New research from Memorial Sloan Kettering Cancer Center (MSK) illuminates new details about Thetis cells that will support efforts to harness them therapeutically; shows how the timing and strength of danger signals steer immune cell fates; and employs single-nucleus DNA sequencing to shed new light on the evolution of pancreatic cancer.
New details about Thetis cells will support efforts to harness them therapeutically
Early in life, the human immune system must learn to make peace with helpful gut microbes and everyday foods.
A rare group of immune cells called Thetis cells — discovered by MSK researchers in 2022 — helps teach this tolerance. Thetis cells surge around the time of weaning and then decline, creating a brief window in which tolerance to beneficial “outsiders” is most easily established. But their origins and what drives this early-life wave were unclear.
Now a new study from the lab of Chrysothemis Brown, MD, PhD, in MSK’s Immuno-Oncology Program, maps the Thetis cell family tree and pinpoints the signals that shape them. The work was led by Yoselin Paucar Iza, a graduate student in the Brown Lab and a Gilliam Fellow at the Howard Hughes Medical Institute.
The authors identified an early RORγt+ progenitor in the fetal liver — called the Thetis-Lymphoid Tissue inducer progenitor (TLP) — that splits into two branches: one that becomes Thetis cells and another that becomes lymphoid tissue inducer (LTi) cells, a lineage that builds our lymph nodes.
The team also uncovered why Thetis cells peak during early life: Thetis cell progenitors are enriched in the fetal liver but wane with age. They also require a developmental “go” signal to differentiate into Thetis cells in lymph nodes. A molecule called RANKL, produced by specialized early-life stromal cells, is essential for forming at least one subset of Thetis cells. The timing of these organizer cells matches the Thetis cell wave — defining the window when tolerance is most efficiently programmed.
By revealing the origins of Thetis cells, along with key regulatory factors and the environmental cues that regulate their development, the research opens new paths to harness Thetis cells therapeutically to prevent or treat food allergies and autoimmune disease.
Read more in Nature.
How the timing and strength of danger signals steer immune cell fates
MSK researchers continue to shed new light on the complexities of the human immune system — with implications for treating cancer and other diseases.
A new study led by Simon Grassmann, MD, a research fellow in the lab of senior author Joseph Sun, PhD at MSK’s Sloan Kettering Institute, started with a simple question with big implications: How do key immune system attackers — natural killer (NK) cells and CD8 T cells — decide whether to become short-lived frontline troops or longer-lived memory cells that stick around to prevent reinfection?
It turns out that the strength and order of the signals they receive during an infection makes all the difference.
In mouse studies, the researchers found that the fate of these immune cells is determined by whether they have first sensed an antigen (a fragment of a pathogen) before encountering inflammatory cues (interleukin signals, a type of cytokine).
Antigen recognition reinforces epigenetic programs that support long-term immune memory, while encountering a cytokine signal first, pushes the cells toward a short-lived attacker state. In T cells, the strength of antigen recognition further tunes the outcome — strong recognition steers cells toward memory formation, while weak recognition biases cells toward becoming short-term shock troops.
Overall, the work proposes a stepwise model for how inflammation locks in either long-term memory or short-term defense programs based on the degree to which an antigen has first primed the immune cell. This helps explain why inflammatory cytokines can be helpful or harmful depending on the context, and suggests vaccine and cancer therapies could be improved by tuning the timing and strength of antigen and cytokine signals.
Read more in Immunity.
Single-nucleus DNA sequencing sheds new light on the evolution of pancreatic cancer
Pancreatic cancer is one of the most difficult to treat, with a five-year survival rate stuck in the low double digits. Now MSK researchers and their collaborators are using a cell-by-cell analysis to shed new light on how the disease evolves — and their findings could help improve precision treatments.
The research team used single-nucleus DNA sequencing to study more than 137,000 cells from primary tumors and metastases from 24 patients. The data, which included cancers caught both early and late, allowed them to build a family tree of cancer cells to understand which genetic changes tend to happen earlier and which happen later.
The study was led by first authors Haochen Zhang, PhD, of MSK, and Palash Sashittal, PhD, of Princeton University, and overseen by senior author Christine Iacobuzio-Donahue, MD, PhD, Director of the David M. Rubenstein Center for Pancreatic Cancer Research at MSK.
The approach allowed the researchers to identify three key features of the evolution of pancreatic cancer, two of which have direct implications for targeted treatments.
First, while KRAS is commonly mutated in pancreatic cancer, not all of these tumors rely on it to the same extent. Some tumor cells actually lose the mutant gene or boost other pathways that drive growth — which could help explain mixed responses to KRAS inhibitors and help identify who is most likely to benefit from them.
Second, in patients with an inherited BRCA2 mutation, the cancer eventually disables the remaining working BRCA2 copy, but the timing of this change varies. Getting a better understanding of that process could help refine how BRCA2-related pancreatic cancers are treated, since timing may influence how well targeted therapies will work.
Third, as tumors become invasive and spread, they often find multiple ways to switch off their response to the TGF-beta pathway, which normally acts as a brake on cell growth and helps keep cells from invading surrounding tissues. This may help explain why drugs aimed at that pathway have not shown clear benefit and highlights how tumors can evolve to achieve the same ends in multiple ways.
Read more in Nature Genetics.