Show Yourself: Making Leukemia Visible To The Immune System Could Prevent Relapse

The Context: The most common treatment for acute myeloid leukemia is bone marrow transplant, in which healthy stem cells are infused into the bloodstream of the patient to kickstart a functional immune system. However, nearly half of patients who relapse do so because their tumor cells hide special ‘HLA proteins’ that are normally present on the cell surface and are essential for the immune system to recognize the tumor.

The Study: Using a class of drug called PRC2 inhibitors already in advanced clinical trials for other cancers, scientists at San Raffaele Telethon Institute for Gene Therapy in Italy led by NYSCF – Robertson Stem Cell Investigator and NYSCF – Druckenmiller Fellow Alumna Raffaella Di Micco, PhD, have found a way to force leukemia cells to bear their HLA proteins, making them visible to the immune system once again. The study appears in Cancer Discovery.

The Importance: This discovery introduces a new therapeutic option to prevent leukemia relapse. And because it employs a drug already in advanced clinical trials, the treatment is afforded an accelerated path to the clinic.

When a leukemia patient receives a bone marrow transplant, immune cells called lymphocytes are created that then patrol the blood looking for potentially harmful substances. When lymphocytes encounter a tumor, HLA proteins that live on the outside of the tumor cells signal that these are dangerous cells to be destroyed.

“Unfortunately, however, in about half of the patients with acute myeloid leukemia undergoing bone marrow transplantation from a healthy donor, the tumor relapses because it is no longer recognizable by the transplanted lymphocytes: the HLA proteins normally present on the cell surface of leukemic cells have in fact been hidden to escape the immune system” explained Luca Vago, PhD, co-senior author on the study in a press release. “Studying these evasion mechanisms and finding effective strategies to thwart them is one of our research goals.”

What Makes Tumor Cells Hide Their HLA Proteins?

Previous research from Dr. Vago established that the disappearance of HLA proteins wasn’t due to genetic mutations in the tumor cells. This led the scientists to suspect that the behavior was driven by epigenetics: changes in DNA accumulated as a result of the environment. They enlisted the help of Dr. Di Micco, an expert in blood cell epigenetics, to better understand what could be happening.

“Research increasingly needs to merge different skills and expertise, because only a multidisciplinary approach can reduce biological complexity and find effective answers to the clinical needs of patients,” remarked Dr. Di Micco. 

“Thanks to the use of the most innovative genomic and epigenomic technologies, and the collaboration with a team of bioinformaticians at San Raffaele, we have identified the protein complex responsible for hiding leukemia’s HLA proteins: a well-known gene-silencer called PRC2.”

PRC2 “hides” the portion of DNA that tells a cell to make the HLA protein. 

“In the case of relapsing leukemic cells, the portion of DNA hidden by PRC2 is precisely the one encoding HLA surface proteins,” noted Valentina Gambacorta, PhD, first author of the study. “This is an effective survival strategy for the tumor after a transplant, because HLA proteins are the main target that transplanted T lymphocytes use to recognize and kill them.” 

A Potential Drug To Prevent Relapse

“To discover the role of PRC2, we compared the blood samples collected longitudinally from our patients at two different times: at the first diagnosis of the disease and in the relapse phase after transplantation,” explained Dr. Vago. 

“Access to clinical samples also allowed us to successfully test, in vitro and in a mouse model of human disease, the efficacy of some PRC2 inhibitors, experimental drugs that could become the first potentially effective therapies against non-genetic acute myeloid leukemia relapses.”

PRC2 inhibitors are already in advanced clinical trials for other types of cancer, and have been tested for safety and efficacy. This means the drugs won’t have to repeat early stages of the clinical trial process, accelerating their path to leukemia patients.

Journal Article:

Integrated Multiomic Profiling Identifies the Epigenetic Regulator PRC2 as a Therapeutic Target to Counteract Leukemia Immune Escape and Relapse
Valentina Gambacorta, Stefano Beretta, Martina Ciccimarra, Laura Zito, Kety Giannetti, Angela Andrisani, Daniela Gnani, Lucia Zanotti, Giacomo Oliveira, Matteo G. Carrabba, Davide Cittaro, Ivan Merelli, Fabio Ciceri, Raffaella Di Micco and Luca Vago. Cancer Discovery. March, 2022. DOI: https://doi.org/10.1158/2159-8290.CD-21-0980

Cover image: Drs. Di Micco and Vago. Credit: San Raffaele Telethon Institute for Gene Therapy