Targeting immune cells that help tumors stay hidden could improve immunotherapy

June 15, 2017
Vignali Lab 3-D microscopic image of a tumor shows Tregs (green), blood vessels (red) and tumor matrix (blue). Credit: Pitt Health Sciences/Vignali Lab

Researchers at University of Pittsburgh School of Medicine and UPMC have discovered a clue that could unlock the potential of immunotherapy drugs to successfully treat more cancers. The findings, published in Cell, were made in mice and showed that targeting a sub-population of immune cells called regulatory T cells could be an effective approach to treating cancers. The findings also point to what could be an important mechanism by which current immunotherapy drugs work, providing clues to making them more effective.

Immunotherapy drugs that push the immune system to detect and kill have been successful against several cancers, yet they are still only effective in approximately 10 to 30 percent of patients with certain types. Exactly why these drugs don't work in more patients has remained a mystery. The discovery points to what could be an important mechanism by which current immunotherapy drugs work, providing clues to making them more effective.

Regulatory T (Tregs; pronounced "tee-regs") help maintain a delicate balance in our immune system. "They act like a dimmer switch, keeping the lights bright enough to detect and eliminate threats, but not so bright that our own cells are hurt," said Dario Vignali, Ph.D., who holds the Frank Dixon Chair in Cancer Immunology, and is professor and vice chair of immunology at Pitt's School of Medicine.

"In , Tregs can be detrimental because by turning down the lights, they prevent the immune system from detecting and killing cancer cells. While creating drugs to eliminate Tregs may seem like a logical approach to treatment, they could lead to life-threatening autoimmune complications, making them unusable in cancer patients. Thus, we need to identify approaches that selectively target Tregs in tumors, sparing those outside the tumor," said Vignali, who also is co-director of the Cancer Immunology Program at the UPMC Hillman Cancer Center.

A few years ago, Vignali and his colleagues discovered that a surface protein called neuropilin-1 (Nrp1), which is expressed on almost all Tregs that infiltrated mouse tumors, was required to maintain the function, integrity and survival of Tregs within the harsh tumor microenvironment. Thus, Nrp1 on Tregs helps suppress the body's natural anti-tumor immune response thereby helping the tumor survive. Importantly, blocking or deleting Nrp1 in Tregs in mice only impacted their function in tumors and not in the rest of the body, resulting in tumor eradication without inducing autoimmune or inflammatory disease.

"What we've shown in the current study is that in mice, Nrp1 expression by Tregs is required to maintain their ability to prevent the immune system from clearing the tumor. Interestingly, when Tregs lose Nrp1, they not only fail to suppress, they also become active participants in the anti-tumor immune response," said Vignali. "Intriguingly, we also found that in cancer patients who had a poor prognosis, the Nrp1-expressing Treg subset was much higher, suggesting that the findings could apply to humans as well."

To arrive at their findings, the research team created a genetically modified mouse model in which the Nrp1 gene was deleted in only half the Treg cell population, but not the other half. Tumor growth in this model, they found, was dramatically reduced when compared to a normal mouse in which Nrp1 was present in all Tregs.

"Not only did Tregs without Nrp1 have a reduced ability to turn down the lights, they also prevented the normal Treg population from performing their own immunosuppressive functions. This allowed the immune system to see and attack the tumor," said Abigail E. Overacre-Delgoffe, a graduate student in Vignali's lab and the first author of the Cell study. Genomic and cellular analyses revealed that a secreted immune molecule called interferon-gamma (IFNγ) prevented the dimmer switch function of Tregs in the mice, particularly and selectively in the tumor microenvironment.

Using another genetically modified mouse model, they found that the role of IFNγ in diminishing Treg function was crucial to the success of immunotherapies targeting the PD1 protein that have been proven to be very effective in patients. "While we thought that IFNγ might impact the function of Tregs and thus influence immunotherapy outcome, the magnitude of the effect really took us by surprise. When we deleted the receptor for IFNγ in Tregs so they were no longer sensitive to the impact of IFNγ, the immunotherapy drug had absolutely no effect," said Vignali. "In essence, IFNγ seems to make Tregs fragile so that they lose their suppressive function, but only in the tumor. Thus, maybe making Tregs fragile is a critical requirement for effective immunotherapy."

