Ludwig researchers uncover novel mechanism by which tumors evade cancer immunotherapies

November 10, 2017

NOVEMBER 10, 2017, New York -- A Ludwig Cancer Research study led by Benoit Van den Eynde, Director of Ludwig Brussels, has identified a novel mechanism by which tumors of the aggressive skin cancer melanoma can resist cancer immunotherapy. Their paper, which appears in Nature Communications, describes how an immune cell recruited to the tumor induces the programmed suicide, or apoptosis, of the killer T cells harnessed by many immunotherapies. It also identifies the specific molecular interaction responsible for this effect. That interaction--between a protein on T cells known as FAS and its ligand produced by suppressive immune cells--could be disrupted to improve the efficacy of cancer immunotherapies.

"Immunotherapy has been delivering some impressive results, but only for a fraction of patients," says Van den Eynde. "Now the million dollar question is, what can we do to improve the proportion of patients that respond to these treatments? There are a variety of mechanisms of immune resistance that operate in the tumor. This is what we are addressing in our studies."

Researchers typically transplant tumors into genetically suitable mice to study the effects of immunotherapies. But such tumors do not reflect how cancers develop in people. To take root and grow, a tumor must evolve mechanisms over months or years to evade immune attack.

"That's what happens in clinical situations and that's what we want to model in our studies," says Van den Eynde. "If you just inject a million tumor cells in a mouse to create a tumor, you do not recapitulate this process--the interplay between the host and the tumor, the immune response that starts but then gets dampened by the tumor, or the tumor's ultimate escape from that response."

To recapitulate that process, the Ludwig Brussels team engineered a mouse to express a cancer-causing gene and a cancer antigen known as P1A, but only when given a particular drug. The researchers then induced melanoma tumors in their model and evaluated the effects of a battery of immunotherapies. These included cancer vaccines against the P1A antigen, and various regimens of checkpoint blockade therapies, which unleash a T cell attack on cancer cells. None worked against the induced tumors. They then tried adoptive T cell therapy (ACT), in which T cells directed against a tumor are infused into a patient.

"To my great surprise, even injecting 10 million activated T cells specific to the P1A antigen did not affect tumor growth in this induced tumor model," says Van den Eynde. When the same induced cancer cells were transplanted into mice to generate tumors, the T cell therapy invariably cleared the transplanted tumors.

To find out why, the researchers took a look at what happened to the T cells delivered by ACT. In both induced and transplanted models, they found, T cells were flooding into the tumor and ready to combat cancer cells. But, after that, their fates diverged significantly.

"We found that in the induced tumors, about half of the T cells were already apoptotic four days after ACT," says Van den Eynde. "This explained why they did not persist: The induced tumor behaves like a sink for these T cells. That does not happen in the transplanted tumors."

Since the cancer cells in both types of tumors were the same, the researchers compared the noncancerous cells present in the induced and transplanted tumors to explore what might be causing the T cell apoptosis. One type of cell, the polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC), was present exclusively in the induced tumors. MDSCs are a family of immune cells that are known to support immune evasion in a variety of ways.

Molecular analysis of the induced tumors revealed that the PMN-MDSCs in the induced tumors express high levels of a surface protein known as FAS-ligand, which induces T cell suicide when it binds its receptor on T cells. The researchers show that depleting PMN-MDSCs from the tumors or blocking FAS-ligand binding to its receptor restored the ability of the T cells to kill induced tumors.

"This is a novel mechanism by which these cells suppress immune responses in tumors," says Van den Eynde. "Targeting FAS-ligand could be a good adjunct therapy to boost the effects of immunotherapeutic drugs." Such drugs, he notes, are already under development. Meanwhile, Van den Eynde and his team are already hard at work looking for the other novel mechanisms of immune suppression in their model.
This research was supported by Ludwig Cancer Research, Walloon Excellence in Life Sciences and Biotechnology (WELBIO, Belgium), FNRS-Télévie (Belgium), Foundation Against Cancer (Belgium), de Duve Institute and Université catholique de Louvain (Belgium).

About Ludwig Cancer Research

Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 40 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit

For further information please contact Rachel Steinhardt, or +1-212-450-1582.

Ludwig Institute for Cancer Research

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to