Immune Cell Behavior May, Ironically, Suppress Effectiveness of Immunotherapy

Researchers have uncovered a surprising process within a key immune cell that may help explain the limitations of immunotherapy as a cancer treatment.

Regulatory T cells (Treg cells) are known to suppress immune function after T cells finish their job in fighting an infection. Cancer immunotherapy functions by boosting the immune system to attack cancer; thus, when Tregs suppress the immune response, the cancer-fighting effect stops.

Removing Tregs didn’t help reverse the situation, as a clinical trial demonstrated no benefit to patients.

But now, more than a decade after discovering the immunosuppressive role of Tregs in human cancer, a new study (“Oxidative Stress Controls Regulatory T Cell Apoptosis and Suppressor Activity and PD-L1-Blockade Resistance in Tumor”), published in Nature Immunology, finds that eliminating Tregs doesn’t eliminate their suppressive qualities.

“Live regulatory T cells (T_reg cells) suppress antitumor immunity, but how T_reg cells behave in the metabolically abnormal tumor microenvironment remains unknown. Here we show that tumor T_reg cells undergo apoptosis, and such apoptotic T_reg cells abolish spontaneous and PD-L1 [programmed death-ligand 1]-blockade-mediated antitumor T cell immunity. Biochemical and functional analyses show that adenosine, but not typical suppressive factors such as PD-L1, CTLA-4, TGF-β, IL-35, and IL-10, contributes to apoptotic T_reg-cell-mediated immunosuppression. Mechanistically, apoptotic T_reg cells release and convert a large amount of ATP to adenosine via CD39 and CD73, and mediate immunosuppression via the adenosine and A2A pathways,” write the investigators.

“Apoptosis in T_reg cells is attributed to their weak NRF2-associated antioxidant system and high vulnerability to free oxygen species in the tumor microenvironment. Thus, the data support a model wherein tumor T_reg cells sustain and amplify their suppressor capacity through inadvertent death via oxidative stress. This work highlights the oxidative pathway as a metabolic checkpoint that controls T_reg cell behavior and affects the efficacy of therapeutics targeting cancer checkpoints.

In essence, when Tregs die, instead of being negated, they become even more suppressive. All the cells are dead but the machine is still running, note the researchers.

“It’s a double-edged sword: If they do not die, they are suppressive. But if they die, they are even more suppressive,” says senior study author Weiping Zou, M.D., Ph.D., Charles B. de Nancrede professor of surgery, immunology, pathology and cancer biology at the University of Michigan. “Nobody expected this—it was a total surprise. But it likely explains why you don’t see benefit when you induce Treg apoptosis.”

In 2004, Dr. Zou’s lab discovered that Treg cells were acting against cancer immunity. They linked higher numbers of these cells to shorter survival in patients. That work led to the failed clinical trial designed to eliminate the Treg cells.

However, this new study discovered that when Treg cells die, they release adenosine triphosphate (ATP), which ordinarily helps supply the body with energy. But dying Tregs quickly convert ATP to adenosine. The adenosine then targets T cells, binding to a receptor on the T-cell surface. This affects the function of the T cells, making them unhealthy.

Tregs travel to the tumor from throughout the body, which explains an earlier finding that there are many Tregs in a tumor. But as the Tregs proliferate, many simultaneously die.

Dr. Zou and colleagues are trying to limit this function by creating a roadblock to prevent the cells from migrating to the tumor microenvironment. They will also investigate options to block or control the suppressive activity.