Mechanism identified of impaired dendritic cell function that weakens response to cancer

December 14, 2017, The Wistar Institute
Credit: The Wistar Institute

A new study from The Wistar Institute revealed the mechanism implicated in the defective function of tumor-associated dendritic cells (DCs), a specialized type of immune cells that expose the antigens on their surface to activate the T cells. The new findings explain why DCs are not effective in executing a specialized process that is required for inducing antitumor immune responses and effective cancer immunotherapy. The work was published online in Nature Communications.

"Dendritic are essential for prompting the immune response against and for driving the clinical success of cancer immunotherapy, but their function is often defective in ," said Dmitry I. Gabrilovich, M.D., Ph.D., Christopher M. Davis Professor and program leader of the Immunology, Microenvironment & Metastasis Program at Wistar. "Our research sheds light on the mechanism of this impairment, pointing us in the direction of new strategies for improving the response to immunotherapy."

DCs are specialized that can ingest foreign antigens, degrade them and present the fragments on their surface to activate T cell-mediated immunity. Antigens are exposed on the surface of DCs in a protein complex along with (MHC) proteins that mediate the recognition and activation of the appropriate T cell subtype. Different classes of MHC molecules exist and are involved in immunity against pathogens and tumor cells as well as the formation of immune tolerance to self-antigens.

DCs are fundamental players in antitumor immunity through a process known as antigen cross-presentation, in which they process tumor-derived antigens into the MHC class I pathway for presentation to T cells that have the ability to kill cancer cells. This DC function is also required for the success of cancer vaccines and immunotherapy, but it is well established that tumor-associated DCs are defective in their ability to perform antigen cross-presentation. DCs from cancer patients and tumor-bearing animal models also accumulate higher amounts of lipids compared with DCs from healthy individuals, a process that has been implicated in defective cross-presentation by DCs. The mechanism underlying this association was unknown.

In collaboration with the group of Valerian Kagan, Ph.D., D.Sc., at the University of Pittsburgh, Gabrilovich and colleagues analyzed in great detail the events that take place in the DCs from tumor-bearing mice models and found that impaired cross-presentation, which occurred in the presence of tumor-derived factors, was associated with defective trafficking of the antigen-MHC complex to the cell surface. Importantly, they also observed that tumor-associated DCs accumulate chemically altered lipids that are the product of oxidative modification. Compared to unaltered lipids, these modified lipids had different ability to interact with target proteins, thus modifying their function.

Computational analysis as well as direct experiments identified some of the that strongly interact with the modified lipids, showing that these proteins are involved in the transport of the antigen-MHC complex to the cell surface. Interfering with the function of their targets, these interactions ultimately impair cross-presentation.

"Our findings present new potential targets for therapeutic regulation of cross-presentation," said Filippo Veglia, Ph.D., first author of the study and staff scientist in the Gabrilovich Lab. "For example, we investigated the effect of the antioxidant vitamin E and found that it abrogated the tumor-induced defects in cross-presentation by DCs."

Explore further: Cellular network identified that 'short circuits' the antitumor effect of immunotherapies

Related Stories

Cellular network identified that 'short circuits' the antitumor effect of immunotherapies

November 13, 2017
Researchers from The Wistar Institute discovered a novel form of crosstalk among tumor cells and other cell types in the tumor microenvironment, elucidating the mechanism of action of an immunotherapeutic strategy that inhibits ...

How a poorly explored immune cell may impact cancer immunity and immunotherapy

November 17, 2017
The immune cells that are trained to fight off the body's invaders can become defective. It's what allows cancer to develop. So most research has targeted these co-called effector T-cells.

New strategy for multiple myeloma immunotherapy

November 27, 2017
In recent decades monoclonal antibody-based treatment of cancer has been established as one of the most successful therapeutic strategies for both solid tumors and blood cancers. Monoclonal antibodies (mAb), as the name implies, ...

Combination immunotherapy targets cancer resistance

November 22, 2017
Cancer immunotherapy drugs have had notable but limited success because in many cases, tumors develop resistance to treatment. But researchers at Yale and Stanford have identified an experimental antibody that overcomes this ...

Study unveils T cell signaling process central to immune response

May 16, 2017
The immune system cells known as T cells play a central role in the body's ability to fight infections and cancer. For decades, however, details of the molecular signaling process that leads to T cell activation have remained ...

Researchers find mechanism for precise targeting of the immune response

October 13, 2017
The immune system checks the health of cells by examining a kind of molecular passport. Sometimes, cells present the wrong passport, which can lead to autoimmune diseases, chronic inflammations or cancer. Scientists of the ...

Recommended for you

Biologists discover how pancreatic tumors lead to weight loss

June 20, 2018
Patients with pancreatic cancer usually experience significant weight loss, which can begin very early in the disease. A new study from MIT and Dana-Farber Cancer Institute offers insight into how this happens, and suggests ...

Researchers find 11 genes responsible for the spread of cancer

June 20, 2018
A groundbreaking discovery by University of Alberta researchers has identified previously-unknown therapeutic targets that could be key to preventing the spread of cancer.

'Kiss of death' cancer: How computational geeks may have uncovered a therapy for a deadly disease

June 19, 2018
It's called the 'kiss of death'. Triple negative breast cancer has no targeted drug therapy and, as such, the only hope for these patients is chemotherapy. Triple negative breast cancer is aggressive and deadly. Patients ...

Ovarian cancer cells switched off by 'unusual' mechanism

June 19, 2018
Scientists at the Ovarian Cancer Action Research Centre at Imperial College London have discovered a mechanism that deactivates ovarian cancer cells.

Team discovers gene mutations linked to pancreatic cancer

June 19, 2018
Six genes contain mutations that may be passed down in families, substantially increasing a person's risk for pancreatic cancer. That's according to Mayo Clinic research published in the June 19 edition of the JAMA. However, ...

Breast cancer could be prevented by targeting epigenetic proteins, study suggests

June 19, 2018
Researchers at the Princess Margaret Cancer Centre in Toronto have discovered that epigenetic proteins promote the proliferation of mammary gland stem cells in response to the sex hormone progesterone. The study, which will ...

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.