Dendritic cell vaccines, a promising cancer immunotherapy approach, usually come from dendritic cells that have been force-fed with tumor antigens. Dendritic cells, however, can also be modified so that they gorge themselves on antigen-carrying exosomes released by tumor cells. Even better, modified dendritic cells aren’t finicky. Although ordinary dendritic cells usually consume antigens from lab-grown cancer cells, modified dendritic cells may feast on antigen-carrying exosomes from a patient’s own tumor, improving the prospects for personalized dendritic cell vaccines.
Modified dendritic cells have been developed by scientists based at the Swiss Institute for Experimental Cancer Research, which is part of the School of Life Sciences at École Polytechnique Fédérale de Lausanne (EPFL). These scientists, led by Michele De Palma, Ph.D., created a lentivirus-encoded chimeric receptor. They call it an extracellular vesicle (EV)-internalizing receptor, or EVIR. It has been optimized, the scientists report, to enable the selective uptake of cancer-cell-derived EVs by dendritic cells.
Details about the EVIR appeared January 22 in the journal Nature Methods, in an article entitled “EVIR: Chimeric Receptors That Enhance Dendritic Cell Cross-Dressing with Tumor Antigens.” This article suggests that EVIRs should facilitate exploring the mechanisms and implications of horizontal transfer of tumor antigens to antigen-presenting cells.
“The EVIR encompasses a truncated (nonsignaling) low-affinity nerve growth factor receptor (dLNGFR) and an extracellular antibody domain,” wrote the article’s authors. “The latter comprises an IgK signal peptide and a single-chain F(ab)2 variable fragment (scFv) with specificity for the human HER2 protein, which is overexpressed in a subset of human breast cancers. A hinge domain derived from dLNGFR connects the transmembrane and extracellular domains of the EVIR.”
After constructing the EVIR, the EPFL team demonstrated that it endowed dendritic cells with the capacity to specifically recognize cancer cell–derived extracellular vesicles.
Exosomes and other extracellular vesicles are profusely released by the tumor and contain a variety of tumor antigens. They are also increasingly implicated in the promotion of metastasis and other processes that may facilitate the growth and spreading of cancer. By capturing exosomes coming from tumors, the EVIR helps the dendritic cells to precisely acquire tumor antigens from the cancer cells. The dendritic cells then present these antigens more efficiently to killer T cells, thus amplifying the patient's immune response against their tumor.
Imaging techniques used in the current study revealed that EVIRs promote the direct transfer of tumor antigens from the exosome surface to the outer membrane of the dendritic cell.
“We call this phenomenon cross-dressing, which alludes to the fact that the dendritic cells acquire immunogenic antigens from the tumor and directly display them on their own surface,” said De Palma. “This is a fascinating and unconventional route for antigen presentation to T cells, which does not require complex and rate-limiting molecular interactions inside the dendritic cell.”
“The EVIR enhances dendritic cell presentation of EV-associated tumor antigens to CD8+ T cells primarily through MHCI [major histocompatibility complex class I] recycling and cross-dressing,” the study’s authors indicated.
The study opens up new avenues for developing more sophisticated and potent cancer immunotherapies. “The EVIR technology can intercept a natural phenomenon—the release of exosomes from tumors—to the patient's benefit,” says Mario Leonardo Squadrito, Ph.D., first author of the study. “It exploits protumoral exosomes as selective nanocarriers of tumor antigens, making them available to the immune system for cancer recognition and rejection.”
Although the new technology has the potential to increase the efficacy and specificity of dendritic cell vaccines, further preclinical work is required before it can be translated into a cancer treatment. “We are currently exploring potential clinical applications of our technology together with colleagues at the CHUV University Hospital of Lausanne,” noted De Palma.