Intratumoural bacteria drives radiation therapy resistance

Lactate-producing intratumoural bacteria has been discovered to drive resistance to radiation therapy by scientists at The University of Texas MD Anderson Cancer Center. This suggests that lactic acid-producing bacteria existing in various cancers could serve as new therapeutic targets.

The study found that a certain bacterial species, Lactobacillus iners (L. iners), caused cancer cells to respond to radiation by rewiring metabolic signalling pathways to resist treatment. L. iners was also associated with poorer clinical outcomes in cervical cancer patients.

Corresponding author and Assistant Professor of Radiation Oncology Dr Lauren Colbert said: “These lactic acid-producing bacteria are seemingly responsible for changing signalling pathways by priming cancer cells to use lactate instead of glucose to fuel growth and proliferation from oxidative stress following radiation therapy.”  She continued: “This is potentially paradigm shifting, and we currently are working on novel approaches to target these specific intratumoural bacteria. We are hopeful that these efforts will lead us to approaches that can benefit patients across several types of cancer.”

Cervical cancer is a human papillomavirus (HPV)-related cancer. It originates in the same way and is similar microscopically and genomically to colorectal and head and neck cancer. These cancers are commonly treated with varying amounts of radiation. Cervical cancers often respond well to treatment, but some patients develop resistance, leading Colbert and her team to examine the role of the tumour microbiome in driving differential responses. Microbiome sequencing, targeting bacterial cultures and in vitro models were used to study the tumour microbiome in this context.

Cervical cancer presents an opportunity for easier repeated tumour microbiome sampling,  permitting the scientists to perform large-scale sequencing analyses and targeted culture of tumour-resident bacteria from 101 patients with cervical cancer undergoing chemoradiation between September 2015 and March 2022.

They found that L. iners was associated with poor response to radiation and with decreased recurrence-free survival (RFS) and overall survival (OS), even when accounting for known clinical risk factors, gut microbiome factors and immune environment factors both in the tumour and in patients’ blood. This led the researchers to perform targeted culture of this specific bacteria from patient samples.

L. iners is part of a group of fermenting bacteria that produce lactic acid as a metabolic end product. The scientists found that cancer-derived L. iners within tumours generate L-lactate, which cancer cells use instead of glucose to power metabolic cycles and to resist oxidative stress that occurs after radiation. Tumour lactate and lactate dehydrogenase (LDH) expression are already associated with aggressive tumour growth and poor survival across numerous cancer types.

Co-led by Dr Ann Klopp, Professor of Radiation Oncology, the researchers induced treatment resistance by introducing lactate-producing L. iners to cancer cells in vitro, which resulted in the rewiring of the tumour cell metabolism to use that increased lactate.

The findings also showed that L. iners have functions inside of tumours that are not present in healthy patients, indicating that some changes in these bacteria themselves possibly occurs before cancer development.

Although this study focused on L. iners, the team observed a considerable association between other tumour-associated lactic acid-producing bacteria and poor survival across multiple cancers, noting that 40% of species are associated with RFS in subsets of lung, colorectal, skin and head and neck cancers.

Presently, Colbert and her colleagues are developing new approaches to specifically target these bacteria inside tumours, including topical applications to deliver anti-cancer drugs and improve patient outcomes for various cancer types.

This research was published in Cancer Cell.