Targeting turncoat immune cells to treat cancer

February 18, 2020

FEBRUARY 18, 2020, NEW YORK -- A Ludwig Cancer Research study has identified a mechanism by which regulatory T cells, which suppress immune responses, adapt their metabolism to thrive in the harsh microenvironment of the tumor. This mechanism, the study finds, is exclusively engaged by regulatory T cells (Tregs) that reside in tumors and could be disrupted to selectively target such Tregs and boost the effects of cancer immunotherapy.

"It has long been known that the Tregs found in tumors protect cancer cells from immune attack, so countering Tregs would be an important strategy for cancer immunotherapy," says Ping-Chih Ho, associate member of the Lausanne Branch of the Ludwig Institute for Cancer Research, who led the study. "But a major hurdle to such interventions is that the systemic suppression of Treg activity can cause severe autoimmune reactions. We have discovered a potential approach to overcoming that problem, one that selectively targets Tregs in tumors and could therefore prevent such adverse effects."

Tregs play a critical role in healthy tissues, where they prevent autoimmune disease and aid wound-healing. But, when recruited into tumors, Tregs also thwart anti-cancer immune responses--and immunotherapy. The current study, published in Nature Immunology, identifies a protein that drives the metabolic adaptations of intratumoral Tregs. The researchers show in a mouse model of melanoma that targeting that protein with an antibody significantly boosts the efficacy of immunotherapy without causing autoimmune side effects.

The cores of tumors are often acidic and starved of oxygen and vital nutrients, which forces resident cells to adapt their metabolism to survive. Ho and graduate student Haiping Wang suspected those adaptations might also reveal vulnerabilities unique to intratumoral Tregs. To find those vulnerabilities, they analyzed a dataset of Treg gene expression in breast tumors and blood compiled a few years ago by the laboratory of Ludwig MSK Director Alexander Rudensky.

They found that those and other intratumoral Tregs expressed high levels of genes involved in lipid uptake and metabolism--particularly CD36, a receptor involved in lipid import. An analysis of Tregs from human melanoma patients conducted by Ludwig Memorial Sloan Kettering (MSK) researchers Taha Merghoub and Jedd Wolchok yielded similar results.

To explore the role of CD36 in intratumoral Tregs, the researchers generated mice that lacked the CD36 gene only in their Treg cells and engrafted them with melanoma. "We found that the tumor burden was reduced in CD36-deficient mice," says Wang, "and the number and functionality of Tregs declined only within tumors, not in the other, healthy tissues of the mice."

CD36 deficiency induced in intratumoral Tregs a form of cell suicide known as apoptosis that was driven by a decline in the health and number of mitochondria--the power generators of cells. Further study revealed that CD36 fuels the activity of PPARβ, a protein essential to the genesis and function of mitochondria.

Treating mice bearing melanoma tumors with an antibody to CD36 resulted in a decline of intratumoral Tregs that was not seen in genetically identical control mice. When this antibody was combined with an immunotherapy known as PD-1 blockade, which stimulates a T cell attack on cancer cells, tumor growth slowed significantly, prolonging the survival of the mice. "By targeting CD36 with an antibody, we don't just create trouble for intratumoral Tregs, we also create trouble for the tumor's ability to maintain an immunosuppressive microenvironment and hamper immunotherapy," says Ho.

Ho's lab is now working to translate these findings into a potential cancer therapy while exploring how CD36-targeting might be combined with other interventions to more extensively disable Tregs selectively within tumors. They are also exploring which other types of solid tumors harbor Tregs that are dependent on CD36 for survival.
-end-
This study was supported by Ludwig Cancer Research, the Swiss Cancer Foundation, the Swiss Institute for Experimental Cancer Research, the European Research Council, the Cancer Research Institute, the Society for Immunotherapy of Cancer, the US National Institutes of Health, the Research Foundation--Flanders, the Swiss Cancer Research Foundation, Swim Across America, the Parker Institute for Cancer Immunotherapy and the Breast Cancer Research Foundation.

In addition to his Ludwig post, Ping-Chih Ho is an associate professor at the University of Lausanne.

About Ludwig Cancer Research

Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for 48 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 http://www.ludwigcancerresearch.org.

For further information please contact Rachel Reinhardt, rreinhardt@lcr.org or +1-212-450-1582.

Ludwig Institute for Cancer Research

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events
Brightsurf.com 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 Amazon.com.