“The majority of people don’t respond to immunotherapy,” says Greg Delgoffe, PhD, associate professor at the department of immunology at the University of Pittsburgh School of Medicine. “The reason is that we don’t really understand how the immune system is regulated within this altered tumor microenvironment.”

A study conducted by a team of scientists at Hillman Cancer Center and the University of Pittsburgh School of Medicine, led by Delgoffe and published in a Nature article titled “Metabolic support of tumor-infiltrating regulatory T cells by lactic acid“demonstrates how the composition of the tumor’s immediate environment subverts the immune system and enables the tumor to evade attack.

Cancer evades Immune Response
Cancer evades the immune system by “feeding” the T cells that protect the tumor and “starving” the T cells that would attack. [UPMC, created with BioRender.com]
The study suggests that an existing drug that prevents lactate uptake could boost cancer immunotherapy.

Disrupting the effect of the tumor microenvironment on immune cells in mice, the team was able to shrink tumors, prolong survival and increase sensitivity to immunotherapy.

A subset of immune T cells called regulatory T (Treg) cells suppress activation and division of effector T cells that kill cancer cells, maintain tolerance to self-antigens, and prevent autoimmune diseases such as type I diabetes, Crohn’s disease and multiple sclerosis.  Although crucial for the maintenance of equilibrium in a biological system, Treg cells pose a barrier to anti-cancer immunity.

The tumor microenvironment (TME) attracts Treg cells and promotes their functional specialization. Tumor cells create a metabolite-depleted, oxygen-starved, and acidic TME. This creates a competition for metabolites between effector T cells coming in to kill tumor cells, and the tumor cells, and impairs the functional capacity of the defending effector T cells. At the same time, Treg cells that are metabolically different from effector T cells, strongly suppress the killer cells within the TME.

In the current study scientist find a mechanistic link between the altered metabolic landscape of the TME and the increased activity of Treg cells recruited to the TME. The authors show, Treg cells adopt a variety of flexible approaches in metabolizing glucose in normal and cancer tissues and can engage an alternative metabolic pathway to maintain their suppressive function and even multiply in the TME.

Immune cells, like all other cell types, need to constantly produce energy for their activities. Delgoffe’s team focuses on how these different types of T cells have different appetites, and how tumors—which have large appetites—compete for nutrients with infiltrating immune cells. The researchers report effector and regulatory T cells have very different appetites, and cancer cells exploit this difference to evade attack.

The authors conduct in vitro studies to show Treg cells become unstable and poor suppressors of effector T cells when in high glucose media where Treg cells adopt the glycolytic pathway to metabolize glucose—a pathway that does not require oxygen and produces lactic acid as a by-product.

Unlike most other cells, Treg cells can tolerate high levels of lactate. The authors show when treated with lactate Treg cells stabilize, thrive and multiply in high-glucose conditions.

The authors then delete a gene called MCT1 that encodes a lactate transporter in Treg cells, and reveal that lactate uptake is dispensable for the function of Treg cells in the peripheral circulation away from tumor cells, but is essential in Treg cells within the tumor.

“We starved the T-regs,” says Delgoffe. “When T-reg cells are not being sustained by the tumor, killer T cells can come in and kill the cancer.”

Importantly, the researchers demonstrate, preventing Treg cells in the tumor from taking up lactate slows tumor growth and increases response to immunotherapy. Delgoffe’s team combined MCT1 inhibition with immunotherapy and showed that the anti-cancer effects were stronger than either strategy alone.

“Cancer is wise to the whole situation,” says Delgoffe. “Cancer cells don’t just starve T cells that would kill them but actually feed these regulatory T cells that would protect them.”

Delgoffe’s team found that tumors consume all the vital nutrients in their vicinity that effector T cells would need to attack. Further, tumors also excrete lactic acid that feeds the Treg cells, supporting them to protect tumors from an immune attack. So Treg cells nuzzle up with the tumor to stay fed.

“What better way to recruit a cell than food?” says Delgoffe.

Clinically, the same effect might be achievable using drugs that inhibit MCT1—one of which is currently being tested in people with advanced lymphoma and is well-tolerated.

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