T Cells Secrete DNA to Boost the Immune System’s Cancer-Fighting Ability
Activated immune cells secrete tiny capsules bearing DNA that can enter other immune and tumor cells to stimulate the body’s defense systems, according to a study led by investigators at Weill Cornell Medicine. The discovery extends the scientific understanding of the immune system, identifies a new strategy for boosting immunity against cancers and potentially offers a new tool for delivering genetic payloads to other cells.
Most animal cells secrete tiny capsules known as extracellular vesicles—nanoscale, membrane-bound particles —whose cargo can include proteins, snippets of DNA and other molecules. In the new study, published April 30 in Cancer Cell, the researchers discovered that vesicles secreted by activated T cells—major weapons of the immune system—carry DNA that enters immune cells and nearby tumor cells to enhance the immune response against the tumor. Preclinical experiments showed that this vesicle-associated DNA could be useful therapeutically, boosting T cell attacks against tumors that otherwise evoke little or no immune response.
“These findings reveal a natural mechanism for treating immunologically silent tumors and other diseases that stem from insufficient immune surveillance,” said study co-senior author Dr. David Lyden, the Stavros S. Niarchos Professor in Pediatric Cardiology and a member of the Gale and Ira Drukier Institute for Children's Health and the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
The Lyden lab in recent years has made seminal discoveries about extracellular vesicles and their functions, finding for example that vesicles secreted by tumor cells can influence the immune system’s anti-tumor response. For the new study, they examined the roles of vesicles secreted by immune cells—specifically T cells, the immune system’s principal tumor fighters.
In initial experiments, they found that under physiological conditions, T cell-secreted vesicles tend to home to lymph nodes, spleen and other centers of immune activity. There the vesicles are preferentially taken up by antigen-presenting immune cells, including dendritic cells, which assist in T cell activation, a critical process in the immune response. The researchers found that the overall effect of these vesicles released by activated T cells is to boost the antigen-presenting process, thus promoting T cell priming and broader immune activation. The key payloads in these immune-boosting vesicles turned out to be snippets of T cell DNA.
“These surprisingly abundant DNA fragments are mostly on the surfaces of the vesicles, and are not just random—they are enriched for immune-related genes, including genes that help cells display antigens to the immune system,” said co-senior author Dr. Haiying Zhang, an assistant professor of cell and developmental biology in pediatrics and member of the Lyden lab.
“We also found that these vesicles have, attached to their surfaces, a special enzyme that acts as a molecular drill, enabling the transfer of vesicle-carried DNA into the nucleus of the recipient cell where they can be expressed transiently,” said study co-first author Dr. Diao Liu, a postdoctoral research associate in the Lyden Lab.
A New Concept of Immunotherapy
Infusing DNA-carrying vesicles from activated T cells into mice with tumors, the researchers found that the vesicles were taken up not only by antigen-presenting cells but also by tumor cells themselves. Tumors treated this way grew more slowly and were better infiltrated by T cells and other immune cells, indicating that the vesicles induced a stronger anti-tumor response. Although cancers—and viruses—frequently suppress the antigen-presenting process to make malignant or infected cells “invisible” to the immune system, the main effect of the extracellular vesicular DNA was to reverse this process, restoring tumor cells’ visibility.
The team demonstrated the effectiveness of this approach, alone and in combination with existing immunotherapy, in preclinical models of three different immunologically silent cancers: glioblastoma, pancreatic and triple-negative breast cancer.
“There seems to be a positive-feedback loop, in which the DNA-carrying vesicles from activated T cells amplify the immune response by acting on both antigen-presenting cells, which increase expression of the machinery processing tumor antigens, and tumor cells, promoting their recognition by the immune system as well as their own production of DNA-laden vesicles,” said co-senior author Dr. Irina Matei, an assistant professor of immunology research in pediatrics and member of the Lyden lab.
The researchers are now working to translate their findings into a new, vesicle-based cancer treatment, which could be used on its own or in conjunction with standard immunotherapies or other cancer treatments.
“The surprising ability of these vesicles to transfer DNA from donor T cells into the nuclei of recipient cells suggests their potential as a natural, non-viral platform for transient gene delivery, ” said co-first author Dr. Mengying Hu, a postdoctoral research associate in the Lyden Lab who led the research and is now an assistant professor of pharmaceutical sciences at the Ohio State University. “The results point to a broadly applicable gene-transfer strategy that may offer improved safety and efficiency compared with current gene therapy approaches.”
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profiles for Dr. Irina Matei and Dr. David Lyden .
The research reported in this story was supported by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, both part of the National Institutes of Health, through grant numbers U19AI144301 and R35CA232093, and a CTSC-TL1 training award (2TL1-TR-2386). Additional support was provided by the Thompson Family Foundation, the Tortolani Foundation, the Theodore A. Rapp Foundation, the Pediatric Oncology Experimental Therapeutics Investigator’s Consortium, the Malcolm Hewitt Weiner Foundation, the Manning Foundation, the Pershing Square Sohn Foundation, the AHEPA Vth District Cancer Research Foundation, the Children’s Cancer and Blood Foundation, the Hartwell Foundation, and the Fonds De La Recherche Scientifique Excellence of Science grant 40007532.
Cancer Cell