New research from Memorial Sloan Kettering Cancer Center (MSK) identifies new cancer-specific targets for T cell receptor immunotherapy approaches; sheds light on a critical process in sexual reproduction; describes how regulatory T cells help prevent intestinal inflammation; and uncovers how the spleen helps natural killer immune cells adapt to new threats.
Discovering new cancer-specific targets for T cell receptor immunotherapy
T cell based immunotherapies, which harness the power of the patient’s immune system to fight cancer, increasingly are being used to treat some blood cancers and a handful of solid tumors. With these treatments, a patient’s own immune cells are engineered to recognize proteins (antigens) displayed either on the surface of or inside cancer cells. Despite promising clinical data in some tumor types, extending this treatment to a broader range of cancers is limited by the identification of antigens that are expressed only by tumor cells and not healthy tissues.
A collaborative team from MSK and University of California, San Francisco (UCSF) focused on addressing these challenges in several difficult-to-treat cancer types, including brain tumors. Their research identified a previously unknown class of antigens found in many cancers. These antigens are formed from errors in splicing — a genetic process that stiches together RNA, the instruction manuals for how proteins get made.
The scientists showed that targeting antigens that result from mistakes in splicing enable immune cells to recognize and eliminate brain cancer cells in a lab setting. This approach makes use of reprogrammed immune cells using T cell receptor (TCR) gene therapy. Physician-scientist Christopher A. Klebanoff, MD, an expert in TCR therapy, is a co-corresponding author of the paper and was aided by MSK research associate Iñaki Etxeberria, PhD. Read more in Nature and in a press release from UCSF.
MSK researchers shed light on a critical process in sexual reproduction
During the formation of reproductive cells, genetic material is exchanged between chromosomes contributed by each parent to ensure genetic diversity. This recombination is initiated by a protein called SPO11, which creates double-strand breaks in DNA. These breaks can lead to mutations or cell death, so cells need to balance their benefits and risks.
Now, a study from the lab of Scott Keeney, PhD, a molecular biologist at MSK’s Sloan Kettering Institute, is shedding new light on how cells achieve this balance by developing a purified form of SPO11 so that they could recreate its activity in the lab.
“Since SPO11’s role was first described 25 years ago, this type of reconstitution has been something of a holy grail,” Dr. Keeney says. “Many labs, including my own, had failed at it over and over.”
The team’s findings reveal important and surprising insights into many aspects of how SPO11 achieves and regulates double-strand break formation. They showed, for example, that two SPO11 molecules must come together to create these breaks, but that those complexes are inherently weak, restraining SPO11’s activity and making it dependent on accessory proteins. They also found that SPO11 is capable of resealing broken strands.
The study was published simultaneously with papers describing independent efforts to reconstitute SPO11 activity, including from the lab of former MSK postdoctoral fellow, Corentin Claeys Bouuaert, PhD (now an investigator at the Louvain Institute of Biomolecular Science and Technology).
Defects in SPO11-induced recombination are a major cause of infertility and genetic alterations in eggs or sperm that lead to developmental disabilities or miscarriage. The new system for studying SPO11 activity in the test tube opens the door to answering fundamental questions about the mechanism and control of recombination and will provide new insight to human reproductive health and disease. Read more in Nature.
How regulatory T cells help prevent intestinal inflammation
MSK researchers are providing new insights into the role regulatory T (T reg) cells play in preventing inflammation in the intestines. Better understanding of these cells could lead to new treatments for inflammatory diseases of the gut, like Crohn’s disease or ulcerative colitis.
T reg cells are a type of white blood cell that helps control the immune system and prevent it from attacking the body’s own tissues. The research team — led by MSK research scholar Stanislav Dikiy, PhD (now at Scripps Research), and Immunology Program Chair Alexander Rudensky, PhD — looked at T reg cells in the colon (part of the large intestine) to understand how they adapt and function in this unique environment.
The study uncovered a subset of T reg cells in the colon that are very stable and produce a molecule called IL-10, which is important for reducing inflammation. These stable T reg cells can function without continuous signals from the immune system, making them unique and crucial for maintaining intestinal health. The group’s findings showed that these IL-10 producing T reg cells are essential for preventing inflammation in the colon, highlighting their importance in gut health. Read more in Nature Immunology.
How the spleen helps natural killer immune cells adapt to new threats
Researchers at MSK are shedding new light on natural killer (NK) immune cells and the role played by the spleen in their response to viral infections. NK cells are primarily considered part of the innate immune system, but they also have adaptive features — allowing them to be “trained” to respond more effectively to specific pathogens.
The team — led by first authors Adriana Mujal, PhD, and Mark Owyong in the lab of senior author Joseph Sun, PhD, at the Sloan Kettering Institute — studied how NK cells responded to cytomegalovirus, a common virus related to chickenpox, herpes, and mononucleosis, in mouse models. Unlike other immune cells like B and T cells, NK cells were not thought to require “priming” against a threat inside dedicated lymphoid organs such as the spleen. The researchers found, however, that splenic NK cells give rise to adaptive NK cells more readily. NK cells in the spleen exhibited heightened TNF-alpha signaling, which the team identified as a new, critical regulator of both innate and adaptive responses.
Overall, the findings highlight the central role of the spleen in facilitating the innate-to-adaptive transition NK cells undergo during a viral infection and provide new insights into how scientists might improve NK cell responses in a variety of disease contexts. Read more in Immunity.