Maria Grazia Roncarolo, MD
Researchers identify key aspects of Tr1 cells, which may lead to greater success in cancer treatment.
By Christopher Vaughan
Dec. 15, 2021
Many patients with blood cancers, such as leukemias and lymphomas, have been saved through chemotherapy treatment, followed by transplant of blood stem cells to replace those destroyed by the chemotherapy. The transplanted blood stem cells come from a donor who has a similar immunological profile, but the match is never perfect. Mismatched immune cells from the donor that tag along with the stem cell transplant can attack the patient’s tissues, causing a life-threatening syndrome called graft vs host disease (GvHD).
Researchers in the laboratory of institute co-director Maria Grazia Roncarolo isolated a kind of immune cell, the type 1 regulatory T (Tr1) cell, that can effectively suppress GvHD caused by donor immune cells transplanted together with blood stem cells. The California Institute for Regenerative Medicine (CIRM) recently awarded a grant to Roncarolo and her colleagues to support a clinical trial investigating the effectiveness of Tr1-based cell therapies in improving outcomes of childhood cancer treatments.
Now, in an article in Science Translational Medicine, Roncarolo and her colleagues reveal details about how to generate Tr1 cells, how they work, and how clinicians can effectively track the infused Tr1 cells in patient's blood. The first authors on the paper are Pauline Chen, MD, and Alma-Martina Cepika, MD, PhD. Roncarolo and Rosa Bacchetta, MD are senior authors.
A clue to how Tr1 cells work came in the discovery that in addition to soluble factors called cytokines, some surface inhibitory receptors expressed by Tr1 cells are essential for their suppressor function. Interestingly, these receptors are expressed also on another kind of regulatory T cell marked by a molecule called FOXP3. Regulatory T cells with FOXP3 are well known for developing early in life to protect us from autoimmune attack on our own tissues, whereas Tr1 cells are important for maintaining tolerance to novel antigens, including alloantigens, and for dampening undesired and excessive immune responses.
In a bit of good news for patients, the researchers showed in this paper that they could efficiently generate Tr1 cells by culturing specific types of immune cells from the donor with different immune cells from the patient. This results in a Tr1 enriched group of cells the researchers call T-allo10. This mixture can be generated and collected in advance of transplantation, thus increasing the odds of success for the cancer treatment.
Another useful result to come out of this research is the finding that the T cell receptors of the Tr1 cells come in unique types, that can be tracked in the blood. “Usually, we have to insert a unique marker to track and identify cells and their offspring, which is OK for research but less desirable if we are injecting these cells into patients,” said Cepika, “Because Tr1 cells have distinct patterns of their T cell receptors, it’s like each Tr1 cell and their progeny have their own identifiable barcode.” By being able to track the Tr1 cells, the researchers showed that they can persist in the bloodstream for a year.
“The long term persistence of Tr1 cells in the patient’s body is an important discovery and a mayor advantage of this unique T cell subset” said Roncarolo. “These findings give support to the hope that Tr1 based treatments will not only help suppress GvHD immediately after transplantation, but permanently re-program the immune system of the patient to accept the stem cell transplants”