Abstract 1280: Role of the tumor microbiome in the lung adenocarcinoma immune microenvironment through multi meta-omics analysis

Abstract Lung cancer is the leading cause of death by cancer worldwide. The tumor microbiome has shed light on its role, influence, and modulation in cancer immunosurveillance, where the tumor-bacterial component emerges as a potential mediator for the antitumoral-immune response. Nevertheless, the complexities and functional mechanisms underlying this interaction remain elusive. Here, we outline how the tumor microbiota can impact the host´s immune response to lung adenocarcinoma (LUAD). We explored the microbiome within LUAD tumors and non-tumoral adjacent tissues (NAT) from Chilean patients. We used 10 paired (LUAD and NAT) fresh-frozen samples, 20 exclusively tumor fresh-frozen samples, and 40 exclusively tumor formalin-fixed paraffin-embedded samples. Using 16S rRNA gene sequencing, we assessed revealed variations in alpha diversity, with an intra-tumoral microbiome enriched in Gammaproteobacteria and Actinobacteria, particularly genera Pseudomonas and Corynebacterium in undifferentiated LUAD samples. Notably, a consistent depletion of Verrucomicrobiota with genus Akkermansia was evident in samples where cell differentiation was lost. Metaproteomics analysis revealed bacteria-associated peptides from Pseudomonas and Streptomyces enriched in the tumor, linked to Major facilitator superfamily (MFS) transporters and Glutathione S-transferase N-terminal domain-containing protein, both associated with transport activity and negatively correlated with cancer. The bacterial metabolic analysis uncovered 10 enriched microbial-associated metabolites in the tumor, highlighting adenosine and inosine, two known inducers of immunosuppression on T-cells in the tumor microenvironment. Host proteomics gene-ontology analysis highlighted an enrichment of proteins in the Interferon pathways. Concurrently, a downregulation of proteins like T-cell surface-glycoprotein CD8 and HLA-class I histocompatibility antigen was observed, linked to MHC protein complex binding function, and associated with immune evasion through diminished antigen presentation. Furthermore, upregulated proteins such as macrophage migration inhibition factor (MIF) and eIF-2-alpha kinase GCN2, known to stimulate cell proliferation, were identified. In summary, our multi-omics and bioinformatic analyses unveil a distinct intra-tumoral microbiome and microbe-derived metabolites could induce immune suppression, altering the metabolic profile in the LUAD tumor microenvironment and collectively contribute to tumor progression. Funding information: This work was supported by FONDECYT1231629 and ANID-Subdirección de capital humano/Doctorado Nacional/2023/21231386. Citation Format: Ivania Valdés, Alberto Martin, Eduardo Martínez, Daniel Carvajal Hausdorf, Erick Riquelme. Role of the tumor microbiome in the lung adenocarcinoma immune microenvironment through multi meta-omics analysis [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 1280.