Both the intratumoral immune and microbial microenvironment are linked to recurrence in human colon cancer: Results from a prospective, multicenter nodal ultrastaging trial

// Juliana Noguti 1, 2, * , Alfred A. Chan 1, 2, * , Bradley Bandera 3, * , Colin J. Brislawn 4 , Mladjan Protic 5, 6 , Myung S. Sim 7 , Janet K. Jansson 4 , Anton J. Bilchik 3, ** and Delphine J. Lee 1, 2, 8, 9, ** 1 Dirks/Dougherty Laboratory for Cancer Research, Department of Translational Immunology, John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA, USA 2 Los Angeles Biomedical Research Institute, Harbor – UCLA Medical Center, Torrance, CA, USA 3 Department of Surgical Oncology. The John Wayne Cancer Institute at Providence St. John’s Health Center, Santa Monica, CA, USA 4 Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, USA 5 University of Novi Sad, Faculty of Medicine, Novi Sad, Serbia 6 Oncology Institute of Vojvodina, Sremska Kamenica, Serbia 7 UCLA Department of Medicine, Statistics Core, Los Angeles, CA, USA 8 Division of Dermatology, Department of Medicine, Harbor - UCLA Medical Center, Torrance, CA, USA 9 David Geffen School of Medicine, University of California - Los Angeles, Los Angeles, CA, USA * Co-first authors ** Co-senior authors Correspondence to: Delphine J. Lee, email: delphine.lee@labiomed.org Keywords: colon cancer; microbiota; immune infiltrate; disease free survival; immune cells Received: January 10, 2018     Accepted: April 08, 2018     Published: May 04, 2018 ABSTRACT Colon cancer (CC) is the third most common cancer diagnosed in the United States and the incidence has been rising among young adults. We and others have shown a relationship between the immune infiltrate and prognosis, with improved disease-free survival (DFS) being associated with a higher expression of CD8 + T cells. We hypothesized that a microbial signature might be associated with intratumoral immune cells as well as DFS. We found that the relative abundance of one Operational Taxonomic Unit (OTU), OTU_104, was significantly associated with recurrence even after applying false discovery correction (HR 1.21, CI 1.08 to 1.36). The final multivariable model showed that DFS was influenced by three parameters: N-stage, CD8 + labeling, as well as this OTU_104 belonging to the order Clostridiales. Not only were CD8 + labeling and OTU_104 significant contributors in the final DFS model, but they were also inversely correlated to each other (p=0.022). Interestingly, CD8 + was also significantly associated with the microbiota composition in the tumor: CD8 + T cells was inversely correlated with alpha diversity (p=0.027) and significantly associated with the beta diversity. This study is the first to demonstrate an association among the intratumoral microbiome, CD8 + T cells, and recurrence in CC. An increased relative abundance of a specific OTU_104 was inversely associated with CD8 + T cells and directly associated with CC recurrence. The link between this microbe, CD8 + T cells, and DFS has not been previously shown.