Cleveland Clinic researchers have found that bacteria residing within cancerous tumors may play a crucial role in the varying effectiveness of immunotherapy for patients with head and neck squamous cell carcinoma. Two studies published in Nature Cancer reveal that higher levels of bacteria within the tumor microenvironment can suppress immune responses, contributing to resistance against immunotherapy treatments.
These findings shift the focus of immunotherapy resistance research from merely genetic factors to the less-explored area of the tumor microbiome. Timothy Chan, M.D., Ph.D., who chairs the Department of Cancer Sciences at Cleveland Clinic, emphasized the significance of this research: “By identifying bacteria as a key barrier to treatment, we’re opening the door to new strategies for patient selection and targeted antibiotic therapies, potentially improving outcomes for those who don’t benefit from immunotherapy.”
Insights from Patient Samples and Clinical Trials
The research team, which included Daniel McGrail, Ph.D., and Natalie Silver, M.D. M.S., validated their findings through a combination of patient samples, preclinical models, and data from clinical trials. In one study, Dr. McGrail analyzed tumor genetic data and discovered that elevated bacterial levels—not specific strains—were associated with a weakened immune response. Dr. Silver corroborated these results in preclinical models, where they observed that antibiotics could reduce tumor size and enhance immune responses. Conversely, introducing bacteria into the models rendered tumors more resistant to immunotherapy.
Collaboration with Renata Ferrarotto, M.D., from the University of Texas MD Anderson Cancer Center further enriched the research. Together, they studied clinical trial samples from head and neck cancer patients to understand the relationship between bacterial presence and treatment responses. Dr. Silver noted, “Our research examines how bacteria influence treatment failure. This can help us identify patients most likely to benefit from immunotherapy, with the goal of avoiding unnecessary risk and exposure.”
In another pivotal study, Dr. Chan analyzed data from the Javelin HN100 Phase III clinical trial, which investigated the impact of adding anti-PD-L1 immunotherapy to standard chemoradiotherapy. The results indicated that patients exhibiting high levels of tumor bacteria had significantly poorer outcomes with immunotherapy compared to those receiving standard treatment.
Implications for Future Cancer Treatments
The research further revealed that elevated bacterial levels in tumors attract neutrophils, a type of white blood cell involved in fighting infections. While neutrophils play a vital role in combating bacterial threats, they can suppress the immune system’s effectiveness needed for immunotherapy to succeed.
These discoveries establish a foundation for future research on the dynamics of bacterial attraction to tumors and how such interactions can be modified to enhance treatment efficacy. Dr. Silver has already initiated a clinical trial to explore whether antibiotics can reduce tumor microbiome levels and subsequently improve responses to immunotherapy in head and neck squamous cell carcinoma patients.
Meanwhile, Dr. McGrail is investigating how bacteria influence cancer development and their tendency to inhabit certain tumors, aiming to formulate new therapeutic strategies. Dr. Chan is also exploring how bacteria may induce DNA mutations in tumors.
In summary, these studies mark a significant advancement in understanding the intricate relationship between the tumor microbiome and immune responses in cancer treatment. Dr. McGrail stated, “By uncovering the tumor microbiome’s role in immunotherapy resistance, these studies broaden our perspective on cancer treatment and pave the way for developing personalized therapies to improve outcomes for patients.”
