The crux of tumor immunotherapy response

Immunotherapy has revolutionized the way cancer is treated, but the biggest question is why only a few patients are responsive. Recently, researchers in the United States have found that even the elimination of regulatory T cells in tumors does not eliminate their immunosuppressive effects, which may help explain the causes of limitations.

1 regulatory T cells have anti-tumor immunity

As early as 2004, the research team of Professor Weiping Zou of the University of Michigan found that regulatory T cells (Tregs) have anti-tumor immunity. Tregs are a subset of T cells that control autoimmune reactivity in the body and act to suppress immune function in the immune system. The normal process is: T cells fight infection, and when the threat ends, Tregs signals to stop the effect.

Cancer immunotherapy fights cancer by strengthening the immune system. Therefore, when Tregs are involved, it will suppress the immune response and turn off the anti-cancer effect. Professor Zou's team at the time linked the number of these cells to the shortened patient's survival. But the clinical trials that eliminated Tregs failed, and the results showed that the idea did not help the patient.

2 elimination of regulatory T cells can not eliminate its immunosuppression

More than a decade after the discovery of Tregs immunosuppression in human cancer, Professor Zou's team published a new study in Nature Immunology that eliminates Tregs and does not eliminate its immunosuppressive effects. Apoptosis of Tregs can nullify the body's spontaneous or PD-L1 checkpoint inhibitor-induced T cell anti-tumor immunity. When Tregs die, their inhibitory effects are stronger. When all cells are dead, the inhibitory effect is still working.

Professor Zou said: "If they don't die, they are inhibitory; if they die, the inhibition is stronger. No one expected this before. This may explain why there is no benefit in inducing apoptosis of Tregs." The accumulation of sex T cells from all parts of the body to the tumor also explains the early findings of Professor Zou, why there are many Tregs in the tumor. But as Tregs proliferate, they are also rapidly dying.

3 Molecular mechanism of regulatory T cell immunosuppression

The new study found that Tregs are adenosine when apoptotic, but not the usual inhibitors such as PD-L1 and CTLA-4. When Tregs die, they release a number of metabolites called ATP. Usually ATP helps the body provide energy. However, dying Tregs rapidly convert ATP to adenosine via CD39 and CD73. Adenosine then targets T cells and binds to receptors on the surface of T cells. This affects the function of T cells, so that they are not healthy.

Tregs' apoptosis is due to the weak NRF2-related antioxidant system and high vulnerability of free oxygen in the tumor microenvironment. Therefore, these data support a model in which tumor Tregs maintain and enhance their inhibitory capacity through death under oxidative stress. The findings suggest that the oxidative pathway acts as a metabolic checkpoint to control the behavior of Tregs and influence the efficacy of treating cancer targets.

Next, researchers will look for a way to limit this function: by setting up a roadblock to prevent Tregs from migrating into the tumor microenvironment. They will also study ways to block or control inhibitory activity.