Scientists at the University of Pittsburgh have discovered that tired T cells not only lose their own ability to fight cancer; they also influence surrounding cells to suppress an immune response. And they learned that one of the drivers of exhausted T cells is an environment low in oxygen. In a paper published in Nature Immunology, the team showed that reducing hypoxia may improve immunotherapy by mitigating the suppressive nature of exhausted T cells. These discoveries open a path to potentially manipulating the tumor environment in a manner that may improve the effectiveness of immunotherapy.
For more than 30 years, scientists have known that T cells become exhausted and less functional following constant stimulation from antigens—whether they are infectious or cancerous. So these immune cells that otherwise kill infected or malignant cells, secrete cytokines, and lose that ability.
Previously, the Pitt team, led by Greg Delgoffe, PhD, learned that T-cells have a metabolic profile resembling another type of T cell, a regulatory T cell, whose job is to suppress the immune response to prevent autoimmunity. These regulatory-like T cells are enriched in cancer tissue; it’s a well-known aspect of the tumor’s environment. “But it was very interesting to us that the metabolic profile of the exhausted T cells looked kind of like the metabolic profile of regulatory T cells,” said Delgoffe director of the Tumor Microenvironment Center at UPMC Hillman Cancer Center. “So in this work we asked if tired T cells actually take on a suppressive role.”
The team discovered that this was the case in both in vitro and in vivo animal studies. “The T-cells actually turn against us,” said Delgoffe. “It’s not just that the T cells don’t work; they actually make the surrounding cells not work as well.”
They next sought to identify the mechanism for this ability to suppress different cells. Their search eventually centered on adenosine—a highly suppressive metabolite found in high levels in the tumor microenvironment. “We found that these exhausted T cells are very, very good at making an adenosine rich environment and that’s how they suppress other cells,” said Delgoffe.
In the second part of this research, the Penn team wanted to learn how the T cells acquired their suppressor activity. They discovered that one of the major drivers was exposure to hypoxia, or low levels of oxygen in the tumor’s surroundings. Their next step was to see if they could change the environment and then change the biology of those cells.
Using a mouse model of cancer, when they put the animals on a regimen that changed the tumor environment to become less hypoxic. They put the animals on a two-drug combination aimed at improving the vasculature of the tumor. The first drug, the anti-angiogenic drug axitinib, was delivered at a low dose known as the ‘angiogenesis correction dose’ to create a more perfused vasculature. “We found that when we put the mice on this low dose anti-angiogenic therapy, it improved the vasculature and reduces the hypoxia,” said Delgoffe. Studies showed that the T cells from those treated tumors were less suppressive. The second drug, metformin, a common type-2 diabetes drug targets the tumor cells metabolism, also lowering hypoxia in the tumor. So, both drugs were able to change the environment, not by targeting the T cells, but by targeting the environment to render those T cells less suppressive.
“The idea that exhausted T cells are working against us in cancer opens up new avenues for immunotherapy, such as developing treatments to target the pathway responsible for switching sides, or engineering better T cells for cell-based therapies,” added first author Paolo Vignali, PhD. “While the immunotherapy field has rightfully been focused on correcting T cell loss of anti-cancer functions, our efforts show we should also be studying potential new behaviors gained by these cells.”
The team is now running two Phase I trials based on these discoveries: either metformin or axitinib in combination with immunotherapy in melanoma patients. “We will get a sense of whether or not immunotherapy works better in patients who have been on the combination versus single agent therapy,” Delgoffe said.