Overall, the authors note that their findings are significant because they show that if we can get a portion of the tumor-associated Tregs to lose their immunosuppressive functions—possibly by using IFNγ—it may be enough to set off a chain reaction where these cells can influence other tumor-associated Tregs, consequently promoting anti-tumor immunity without the adverse autoimmune side effects. Additionally, in the near-term, tracking Treg functional fragility may prove to be an effective approach to monitor whether immunotherapy treatments are effective in patients.

Explore further: Antibody for fighting cancer emerges

More information: Abigail E. Overacre-Delgoffe et al, Interferon-γ Drives T regFragility to Promote Anti-tumor Immunity, Cell (2017). DOI: 10.1016/j.cell.2017.05.005

Related Stories

Antibody for fighting cancer emerges

May 19, 2017
While studying the underpinnings of multiple sclerosis, investigators at Brigham and Women's Hospital came across important clues for how to treat a very different disease: cancer. In a paper published in Science Immunology, ...

A novel protein regulates cancer immunity and could offer a therapeutic target

March 13, 2017
In an article published online ahead of print on March 13, 2017 by the Journal of Clinical Investigation, Medical University of South Carolina (MUSC) investigators report preclinical research showing that moesin, a membrane-domain ...

New cancer immunotherapy approach combines tumor fighting power with fewer side effects

May 16, 2016
Basic research into the dual nature of certain immune system cells has set the stage for a new approach to cancer immunotherapy that avoids some of the shortcomings associated with other methods, scientists at Dana-Farber ...

Researchers identify new target for cancer immunotherapy

January 17, 2017
Massachusetts General Hospital investigators have found new evidence that the tumor necrosis factor receptor type II (TNFR2) may be a major target for immuno-oncology treatments, which induce a patient's immune system to ...

New hair growth mechanism discovered

May 25, 2017
In experiments in mice, UC San Francisco researchers have discovered that regulatory T cells (Tregs; pronounced "tee-regs"), a type of immune cell generally associated with controlling inflammation, directly trigger stem ...

Dialing back treg cell function boosts the body's cancer-fighting immune activity

August 18, 2013
By carefully adjusting the function of crucial immune cells, scientists may have developed a completely new type of cancer immunotherapy—harnessing the body's immune system to attack tumors. To accomplish this, they had ...

Recommended for you

Drug suppresses spread of breast cancer caused by stem-like cells

December 12, 2017
Rare stem-like tumor cells play a critical role in the spread of breast cancer, but a vulnerability in the pathway that powers them offers a strategy to target these cells using existing drugs before metastatic disease occurs, ...

MRI scans predict patients' ability to fight the spread of cancer

December 12, 2017
A simple, non-invasive procedure that can indicate how long patients with cancer that has spread to the brain might survive and whether they are likely to respond to immunotherapy has been developed by researchers in Liverpool.

A new weapon against bone metastasis? Team develops antibody to fight cancer

December 11, 2017
In the ongoing battle between cancer and modern medicine, some therapeutic agents, while effective, can bring undesirable or even dangerous side effects. "Chemo saves lives and improves survival, but it could work much better ...

Insights on how SHARPIN promotes cancer progression

December 11, 2017
Researchers at Sanford Burnham Prebys Medical Discovery (SBP) and the Technion in Israel have found a new role for the SHARPIN protein. In addition to being one of three proteins in the linear ubiquitin chain assembly complex ...

Glioblastoma survival mechanism reveals new therapeutic target

December 11, 2017
A Northwestern Medicine study, published in the journal Cancer Cell, has provided new insights into a mechanism of tumor survival in glioblastoma and demonstrated that inhibiting the process could enhance the effects of radiation ...

Liver cancer: Lipid synthesis promotes tumor formation

December 11, 2017
Lipids comprise an optimal energy source and an important cell component. Researchers from the Biozentrum of the University of Basel and from the University of Geneva have now discovered that the protein mTOR stimulates the ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.