Study Finds Link Between Tumor Microbiome and Immunotherapy Outcomes in Soft Tissue Sarcoma

A study published in the Journal for Immunotherapy of Cancer found that patients with soft tissue sarcomas (STS) may have distinct and measurable intratumor microbiomes that may hold prognostic significance and could potentially be targeted in treatment.

STS is a blanket term for cancers that form in soft tissue, including muscles, tendons, fat, nerves, and lymph and blood vessels. The gut microbiome comprises the microorganisms in the digestive tract, including bacteria, fungi, parasites, and viruses. The gut microbiome has been linked to immune function in past research, and there is increasing evidence that an intratumoral microbiome exists in some cancers, including breast, lung, pancreas, and melanoma, the study authors noted.

“Importantly, these tissues have anatomic connections with the outside world, and the question of whether there exists an intratumoral microbiome in STS, a presumed ‘sterile’ tissue, has not yet been explored in depth, despite evidence showing microbial presence in multiple solid cancers with tumor-specific predilections,” the authors wrote.

To characterize the STS tumor microbiome, the researchers sequenced DNA in tissue obtained via strict sterile biopsies from patients with non-metastatic STS undergoing neoadjuvant radiotherapy (RT) and surgery. Stool samples were also collected at diagnosis before neoadjuvant RT, as well as after RT and before surgical resection. Control specimens were collected from surfaces that might interact with samples and from the skin microbiome of some patients to analyze for possible contamination patterns in the test specimens.

Tumor samples from 15 patients were collected for analysis, most of which were located on extremities (67%) and histologic grade 3 (87%). At a median follow-up of 24 months, 4 patients had developed metastasis, and 3 had died. More than 99% of the intratumoral DNA in the samples was found to be human, but a small amount of bacterial DNA was present in all of the tumors.

Bacterial DNA, including Proteobacteria, Bacteroidetes, and Firmicutes, only made up 0.02-0.03% of tumor DNA overall in the study. However, the proportion of bacterial DNA was consistent across samples, and this finding is significant, considering STS tissue was previously thought to be sterile. Viral species were also present in the samples.

“We found that soft tissue sarcomas harbor a quantifiable amount of microbiome within the tumor environment. Most importantly, we found that the amount of microbiome at diagnosis may be linked with the patient’s prognosis,” Robert Canter, MD, the lead author of the study and chief of the surgical oncology division at UC Davis, said in a statement.

There was a significant positive correlation between the relative viral abundance and the infiltration of natural killer (NK) cells within the tumor tissue. NK cells are a key target for increasing immunotherapy effectiveness, the authors noted; and increased NK infiltration was linked to better overall survival and metastasis-free survival based on immunohistochemical, flow cytometry, and multiplex immunofluorescence analyses in the study.

“The study’s data show new lines of research in the paradigm-shifting concept that the microbiome of a patient and their immune system can interact and shape one another, as well as be potentially engineered to improve patient outcomes,” Canter said.

While further research is needed to gauge the clinical impact of the study’s findings, the data suggest that the STS tumor microbiome Is measurable and has potential prognostic significance.

“It has become clear that the microbiome in the gut and other parts of the body has a major impact on human health and disease,” Canter said. “Amazingly, it shapes the immune system throughout the body and, because of its interaction with the immune system, we now know it also has a big role in how the body responds to cancer and cancer treatments like immunotherapy.”

Reference

Perry LM, Cruz SM, Kleber KT, et al. Human soft tissue sarcomas harbor an intratumoral viral microbiome which is linked with natural killer cell infiltrate and prognosis. Journ ImmunoTher Cancer. 2023;11(1):e004285. doi:10.1136/jitc-2021-004285