About one in five cancer patients benefit from immunotherapy – a treatment that harnesses the immune system to fight cancer. Such a cancer-fighting approach has seen significant success in lung cancer and melanoma, among others. Optimistic about its potential, researchers are exploring strategies to improve immunotherapy for cancers that do not respond well to treatment, in hopes of benefiting more patients.
Now, researchers at Washington University School of Medicine in St. Louis have discovered, in mice, that a strain of gut bacteria— Ruminococcus gnavus – can enhance the effects of cancer immunotherapy. The study, which appears May 17 in Science Immunologysuggests a new strategy of using gut microbes to help unlock the untapped potential of immunotherapy to fight cancer.
The microbiome plays an important role in mobilizing the body’s immune system to attack cancer cells. Our findings shed light on a bacterial species in the gut that helps an immunotherapy drug eradicate tumors in mice. Identifying such microbial partners is an important step in the development of probiotics that will help improve the effectiveness of immunotherapy drugs and benefit more cancer patients.”
Marco Colonna, MD, senior author of the study, Robert Rock Belliveau, MD, Professor of Pathology
Cancer immunotherapy uses the cells of the immune system to target and destroy tumors. One such treatment uses immune checkpoint inhibitor drugs to unleash the immune system by releasing the natural brakes that keep immune T cells quiet, a feature that prevents the body from harming itself. But some tumors fight back to suppress the attacking immune system cells, reducing the effectiveness of such inhibitors.
Colonna and co-first author Martina Molgora, PhD, a postdoctoral researcher, previously collaborated with colleague Robert D. Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor, in which they completely eradicated sarcoma tumors in mice using a dual inhibition approach. The researchers inhibited TREM2, a protein produced by tumor macrophages to stop T cells from attacking the growing tumor. They then showed that an immunotherapy drug for cancer was more effective when TREM2 was blocked. The result showed that TREM2 reduces the effectiveness of immunotherapy.
In an experiment that formed the basis of the new study, the researchers made a surprising observation. TREM2 mice had the same beneficial response to the checkpoint inhibitor when housed with mice lacking the protein. This result came about when the researchers deviated from their standard protocol of separating the mice before treating them with the inhibitor.
Mice that live together share germs with each other. The researchers suspected that the results might be due to exchanges of gut bacteria. The researchers collaborated with Jeffrey I. Gordon, MD, Drs. Robert J. Glaser Distinguished University Professor and co-first author Blanda Di Luccia, PhD, a postdoctoral researcher, to study the microbes in the guts of the treated mice. successfully with immunotherapy. They found an extension of it Ruminococcus gnavuscompared to the lack of such microbes in mice that did not respond to treatment.
R. gnavus has been found in the gut microbiota of cancer patients who respond well to immunotherapy, Colonna explained. In clinical trials, stool transplants from such individuals have helped some unresponsive patients reap the benefits of immunotherapy.
The researchers, including co-author and graduate student Darya Khantakova, presented R. gnavus in mice and then treated the tumors with a checkpoint inhibitor. The tumors shrank, even when TREM2 was available as a weapon to reduce the effect of immunotherapy.
Gordon, director of the Edison Family Center for Genome Sciences & Systems Biology, noted that there is growing evidence that the microbiota enhances immunotherapy. Identification of relevant items, such as e.g R. gnavuscould lead to a next-generation probiotic that could work with immunotherapy to improve cancer care, he explained.
Scientists then aim to figure out how R. gnavus helps tumor rejection, which may reveal new ways to help cancer patients. For example, if the microbe produces a metabolite that activates the immune system through the process of digesting food, this knowledge opens up the opportunity to use metabolites as immunotherapy enhancers. The microbes can also leak out of the gut and trigger an immune response to the tumor or activate gut T cells that migrate to the tumor to mount an attack, Colonna explained. The researchers are investigating three possibilities.
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Journal Reference:
DiLuccia, B., et al. (2024). TREM2 deficiency reprograms intestinal macrophages and microbiota to enhance anti-PD-1 tumor immunotherapy. Science Immunology. doi.org/10.1126/sciimmunol.adi5374.
