Vitamin B2 and Tumor Bacteria Point to a New Lung Cancer Therapy

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, pointing to a possible new cancer treatment strategy. The findings were published in the Proceedings of the National Academy of Sciences.

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, or MAIT cells, 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," said Franck Housseau of the Johns Hopkins University School of Medicine, now research director of the French National Institute of Health and Medical Research.

Combining microbiome sequencing of human tumors, RNA sequencing of immune cells and cell culture experiments, the team found an unexpected result. They had anticipated that bacteria capable of producing the vitamin B2 metabolite would activate MAIT cells, but instead found that a type of enterococci that did not produce the metabolite could still strongly increase MAIT cell activation once the metabolite was added 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," said Pakhi Birla, who led the study.

Birla also revisited data from an earlier study of lung cancer patients who received neoadjuvant PD-1 blockade immunotherapy before their main cancer treatment. One patient who responded strongly to the therapy had large numbers of MAIT cells, suggesting the cells may have contributed to that response. The researchers have started preclinical studies testing whether injecting the B2 metabolite directly into lung tumors in mice can provoke an immune response.

The team also intends to investigate whether adaptive immune T cells can be engineered to recognize MR1 and use it to target tumor cells. Current T cell treatments are typically tailored to proteins specific to an individual patient, making them expensive and complex. "It is very expensive and very complex to personalize immunotherapy, maybe not accessible to every patient," Housseau said. "But if we are successful, we could develop a new concept: tumor-agnostic, off-the-shelf therapy that works for every patient."