Acidovorax Temperans Modulates The Host Immune Microenvironment To Promote Lung Cancer Development.

Abstract Lung cancer is the most common cause of cancer-related death worldwide in both men and women. The overall survival of lung cancer remains poor due to limitations in diagnostic and therapeutic strategies. Therefore, the development of novel biomarkers is urgently needed to improve patient prognosis. Growing evidence has demonstrated alterations of the normal microbiome in lung cancer. Dysbiosis may alter normal microbiota-host interactions and induce immune dysregulation, and therefore contribute to the promotion of tumorigenesis. Although multiple studies show an association between dysbiosis, host immune response and tumorigenesis, the underlying mechanisms are still unclear. We previously characterized a distinct group of taxa that are enriched in lung adenocarcinoma and squamous cell carcinoma. Among these taxa, Acidovorax spp. were associated with cigarette smoking and TP53 mutations, with Acidovorax temperans identified by full-length 16S sequencing. We hypothesized that enrichment of A. temperans in the lung microbial community may modulate the immune microenvironment and therefore contribute to tumor development. We used an autochthonous mouse model of lung adenocarcinoma, in which tumorigenesis is driven by oncogenic K-Ras and a gain-of function mutant p53 under the control of the Cre-lox system. We administered biweekly intranasal instillations of A. temperans to mimic the effects of chronic tobacco smoking. Following bacterial instillation, the lung tumor development was determined by magnetic resonance imaging (MRI) at 13 weeks post Ad-Cre instillation. Mice challenged with A. temperans exhibited significantly larger tumor burden and a deleterious effect on survival compared to the sham group. Given the importance of the immune system in modulating tumor development, we then investigated whether A. temperans exposure induced changes in the immune microenvironment through high parametric flow cytometry post 5th instillation and post MRI. Lungs from mice instilled with A. temperans showed an increased number of total leukocytes. The vast majority of leukocytes were pro-inflammatory cells and predominantly neutrophils. Moreover, we also found an increase in CD4+ T cells and double negative T cells, and an increase in RORγt+/IL17+ subpopulations in both of these T cell groups. Consistent with these results, the IL-17 expression level was upregulated in response to A. temperans instillation. Taken together, these results indicate that A. temperans exposure induces a robust pro-inflammatory response, thereby increasing immune infiltration in the tumor microenvironment and promoting development of lung adenocarcinoma. Citation Format: Chenran Zhang, Natalia von Muhlinen, Araya Romina, Joshua Stone, Romina Goldszmid, Curtis Harris. Acidovorax temperans modulates the host immune microenvironment to promote lung cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1782.