New research points to lactate-producing intratumoral bacteria as a driving cause of radiation therapy resistance in cervical cancer. The study, published in Cancer Cell, found that Lactobacillus iners (L. iners), causes cervical cancer cells to respond to radiation by rewiring metabolic signaling pathways that ultimately lead to radiation resistance. The researchers also found that L. iners was associated with poorer clinical outcomes in patients with the disease.
Just as resistance develops to chemotherapeutics, radiation resistance is not uncommon. In fact, in the case of cervical cancer—which is almost exclusively treated with chemoradiation—about 40% of treated patients do not respond.
“In the case of cervical cancer our primary treatment is chemoradiation and our ability to control the tumor locally with radiation is very closely related to survival,” says corresponding author Lauren Colbert, MD, of the MD Anderson Cancer Center. “So anything in the tumor microenvironment that effects a response to radiation relates to survival.”
Realizing that radiation therapy was often ineffective for locally advanced cervical cancer, a disease that usually affects relatively healthy women in their 30s and 40s, the MD Anderson team set out to develop a prospective biomarker profiling study to identify anything that would point the way to new therapeutic avenues.
They focused on HPV-related cancers which are found in the head/neck, cervix, vagina, vulva, and anus. While all these cancers are generally treated with chemoradiation and have similar molecular profiles, the team noted that the amount of radiation needed to kill cervical cancer cells was about 30% to 40% more than those other cancers.
“One of the big differences between these tumor sites is the microbiome—they all have different bacteria,” explains Colbert. Because of this, the team added bacteria collection protocols both from the gut microbiome and from bacteria inside the tumors themselves.
What ended up repeatedly showing up was the Lactobacillus iners finding. “What was mostly strongly associated with a poor tumor response and reduced survival was having L. iners in the tumor more than anything else,” adds Colbert. The team enrolled more patients into a validation study, refined their microbiome bioinformatics platform, and performed targeted cultures. “It was L. iners that showed up when it had rarely been described in the tumor microbiome previously,” she adds.
L. iners is the most common vaginal microbe in women worldwide. Previous association studies have a relationship between the bacteria and progression of HPV infection to dysplasia to cancer.
Mechanistically, the MD Anderson team discovered that it was the obligate L lactate isoform of L. iners that causes the radiation resistance. When they treated cervical cancer organoids with supernatant from that bacteria, those cells became resistant to radiation.
“L lactate L. iners are very efficient at producing lactate in order to drive their own metabolism and survival,” Colbert explains. One of the biggest metabolic stressors is radiation. Bacteria that are irradiated are metabolically stressed and switch from glucose to lactate so they won’t die.
“These lactic acid-producing bacteria are seemingly responsible for changing signaling pathways by priming cancer cells to use lactate instead of glucose to fuel growth and proliferation from oxidative stress following radiation therapy,” said Colbert.
The team is currently working on novel approaches to target these specific intratumoral bacteria.
“The field of tumor metabolism has very recently been developing with new therapeutics,” says Colbert. “If we consider that there are bacteria in the tumor microenvironment that may be playing a role in how the tumors are metabolizing, it’s a totally different way of looking at it that we haven’t identified until now.”
