Scientists at the University of California at San Francisco have discovered a new way to control immune system “natural killer” (NK) cells, a discovery with implications for new cell therapies and tissue implants that can escape immune rejection. The findings can also be used to increase the ability of cancer immunotherapies to detect and destroy hidden tumors.
The study, published today (8 January 2021) in the Journal of Experimental Medicine, addresses a major challenge for the field of regenerative medicine, said lead author Tobias Deuse, MD, Julien IE Hoffman, MD, president of cardiac surgery in the UCSF Department of Surgery.
“As a cardiac surgeon, I would love to leave the market being able to implant healthy cardiac cells to repair heart disease,” said Deuse, who is acting president and director of minimally invasive cardiac surgery in the Adult Cardiothoracic Surgery Division. “And there are high hopes of one day having the ability to implant insulin-producing cells in patients with diabetes or to inject cancer cells with immune cells designed to look for and destroy tumors. The main obstacle is how to do this in a way that avoids the immediate rejection of the immune system. “
Deuse and Sonja Schrepfer, MD, PhD, also a professor at the Stem Cell Transplantation and Immunobiology Laboratory of the Surgery Department, study stem cell immunobiology. They are world leaders in a growing scientific subfield working to produce “hypoimmune” cells and tissues grown in the laboratory – able to escape detection and rejection by the immune system. One of the main methods for doing this is engineering cells with molecular passwords that activate immune cell “switches” called immune control points, which usually help prevent the immune system from attacking the body’s own cells and modulating the intensity of responses. immune systems to prevent excess collateral damage.
Schrepfer and Deuse recently used genetic modification tools to create hypoimmune stem cells in the laboratory, which are effectively invisible to the immune system. Notably, in addition to avoiding the body’s learned or “adaptive” immune responses, these cells can also escape the body’s automatic “innate” immune response against potential pathogens. To achieve this, the researchers adapted a strategy used by cancer cells to keep innate immune cells under control: they designed their cells to express significant levels of a protein called CD47, which turns off certain cells in the innate immune system by activating a molecular switch found in them. cells, called SIRPα. His success has become part of the founding technology of Sana Biotechnology, Inc, a company co-founded by Schrepfer, who now leads a team developing a platform based on these hypoimmune cells for clinical use.
But the researchers were left with a mystery on their hands – the technique was more successful than anticipated. In particular, the field was intrigued by the fact that such projected hypoimmune cells were able to deftly escape detection by NK cells, a type of innate immune cell that should not express a SIRPα checkpoint.
NK cells are a type of white blood cell that acts as a first immune response, quickly detecting and destroying any cells without proper molecular identification proving that they are “their own” – native body cells or at least permanent residents – that take the form of highly individualized cells molecules called MHC class I (MHC-I). When MHC-I is knocked out artificially to prevent transplant rejection, the cells become susceptible to the accelerated death of NK cells, an immune rejection that no one in the field has been able to fully inhibit. The 2019 Deuse and Schrepfer data, published in Nature Biotechnology, suggested that they may have found an off button that could be used for this purpose.
“All the literature says that NK cells don’t have that checkpoint, but when we look at cells from human patients in the laboratory, we find SIRPα there, clear as day,” recalled Schrepfer. “We can clearly demonstrate that the stem cells that we designed to overexpress CD47 are able to shut down NK cells through this path.”
To explore their data, Deuse and Schrepfer approached Lewis Lanier, PhD, a world expert in NK cell biology. At first Lanier was sure that there must be some mistake, since several groups had already looked for SIRPα in NK cells and it was not there. But Schrepfer was confident in his team’s data.
“I finally figured it out,” said Schrepfer. “Most of the studies looking for checkpoints on NK cells were done on immortalized cell lines grown in the laboratory, but we were studying primary cells directly from human patients. I knew it must be the difference. “
Further examination revealed that NK cells only begin to express SIRPα after being activated by certain immune signaling molecules called cytokines. As a result, the researchers realized that this inducible immunological checkpoint takes effect only in already inflammatory environments and probably works to modulate the intensity of attack by NK cells to cells without adequate MHC class I identification.
“NK cells have been a major barrier to the growing interest in the field in the development of universal cell therapy products that can be transplanted” off the shelf “without rejection, so these results are extremely promising,” said Lanier, president and distinguished professor J Michael Bishop in the Department of Microbiology and Immunology.
In collaboration with Lanier, Deuse and Schrepfer have comprehensively documented how cells that express CD47 can silence NK cells via SIRPα. While other approaches may silence some NK cells, this was the first time that anyone has been able to completely inhibit them. Notably, the team found that the sensitivity of NK cells to inhibition by CD47 is highly species-specific, in line with their role in distinguishing “self” from “potentially other”.
As a demonstration of this principle, the team designed adult human stem cells with the rhesus monkey version of CD47 and then implanted them in rhesus monkeys, where they successfully activated SIRPα in the monkeys’ NK cells and avoided killing human cells transplanted. In the future, the same procedure may be performed the other way around, expressing human CD47 in swine cardiac cells, for example, to prevent them from activating NK cells when transplanted into human patients.
“CAR T cell therapies currently designed for cancer and incipient forms of regenerative medicine, all have the ability to extract cells from the patient, modify them in the laboratory and then put them back in the patient. This avoids the rejection of foreign cells, but it is extremely laborious and expensive, ”said Schrepfer. “Our goal in establishing a platform for hypoimmune cells is to create ready-to-use products that can be used to treat disease in all patients everywhere.”
The findings may also have implications for cancer immunotherapy, as a way of boosting existing therapies that try to overcome the immune control points that cancers use to escape immune detection. “Many tumors have low levels of self-identifying MHC-I protein and some compensate by overexpressing CD47 to keep immune cells in check,” said Lanier, who is director of the Parker Institute for Cancer Imunotherapy at UCSF Helen Diller Family Comprehensive Cancer Center. “This could be the sweet spot for antibody therapies that target CD47.”
Reference: January 8, 2021, Journal of Experimental Medicine.
Authors: The study’s main authors were Deuse and UCSF TSI laboratory research scientist Xiaomeng Hu; Lanier and Schrepfer were the senior authors of the study, and Schrepfer is the corresponding author. Other authors were Sean Agbor-Enoh of the Johns Hopkins School of Medicine and the National Heart, Lung and Blood Institute (NHLBI); Moon K. Jang on the NHLBI; Hannah Valantine at Stanford; Malik Alawi and Ceren Saygi of the University Medical Center Hamburg-Eppendorf in Germany; Alessia Gravina, Grigol Tediashvili and Vinh Q. Nguyen from UCSF; and Yuan Liu, of Georgia State University.
Funding: Research and researchers are supported by the NHLBI (R01HL140236), the Parker Institute of Cancer Immunotherapy and the US National Institutes of Health (NIH P30 DK063720 NIH S10 1S10OD021822-01).
Disclosures: Deuse is a scientific co-founder and Schrepfer is a scientific founder and senior vice president of Sana Biotechnology Inc. Xiaomeng Hu is now a senior scientist at Sana Biotechnology Inc. No reagents or funding from Sana Biotechnology Inc. was used in this study. UCSF has filed for patents covering these inventions.