By recruiting the immune system to combat tumor cells, immunotherapy has improved survival rates, offering hope to millions of cancer patients. However, only about one in five people responds favorably to these treatments.
With a goal of understanding and addressing immunotherapy’s limitations, researchers at Washington University School of Medicine in St Louis have found that the immune system can be its own worst enemy in the fight against cancer. In a new study in mice, a subset of immune cells — type 1 regulatory T cells, or Tr1 cells — did its normal job of preventing the immune system from overreacting but did so while inadvertently restraining immunotherapy’s cancer-fighting power.
“Tr1 cells were found to be a heretofore unrecognized obstacle to immunotherapy’s effectiveness against cancer,” said senior author Robert D. Schreiber, the Andrew M. and Jane M. Bursky Distinguished Professor in the Department of Pathology & Immunology, and director of the Bursky Center for Human Immunology & Immunotherapy at Washington University School of Medicine. “By removing or circumventing that barrier in mice, we successfully reenergized the immune system’s cancer-fighting cells and uncovered an opportunity to expand the benefits of immunotherapy for more cancer patients.”
The study is available in Nature.
Cancer vaccines represent a new approach to personalize cancer immunotherapy. Aimed at the mutant proteins specific to a patient’s tumor, such vaccines induce killer T cells to attack tumor cells while leaving healthy cells unharmed. Schreiber’s group previously showed that more effective vaccines also activate helper T cells, another immune cell type, that recruit and expand additional killer T cells to destroy the tumors. But when they tried to add increased amounts of the helper T cell target to supercharge the vaccine they found they generated a different type of T cell that inhibited rather than promoted tumor rejection.
“We tested the hypothesis that by increasing helper T cell activation we would induce enhanced elimination of the sarcoma tumors in mice,” said first author Hussein Sultan, an instructor in pathology & immunology. So he injected groups of tumor bearing mice with vaccines that activated killer T cells equally while triggering a different degree of helper T cell activation.
Much to the researchers’ surprise in this latest study, the vaccine meant to hyperactivate helper T cells produced the opposite effect and inhibited tumor rejection.
“We thought that more helper T cell activation would optimize elimination of the sarcoma tumors in mice,” Sultan said. “Instead, we found that vaccines containing high doses of helper T cell targets induced inhibitory Tr1 cells that completely blocked tumor elimination. We know that Tr1 cells normally control an overactive immune system, but this is the first time they have been shown to dampen its fight against cancer.”
Tr1 cells normally put the brakes on the immune system to prevent it from attacking the body’s healthy cells. But their role in cancer has not been seriously explored. Looking through previously published data, the researchers found that tumors from patients who had responded poorly to immunotherapy had more Tr1 cells compared with tumors of patients who had responded well. The number of Tr1 cells also increased in mice as tumors grew bigger, rendering the mice insensitive to immunotherapy.
To bypass the inhibiting cells, the researchers treated the vaccinated mice with a drug that enhances killer T cells’ fighting power. The drug, developed by biotechnology startup Asher Biotherapeutics, carries modifications in the immune-boosting protein called interleukin 2 (IL-2) that specifically revs up killer T cells and reduces the toxicity of unmodified IL-2 treatments. The additional boost from the drug overcame Tr1 cells’ inhibition and rendered the immunotherapy more effective.
“We are committed to personalizing immunotherapy and broadening its effectiveness,” said Schreiber. “Decades of researching basic tumor immunology have expanded our understanding of how to trigger the immune system to achieve the most robust antitumor response. This new study adds to our understanding of how to improve immunotherapy to benefit more people.”
As co-founder of Asher Biotherapeutics — which provided the mouse version of the modified IL-2 drugs — Schreiber is indirectly involved in the company’s clinical trials testing the human version of the drug as a monotherapy in cancer patients. If successful, the drug has the potential to be tested in combination with cancer treatment vaccines.
Sultan H, Takeuchi Y, Ward JP, Sharma N, Liu TT, Sukhov V, Firulyova M, Song Y, Ameh S, Brioschi S, Khantakova D, Arthur CD, White JM, Kohlmiller H, Salazar AM, Burns R, Costa HA, Moynihan KD, Yeung YA, Djuretic I, Schumacher TN, Sheehan KCF, Colonna M, Allison JP, Murphy KM, Artyomov MN, and Schreiber RD. Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy. Nature. July 24, 2024. DOI: 10.1038/s41586-024-07752-y
This work was supported by grants from the National Cancer Institute of the National Institutes of Health (NIH), grant numbers R01CA190700, 5K08CA245215, P30CA91842 and T32CA009547; the NIH, grant numbers R01AI150297, R01CA248919, R21AI164142, R01AI162643 and R21AI16342; Parker Institute for Cancer Immunotherapy; Stand Up to Cancer-Lustgarten Foundation Pancreatic Cancer Foundation Convergence Dream Team Translational Research Grant administered by the American Association for Cancer Research; Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy; Alvin J. Siteman Cancer Center; Rheumatic Diseases Research Resource-based Center at Washington University, supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH, grant number P30AR073752; and the Ministry of Science and Higher Education of the Russian Federation, agreement number 075-15-2022-301. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Robert D. Schreiber is a cofounder, scientific advisory board member, stockholder and royalty recipient of Asher Biotherapeutics, and is a paid scientific advisory board member for A2 Biotherapeutics, NGM Biopharmaceuticals, BioLegend, Sensei Biotherapeutics Neuvogen and BlueSphere Biopharmaceuticals. Kenneth M. Murphy is on the scientific advisory board for Harbour Biomed.
About Washington University School of Medicine
WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,900 faculty. Its National Institutes of Health (NIH) research funding portfolio is the second largest among U.S. medical schools and has grown 56% in the last seven years. Together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,900 faculty physicians practicing at 130 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.
Originally published on the School of Medicine website
