Nature Immunology: When cancer-fighting T cells are depleted, they may change sides

When T cells, the immune system's main anticancer agent, work overtime to fight tumors, they enter a state of exhaustion and no longer work properly
.
In a new study, researchers at the University of Pittsburgh and UPMC Hillman Cancer Center report that the tumor's low-oxygen environment prompts these tired T cells to switch allegiances, suppressing the immune system rather than fighting cancer
.

"We often think of our immune system in absolute terms: certain types of cells are 'good' and some are 'bad,'" said senior author Dr.
Greg Delgov, an associate professor of immunology at the Pitt School of Medicine and director of
the Center for Tumor Microenvironment at UPMC Hillman Cancer Center.
"The key takeaway from our work is that our immune system is very sensitive
to the local environment.
Under the right circumstances, cells normally considered cancer-fighting can change sides against
us.
”

The new study, led by Dr.
Paul Wienery, a student in the Pitt University Medical Scientist Training Program, also showed that targeting low oxygen levels reduced the inhibitory properties of depleted T cells and improved response
to immunotherapy.

Delgoffe and Vignali elaborate on the study's findings and how they can inform the next steps in developing therapies
.

What are depleted T cells? What role do they play in cancer and other diseases?

GD: Exhausted T cells are soldiers of our immune system who are constantly battling cancer without rest
.
Our immune system uses T cells to find and kill abnormal cells, such as those that are cancerous or virus-infected, and they continue to fight until each abnormal cell is cleared
.
But in diseases like cancer, where cancer cells are in sync with the immune system, T cells may not be able to do their job, and abnormal cells stay
.
As T cells continue to fight these cancer cells, their job gets worse and worse
.

PV: Exhausted T cells are an adaptive response to
too many "signals.
" These signals may come from pathological sources, such as cancer or viruses, but they also appear in healthy tissue, so we find depleted T cells in autoimmune diseases, where the immune system inappropriately attacks the host, and in the placenta, the mother's immune system adapts to the growing fetus
.
In these cases, T cell exhaustion is a good thing: it helps control unnecessary damage
to the cells that activate it.

What do you know about depleted T cells in this new study?

GD: Since depleted T cells no longer kill cancer cells well, they are targeted
by immune-based cancer treatments.
The idea is that if we can reinvigorate them, they can effectively kill cancer cells
again.
We learned in our research that when depleted T cells enter tumors, they not only function poorly on their own; In effect, they alter their surroundings and actively shut down other nearby cells
.
In other words, depleted T cells aren't just unable to work for us; They are actively working against us
.

PV: The idea that depleted T cells work against us in cancer opens up new avenues for immunotherapy, such as developing treatments that target pathways responsible for changing direction, or designing better T cells for cell-based therapies
.
While the immunotherapy field has focused on correcting the loss of T cells' cancer-fighting function, our efforts suggest that we should also study their potential to acquire new
behaviors in these cells.

Are you surprised by these results?

GD: Failing T cells have a lot in common with regulatory T cells, which are T cells
that help the immune system control itself to prevent autoimmune diseases.
We found that depleted T cells functionally mimic regulatory T cells
by suppressing the immune system.
We have some hints about this finding, so it's not too surprising
.
However, we were surprised to find that the immunosuppressive function of exhausted T cells was related to
the environment in which we studied them.
In short, we found that more aggressive tumors tend to have more immunosuppressively depleted T cells, while slower-growing tumors have weaker functioning T cells but no inhibitory effect
.

What do your findings suggest for treatments that target depleted T cells?

GD: The observation that the local tumor environment determines whether depleted T cells have immunosuppressive effects is a clue
.
It tells us that if we can reprogram or modulate the local environment, perhaps the inhibitory nature of these cells can be reversed
.
It turns out this: The drugs we use don't specifically target T cells, but change the battlefield
of their battles by targeting tumor blood vessels and metabolism.
We found that creating more favorable conditions was enough to moderate these anti-inflammatory functions by depleted T cells in these treated tumors, which improved tumor response
to several immune-based cancer therapies.

PV: It's especially exciting
to discover that we can reverse the anti-inflammatory function of T cells.
Many large, complex studies tell us that most of the characteristics of depleted T cells are irreversible – they can only be poor tumor killers
.
However, the battle between the immune system and cancer is a delicate balance
.
Here, our data show that we can target the battlefield, altering the balance in favor of immune cells, even in
large, aggressive tumors.

What's next for this research?

GD: We are currently conducting several clinical trials in Pittsburgh to use these environmentally-modifying drugs
in cancer patients.
The next big question will be whether we can reverse the immunosuppressive properties
of depleted T cells in these patients.
We are also interested in
developing drugs that directly target the inhibitory properties of T cells in patients.
In addition to cancer, depleted T cells are found in chronic infections such as hepatitis and AIDS, autoimmune diseases such as lupus and type 1 diabetes, and in the gut
.
Discovering the role of these cells and their inhibitory properties in other environments will be a new direction
in this study.