Modulating T-cell metabolism uncovers new technology for enhancing immunotherapy

September 11, 2017

T lymphocytes found in tumors and implicated in killing tumor cells cope with the shortage of oxygen and nutrients in the tumor microenvironment by using fat as the main source of energy. Promoting a switch from glucose to fatty acid to generate energy enhances T cell antitumor activity. These findings from a study conducted at The Wistar Institute were published in the journal Cancer Cell.

The presence of infiltrating T lymphocytes (TILs) in solid tumors is often associated with better clinical outcomes and better patient responses to some immunotherapeutic treatments. These cells can be isolated from a cancer patient, manipulated ex vivo, and infused into the same patient to treat her/his own cancer. However, the effectiveness of TILs antitumor responses is limited by their progressive loss of functions. Metabolic stress plays a central role in the exhaustion of T cells as they compete with for oxygen and nutrients in the . In these unfavorable conditions, the function of TILs is impaired, reducing their potency against the tumor and the efficacy of T cell-based immunotherapy.

"The mechanisms behind TILs exhaustion are poorly understood," said lead author of the study Hildegund C.J. Ertl, M.D., Caspar Wistar Professor in Vaccine Research and member of Wistar's Vaccine & Immunotherapy Center. "Considering the central importance of TILs for , we believe that our findings may have critical implications to boost the efficacy of T cell-based therapies."

This study by Ertl and colleagues shows that low oxygen levels combined with low glucose availability cause TILs to adapt their metabolism and change their source for energy production from glucose to fatty acids, the building blocks of fat. Further inducing this metabolic shift instructs the T cells to increase their use of fatty acids for energy production, thus improving TILs' effector functions and their ability to delay tumor progression.

The Ertl lab studied the effectiveness of metabolic manipulations to improve TIL functions in two melanoma mouse models and in the context of two different immunotherapy approaches. Ertl and colleagues confirmed the clinical relevance of these observations by showing that T isolated from metastases of melanoma patients have increased fatty acid metabolism compared with circulating lymphocytes from healthy donors. Furthermore, using fibrates, a class of FDA approved drugs used to lower cholesterol levels, they promoted the breakdown of and observed that this enforced metabolic switch is associated with improved T cell functions within tumors. Importantly, these drugs can also synergize with immune checkpoint blockade therapy, improving the efficacy of this melanoma immunotherapy.

"Pharmacological interventions aimed at promoting the metabolic adaptation of TILs towards may have a broad implication for T cell-based immunotherapy for different cancer types," added Ertl.

Explore further: Finding antitumor T cells in a patient's own cancer

Related Stories

Finding antitumor T cells in a patient's own cancer

November 13, 2013
Patients with tumors that contain increased numbers of T lymphocytes generally survive longer than those with tumors without T-cell involvement, suggesting that T cells with potent antitumor function naturally exist in cancer ...

New approach identifies cancer mutations as targets of effective melanoma immunotherapy

July 1, 2014
A new approach demonstrated that the recognition of unique cancer mutations appeared to be responsible for complete cancer regressions in two metastatic melanoma patients treated with a type of immunotherapy called adoptive ...

Cellular immunotherapy targets a common human cancer mutation

December 7, 2016
In a study of an immune therapy for colorectal cancer that involved a single patient, a team of researchers at the National Cancer Institute (NCI) identified a method for targeting the cancer-causing protein produced by a ...

Scientists develop novel immunotherapy technology for prostate cancer

August 17, 2017
A study led by scientists at The Wistar Institute describes a novel immunotherapeutic strategy for the treatment of cancer based on the use of synthetic DNA to directly encode protective antibodies against a cancer specific ...

New tool helps identify lung cancer patients who will respond to immune therapies

February 5, 2015
A Yale-led team of researchers has developed a new assay, or investigative tool, to measure the anti-tumor immune activity in non-small cell lung cancer tumors that could lead to a more accurate determination of which patients ...

Scientists find the key to improved cancer immunotherapy

July 18, 2017
Researchers at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (F.S.P.) have investigated how different subtypes of essential immune-response cells called CD8+ T lymphocytes cooperate to mount a stronger ...

Recommended for you

Targeted antibiotic use may help cure chronic myeloid leukaemia

September 19, 2017
The antibiotic tigecycline, when used in combination with current treatment, may hold the key to eradicating chronic myeloid leukaemia (CML) cells, according to new research.

Brain powered: Increased physical activity among breast cancer survivors boosts cognition

September 19, 2017
It is estimated that up to 75 percent of breast cancer survivors experience problems with cognitive difficulties following treatments, perhaps lasting years. Currently, few science-based options are available to help. In ...

Bone marrow protein a 'magnet' for passing prostate cancer cells

September 19, 2017
Scientists at the University of York have shown that a protein in the bone marrow acts like a 'magnetic docking station' for prostate cancer cells, helping them grow and spread outside of the prostate.

Brain cancer breakthrough could provide better treatment

September 19, 2017
A new discovery about the most common type of childhood brain cancer could transform treatment for young patients by enabling doctors to give the most effective therapies.

Researchers compose guidelines for handling CAR T cell side effects

September 19, 2017
Immune-cell based therapies opening a new frontier for cancer treatment carry unique, potentially lethal side effects that provide a new challenge for oncologists, one addressed by a team led by clinicians at The University ...

A new paradigm for treating transcription factor-driven cancers

September 18, 2017
In the current issue of Proceedings of the National Academy of Sciences, researchers from Nationwide Children's Hospital describe a new paradigm for treating transcription factor-driven cancers. The study focuses on Ewing ...

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.