Researchers Identify Tumor Bacteria Linked to Immunotherapy Resistance

Researchers at the Cleveland Clinic have uncovered a significant factor contributing to the varying effectiveness of immunotherapy in patients with head and neck cancer. Their studies indicate that the presence of bacteria within cancerous tumors may suppress the immune response, resulting in resistance to treatment. The findings, published in the journal Nature Cancer, highlight the need to consider the tumor microbiome alongside traditional genetic factors when evaluating treatment resistance.

In two distinct studies, lead author Timothy Chan, M.D., Ph.D., who chairs the Department of Cancer Sciences at the Cleveland Clinic, emphasized that this research shifts the focus from solely tumor genetics to the complex interactions involving the tumor microbiome. “By identifying bacteria as a key barrier to treatment, we’re opening the door to new strategies for patient selection and targeted antibiotic therapies,” Dr. Chan stated. This approach could potentially improve outcomes for patients who currently do not benefit from immunotherapy.

The research team, which included Daniel McGrail, Ph.D., and Natalie Silver, M.D., M.S., validated their findings using various methods, including patient samples, preclinical models, and clinical trial data. In the first study, Dr. McGrail analyzed genetic data from tumor samples, discovering that elevated bacterial levels—rather than specific strains—can weaken the immune response. Dr. Silver confirmed these results in preclinical models, demonstrating that antibiotics not only reduced tumor size but also enhanced immune response. Conversely, introducing bacteria made tumors more resistant to immunotherapy.

Collaboration with Renata Ferrarotto, M.D., from the University of Texas MD Anderson Cancer Center, further bolstered their research. The team examined clinical trial samples from head and neck cancer patients, aiming to understand how bacterial presence influences treatment failure. “Immunotherapy is a promising treatment option for patients with head and neck cancer, but the majority unfortunately do not respond,” Dr. Silver noted. “Our research examines how bacteria influence treatment failure, enabling us to identify patients most likely to benefit from immunotherapy.”

In the second study, Dr. Chan spearheaded a data analysis of the Javelin HN100 Phase III clinical trial, which investigated the efficacy of combining anti-PDL1 immunotherapy with standard chemoradiotherapy. The analysis revealed that patients with high levels of bacteria in their tumors experienced poorer outcomes when treated with immunotherapy compared to those receiving standard chemoradiotherapy.

The studies collectively revealed that increased bacterial levels in tumors attract neutrophils, a type of white blood cell essential for combating infections. While beneficial in fighting off bacteria, neutrophils can hinder the immune system’s ability to respond effectively to cancer treatment. These insights lay the groundwork for further investigation into the reasons behind bacteria’s attraction to tumors and potential methods to modify this interaction.

Building on these findings, Dr. Silver has initiated a clinical trial to assess whether antibiotics can reduce tumor microbiome levels and enhance immunotherapy responses in patients with head and neck squamous cell carcinoma. Dr. McGrail is also exploring how bacteria influence cancer development and why certain tumors harbor more bacteria, with the goal of developing new therapeutic strategies. Meanwhile, Dr. Chan is investigating how bacteria may induce DNA mutations within tumors.

“By uncovering the tumor microbiome’s role in immunotherapy resistance, these studies mark a significant step forward in understanding the complex interactions between cancer and the immune system,” stated Dr. McGrail. “This research broadens our perspective on cancer treatment and paves the way for developing personalized therapies to improve outcomes for patients.”

The implications of this research extend beyond head and neck cancer, potentially influencing the approach to immunotherapy resistance in various cancer types in the future.