" focused="" mm="" on="" rarely="" spread="" t2="" t3="" t4="" team="" the="">4mm) primary melanomas.

A challenge that the team faced was obtaining enough samples to ensure the study was robust. Unlike most tumors, skin lesions are often not concentrated in a hospital setting because they have been removed in private and ambulatory clinics. They also must be stored for several years before they can be made available for research.

To ensure an adequate number of lesion samples, the Brigham investigators teamed up with colleagues at the Melanoma Institute of Australia and the Zealand University Hospital in Denmark to share resources.

What did the researchers find?
Using high-throughput DNA sequencing, the team assessed the T cell repertoire of 300 samples from patients across these sites and compared primary melanomas that had metastasized with those that had not.

The researchers found that of all the variable features identified, the T-cell fraction (TCFr) was a potent and independent predictor of which patients would experience disease progression.

Even among patients who had lesions of the same thickness, TCFr predicted which ones were at a greater risk of metastasis.

Patients were at a greater risk of progression if their TCFr was lower, rather than higher, than 2%.

For example, among patients with T3 melanoma (2-4mm thickness) five years after the primary lesion had been removed, a whole half of those with the lower TCFr experienced recurrence, compared with only a quarter of those with the higher TCFr.

Prospective studies are now needed to validate the test

The new test is currently only available for research purposes and cannot be accessed in the clinic. The authors also point out that the current study is retrospective, with the outcomes already known, and that prospective studies will be needed in the future to validate the test. 

However, if the test were implemented in the clinic, Kupper and the team think it could strengthen current prediction models and improve patient care.

Kupper says the simple and elegant test is quantitative rather than subjective and may be able to add value to predictions about disease progression.

"In the future, such a test could help us tailor treatment; patients with high TCFr may further benefit from checkpoint inhibitor therapy, while low TCFr patients may need additional intervention,” he concludes.

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