An unusual immune signature in lung cancer has led researchers toward a potential therapy involving tumor microbes and MAIT cells.
Bacteria living inside lung tumors may be doing more than simply occupying the tumor environment. In preclinical research from the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy, researchers found that these bacteria may help activate innate immune cells when a common vitamin metabolite is present.
The findings were published in the Proceedings of the National Academy of Sciences.
The work points to a possible way of encouraging the immune system to attack cancer. Researchers found that exposing bacteria from lung tumors to a vitamin B2 metabolite increased the amount of a protein called MR1 on the surface of antigen-presenting immune cells. MR1 can then activate mucosal-associated invariant T-cells (MAIT), innate immune cells that rapidly respond to potential threats.
“We are opening a new field of immunotherapy by using a metabolite that, in combination with these bacteria, increases the expression of MR1 and triggers the activation of MAIT cells toward the tumor,” says Franck Housseau, Ph.D., PharmD, an associate professor of oncology at the Johns Hopkins University School of Medicine, now research director of the French National Institute of Health and Medical Research, who studies interactions between the microbiome and tumors in the response to immunotherapy.
MAIT cells offer another immunotherapy route
Many newer cancer treatments, including immune checkpoint inhibitors, work by restoring the activity of T cells in the adaptive immune system so they can recognize and attack tumor cells. MAIT cells have received less attention, Housseau says. These cells normally act as early responders to infection or injury, identifying and eliminating threats along the mucosa, the protective tissue that separates the body from the outside environment. Growing research suggests they may also have potential in cancer treatment.
MAIT cells respond to MR1, a protein displayed by antigen-presenting immune cells when bacteria, injury, or other dangers are detected. To understand how this system might operate inside tumors, the researchers combined microbiome sequencing of human tumors, RNA sequencing of immune cells from patient samples, and cell culture experiments. The results produced an unexpected clue.
Housseau and colleagues anticipated that bacteria capable of producing the vitamin B2 metabolite would activate MAIT cells. Instead, they found that one type of enterococci that did not produce the B2 metabolite could also strongly increase MAIT cell activation when researchers added the metabolite to cell cultures.
“Tumor-associated bacteria may regulate the immune response to tumors by regulating the expression of MR1 on antigen-presenting cells and activating the MAIT cells in the tumor microenvironment, which could have anti-tumor effects,” explains Pakhi Birla, Ph.D., a cancer immunologist who led the study while completing her doctorate in the laboratories of Housseau and Drew Pardoll, M.D., Ph.D.
A strong responder had abundant MAIT cells
Birla also revisited data from an earlier study by Pardoll and Kellie Smith, Ph.D., an associate professor of oncology at Johns Hopkins Medicine. The previous research involved lung cancer patients who received neoadjuvant PD-1 blockade immunotherapy, meaning treatment was given before the main cancer treatment. One patient who responded strongly to therapy had large numbers of MAIT cells, suggesting the cells may have contributed to that response.
The research brought together specialists from several fields: Housseau, who studies mucosal immunology; Pardoll, director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy and an expert in tumor immunology and immunotherapy; Cynthia L. Sears, M.D., an infectious diseases expert and the Bloomberg~Kimmel Professor of Cancer Immunotherapy at Johns Hopkins; and Fyza Y. Shaikh, M.D., Ph.D., an assistant professor of cancer immunology at Johns Hopkins Medicine.
MR1 could enable broader T cell therapy
The researchers have already started preclinical studies testing whether injecting the B2 metabolite directly into lung tumors in mice can provoke an immune response. They also intend to investigate whether adaptive immune T cells can be engineered to recognize MR1 and use it to target tumor cells. Current adaptive immune T cell treatments are generally tailored to proteins specific to an individual patient, while an MR1-targeted approach could potentially work across a much broader group of patients.
“It is very expensive and very complex to personalize immunotherapy, maybe not accessible to every patient,” Housseau explains. “But if we are successful, we could develop a new concept: tumor-agnostic, off-the-shelf therapy that works for every patient.”
Reference: “Select intratumoral riboflavin-auxotrophic Enterococcus species enhance cell surface MR1 expression and MAIT TCR activation in lung cancer” by Pakhi Birla, Lansaol Yang, Wanting Shan, Sakura Minamisawa, Omkar Dhaygude, Haritha Manoj, Alex J. Lee, Jacqueline Ferri, Ying Zheng, Andrew Northcutt, Hongni Fan, Hadley Beauregard, Zhen Zeng, Kellie N. Smith, Fyza Y. Shaikh, Cynthia L. Sears, Drew M. Pardoll and Franck Housseau, 18 August 2026, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2617943123
The research was supported by the Commonwealth Foundation and the Bloomberg~Kimmel Institute for Cancer Immunotherapy.
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