Abstract 1277: Unveiling the impact of intratumoral microbiota in the treatment efficacy of soft tissue sarcoma

Abstract Tumor resident microbiota is an emerging component of the tumor microenvironment with unclear biological function. Among all microorganisms harbored within tumor tissue, bacteria are currently the most studied due to their ability to interact with the host. To date, the tumor microbiome is reported as composed of tumor type-specific bacteria, commonly found within host cells, which can affect tumor biology as well as play a role in cancer formation, progression, and response to therapy. So far, the contribution of intratumoral microbiota in the context of soft tissue sarcoma (STS) has been underestimated; therefore, this project aims to characterize the STS microbiota and understand if it can impair the sensitivity to chemotherapeutic regimens. STS are heterogeneous cancers with more than 100 histological subtypes, different in molecular alterations, which make its personalized therapy very complex. Thus, doxorubicin is the gold standard of chemotherapy for advanced STS but it is effective for less than 50% of patients. Doxorubicin is a natural anthracycline produced by different strains of Streptomycetaceae which exploit the toxic properties of this molecule for inter-specific competition. Hence, the hypothesis that certain bacteria developed drug-inactivating mechanisms seems evolutionarily plausible. Targeting the bacterial 16S rRNA gene through a Fluorescence in situ hybridization, we were able to detect bacteria within different histotypes of sarcoma. In addition, we analyzed the microbiome composition of sarcoma tissues and adjacent healthy tissues showing that sarcomas harbor a distinct microbiome composition. Besides, comparison of different sarcoma histotypes revealed that microbiome composition seems to be shaped according to histological features. Moreover, we isolate live bacteria harbored within sarcoma tissues. To date, isolated bacteria were mainly strictly or facultative anaerobes; thus, well adapted to live in the hypoxic environment of tumors. These bacteria gave us the opportunity to investigate their ability to interfere with chemotherapy. We exposed several sarcoma-isolated bacteria strains to doxorubicin, we found that certain bacteria strains were responsible for drug degradation. This result was confirmed with functional experiments evaluating drug toxicity after bacterial exposure. In addition, we showed in vivo that the intratumoral presence of doxorubicin-degrading bacteria is sufficient to provoke the occurrence of chemoresistance in a doxorubicin-sensitive mouse model of fibrosarcoma. This study offers new insights about the relationship between the intratumoral microbiota and the occurrence of chemoresistance in cancer therapies, suggesting that microbial communities hosted within the tumor should be deeply investigated, and then manipulated, to improve the outcome of therapies. Citation Format: Luca Tiraboschi, Daniele Braga, Alessia Melacarne, Valentina Ferrari, Gerlanda Vella, Alessandro Mozzarelli, Antonino Lo Cascio, Giulia Fornasa, Michela Lizier, Sara Carloni, Giuseppe Martano, Sara Timo, Alessandro Bernardinello, Salvatore Lorenzo Renne, Ferdinando Cananzi, Alessia Bertuzzi, Giuseppe Penna, Maria Rescigno. Unveiling the impact of intratumoral microbiota in the treatment efficacy of soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1277.