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A new approach to cancer immunotherapy may avoid some of the shortcomings associated with other methods, according to researchers.
The group found that eliminating a key protein in regulatory T cells (Tregs) makes them so unstable that they become effector T cells (Teff) and begin to attack the cancer.
And this conversion from Treg to Teff occurs only in the inflammatory conditions that prevail within many tumors.
As a result, Tregs embedded in normal tissue throughout the body continue to have a restraining effect on their local Teffs, protecting healthy organs and tissues from attack.
The researchers said this raises the prospect of therapies that concentrate the immune system’s firepower on tumors without producing residual damage and harmful side effects.
“Many current approaches to immunotherapy involve depleting or blocking Tregs in order to shift the balance toward Teff cells,” said Harvey Cantor, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“This, however, runs the risk of triggering an autoimmune response in which the Teff cells attack normal as well as malignant tissue. The key to our approach is that it singles out the Tregs inside a tumor for conversion, leaving Tregs elsewhere in the body unchanged.”
Dr Cantor and his colleagues described the approach in PNAS.
The study builds on research published last year in Science. That study showed that Tregs maintain their immune-suppressive properties under inflammatory conditions as long as they have high enough levels of a protein called Helios. Depriving Tregs of sufficient Helios caused them to lose that stability and turn into Teff cells.
The new study explored whether this convertibility could be harnessed for therapeutic purposes in cancers.
The first set of experiments involved mice engineered to lack Helios in their Tregs. When the animals were injected with melanoma or colon cancer cells, they developed tumors far more slowly than animals with normal Tregs.
“Inspection of the animals’ tumor tissue showed an unstable set of T regulatory cells, many of which had converted into Teffs,” said Hye-Jung Kim, PhD, also of the Dana-Farber Cancer Institute.
The researchers then explored whether stanching Helios production in tumor-dwelling Tregs could have the same effect. They tested several antibodies that bind to key receptors on Tregs and cause a downturn in Helios production.
The team chose an antibody that worked well, DTA-1, and tested it in mice with Treg-laden tumors. When they analyzed the tumor tissue, it was clear that DTA-1 had triggered conversion of Tregs to Teffs.
“This represents a next stage in cancer immunotherapy,” Dr Cantor said. “We now have a very specific, targeted way of inducing a T-effector-cell attack on cancer while lowering the risk of adverse effects on healthy tissue. The next step will be to organize a clinical trial using this approach in patients.” 
Image by Kathryn T. Iacono
A new approach to cancer immunotherapy may avoid some of the shortcomings associated with other methods, according to researchers.
The group found that eliminating a key protein in regulatory T cells (Tregs) makes them so unstable that they become effector T cells (Teff) and begin to attack the cancer.
And this conversion from Treg to Teff occurs only in the inflammatory conditions that prevail within many tumors.
As a result, Tregs embedded in normal tissue throughout the body continue to have a restraining effect on their local Teffs, protecting healthy organs and tissues from attack.
The researchers said this raises the prospect of therapies that concentrate the immune system’s firepower on tumors without producing residual damage and harmful side effects.
“Many current approaches to immunotherapy involve depleting or blocking Tregs in order to shift the balance toward Teff cells,” said Harvey Cantor, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“This, however, runs the risk of triggering an autoimmune response in which the Teff cells attack normal as well as malignant tissue. The key to our approach is that it singles out the Tregs inside a tumor for conversion, leaving Tregs elsewhere in the body unchanged.”
Dr Cantor and his colleagues described the approach in PNAS.
The study builds on research published last year in Science. That study showed that Tregs maintain their immune-suppressive properties under inflammatory conditions as long as they have high enough levels of a protein called Helios. Depriving Tregs of sufficient Helios caused them to lose that stability and turn into Teff cells.
The new study explored whether this convertibility could be harnessed for therapeutic purposes in cancers.
The first set of experiments involved mice engineered to lack Helios in their Tregs. When the animals were injected with melanoma or colon cancer cells, they developed tumors far more slowly than animals with normal Tregs.
“Inspection of the animals’ tumor tissue showed an unstable set of T regulatory cells, many of which had converted into Teffs,” said Hye-Jung Kim, PhD, also of the Dana-Farber Cancer Institute.
The researchers then explored whether stanching Helios production in tumor-dwelling Tregs could have the same effect. They tested several antibodies that bind to key receptors on Tregs and cause a downturn in Helios production.
The team chose an antibody that worked well, DTA-1, and tested it in mice with Treg-laden tumors. When they analyzed the tumor tissue, it was clear that DTA-1 had triggered conversion of Tregs to Teffs.
“This represents a next stage in cancer immunotherapy,” Dr Cantor said. “We now have a very specific, targeted way of inducing a T-effector-cell attack on cancer while lowering the risk of adverse effects on healthy tissue. The next step will be to organize a clinical trial using this approach in patients.”
Image by Kathryn T. Iacono
A new approach to cancer immunotherapy may avoid some of the shortcomings associated with other methods, according to researchers.
The group found that eliminating a key protein in regulatory T cells (Tregs) makes them so unstable that they become effector T cells (Teff) and begin to attack the cancer.
And this conversion from Treg to Teff occurs only in the inflammatory conditions that prevail within many tumors.
As a result, Tregs embedded in normal tissue throughout the body continue to have a restraining effect on their local Teffs, protecting healthy organs and tissues from attack.
The researchers said this raises the prospect of therapies that concentrate the immune system’s firepower on tumors without producing residual damage and harmful side effects.
“Many current approaches to immunotherapy involve depleting or blocking Tregs in order to shift the balance toward Teff cells,” said Harvey Cantor, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“This, however, runs the risk of triggering an autoimmune response in which the Teff cells attack normal as well as malignant tissue. The key to our approach is that it singles out the Tregs inside a tumor for conversion, leaving Tregs elsewhere in the body unchanged.”
Dr Cantor and his colleagues described the approach in PNAS.
The study builds on research published last year in Science. That study showed that Tregs maintain their immune-suppressive properties under inflammatory conditions as long as they have high enough levels of a protein called Helios. Depriving Tregs of sufficient Helios caused them to lose that stability and turn into Teff cells.
The new study explored whether this convertibility could be harnessed for therapeutic purposes in cancers.
The first set of experiments involved mice engineered to lack Helios in their Tregs. When the animals were injected with melanoma or colon cancer cells, they developed tumors far more slowly than animals with normal Tregs.
“Inspection of the animals’ tumor tissue showed an unstable set of T regulatory cells, many of which had converted into Teffs,” said Hye-Jung Kim, PhD, also of the Dana-Farber Cancer Institute.
The researchers then explored whether stanching Helios production in tumor-dwelling Tregs could have the same effect. They tested several antibodies that bind to key receptors on Tregs and cause a downturn in Helios production.
The team chose an antibody that worked well, DTA-1, and tested it in mice with Treg-laden tumors. When they analyzed the tumor tissue, it was clear that DTA-1 had triggered conversion of Tregs to Teffs.
“This represents a next stage in cancer immunotherapy,” Dr Cantor said. “We now have a very specific, targeted way of inducing a T-effector-cell attack on cancer while lowering the risk of adverse effects on healthy tissue. The next step will be to organize a clinical trial using this approach in patients.”