Human soft tissue sarcomas harbor an intratumoral viral microbiome which is linked with natural killer cell infiltrate and prognosis

Abstract

BackgroundGroundbreaking studies have linked the gut microbiome with immune homeostasis and antitumor immune responses. Mounting evidence has also demonstrated an intratumoral microbiome, including in soft tissue sarcomas (STS), although detailed characterization of the STS intratumoral microbiome is limited. We sought to characterize the intratumoral microbiome in patients with STS undergoing preoperative radiotherapy and surgery, hypothesizing the presence of a distinct intratumoral microbiome with potentially clinically significant microbial signatures.MethodsWe prospectively obtained tumor and stool samples from adult patients with non-metastatic STS using a strict sterile collection protocol to minimize contamination. Metagenomic classification was used to estimate abundance using genus and species taxonomic levels across all classified organisms, and data were analyzed with respect to clinicopathologic factors.ResultsFifteen patients were enrolled. Most tumors were located at an extremity (67%) and were histologic grade 3 (87%). 40% were well-differentiated/dedifferentiated liposarcoma histology. With a median follow-up of 24 months, 4 (27%) patients developed metastases, and 3 (20%) died. Despite overwhelming human DNA (>99%) intratumorally, we detected a small but consistent proportion of bacterial DNA (0.02–0.03%) in all tumors, includingProteobacteria, Bacteroidetes,andFirmicutes, as well as viral species. In the tumor microenvironment, we observed a strong positive correlation between viral relative abundance and natural killer (NK) infiltration, and higher NK infiltration was associated with superior metastasis-free and overall survival by immunohistochemical, flow cytometry, and multiplex immunofluorescence analyses.ConclusionsWe prospectively demonstrate the presence of a distinct and measurable intratumoral microbiome in patients with STS at multiple time points. Our data suggest that the STS tumor microbiome has prognostic significance with viral relative abundance associated with NK infiltration and oncologic outcome. Additional studies are warranted to further assess the clinical impact of these findings.

Intratumor microbiome: selective colonization in the tumor microenvironment and a vital regulator of tumor biology

“…Of note, gut commensal fungi and bacteria might have opposite influences on antitumor immunity following radiation, with bacteria promoting the response and fungi reducing it 194 . In soft tissue sarcoma, a strong positive correlation between viral relative abundance and NK cell infiltration was observed, and more NK infiltration was associated with superior metastasis‐free and OS, 195 highlighting the potential roles of intratumor virus in tumor biology. And virus may bring another level of messages in the tumor microenvironment 196 .…”

Intratumoural microbiota: a new frontier in cancer development and therapy

“… 118 A recent prospective analysis demonstrated the prognostic significance of the measurable microbiome in soft tissue sarcoma, especially intratumoural viral microbiome, which is associated with higher NK cell infiltration and improved clinical outcomes. 266 Beyond the individual roles of certain microorganisms, microbial clustering or combinations demonstrate unique prognostic value. Sun et al identified two hepatotypes based on the microbial profile clustering, representing independent prognostic factors in patients with resected HCC.…”

Tumor-resident microbes: the new kids on the microenvironment block

“…Depletion of fungi leads to diminished activation of Th2 and ILC2 cells, leading to suppression of tumor growth. Furthermore, a recent study showed that intratumoral viruses induce NK cell infiltration and improve the prognosis of soft tissue sarcoma patients [ 58 ]. Thus, in addition to bacteria, the immunoregulatory roles of other microorganisms such as fungi, viruses, and bacteriophages in carcinogenesis, metastasis, and cancer therapies should also be explored ( Figure 1B ).…”