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

Abstract

Background: 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) associated with a higher expression of CD8+ T cells. Additionally, numerous studies indicate the gut microbiota is linked to colon cancer and clinical outcomes. Therefore, we hypothesized a microbial signature might be associated with both the intratumoral immune cells as well as DFS. Results: Ninety-one patients were randomly selected from a prospective NCI-sponsored multicenter trial evaluating ultrastaging in CC to investigate the intratumoral microbiota by 16S rRNA gene amplicon sequencing. Operational taxonomic units (OTUs) were grouped by 97% sequence similarity. A series of clinical, immunohistochemical, and microbiota-related data were first evaluated by univariable cox regression to determine candidate variables associated with DFS. DFS was influenced by three parameters: N-stage, CD8+ labeling, and one microbiota principal component by multivariate analysis (MVA). Not only were the microbiota and CD8 significant contributors to the DFS model, but they were also significantly associated with each other. Alpha diversity showed an inverse correlation to CD8+ T cells (p=0.010, R=-0.278) and beta diversity showedmore » an association with the CD8+ T cells (u-UniFrac p=0.026, w-UniFrac p=0.034). Further analysis at the OTU level with false discovery correction revealed one OTU, OTU_104, belonging to the order Clostridiales to be associated with increased recurrence (HR 1.21, CI 1.08 to 1.36). This OTU_104 was then found to be inversely correlated to CD8+ T cells (p=0.031, R=-0.35). Conclusions: This study is the first to demonstrate an association between the intratumoral microbiota, CD8+ T cells, and recurrence in CC. An increased relative abundance of a specific OTU_104 was inversely associated with CD8+ T cells and increased CC recurrence. The link between this microbe, CD8+ T cells and DFS has not been previously shown. Further studies are warranted to examine the role of infiltrating immune cells and the microbiota on colon cancer.« less

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1455291
Report Number(s):
PNNL-SA-130502
Journal ID: ISSN 1949-2553
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Oncotarget
Additional Journal Information:
Journal Volume: 2018; Journal Issue: 9; Journal ID: ISSN 1949-2553
Publisher:
Impact Journals
Country of Publication:
United States
Language:
English
Subject:
colon cancer; microbiota; immune infiltrate; disease free survival

Citation Formats

Noguti, Juliana, Chan, Alfred A., Bandera, Bradley, Brislawn, Colin J., Protic, Mladjan, Sim, Myung S., Jansson, Janet K., Bilchik, Anton J., and Lee, Delphine J. Both the intratumoral immune and microbial microenvironment are linked to recurrence in human colon cancer: results from a prospective, multicenter nodal ultrastaging trial. United States: N. p., 2018. Web. doi:10.18632/oncotarget.25276.
Noguti, Juliana, Chan, Alfred A., Bandera, Bradley, Brislawn, Colin J., Protic, Mladjan, Sim, Myung S., Jansson, Janet K., Bilchik, Anton J., & Lee, Delphine J. Both the intratumoral immune and microbial microenvironment are linked to recurrence in human colon cancer: results from a prospective, multicenter nodal ultrastaging trial. United States. doi:10.18632/oncotarget.25276.
Noguti, Juliana, Chan, Alfred A., Bandera, Bradley, Brislawn, Colin J., Protic, Mladjan, Sim, Myung S., Jansson, Janet K., Bilchik, Anton J., and Lee, Delphine J. Fri . "Both the intratumoral immune and microbial microenvironment are linked to recurrence in human colon cancer: results from a prospective, multicenter nodal ultrastaging trial". United States. doi:10.18632/oncotarget.25276.
@article{osti_1455291,
title = {Both the intratumoral immune and microbial microenvironment are linked to recurrence in human colon cancer: results from a prospective, multicenter nodal ultrastaging trial},
author = {Noguti, Juliana and Chan, Alfred A. and Bandera, Bradley and Brislawn, Colin J. and Protic, Mladjan and Sim, Myung S. and Jansson, Janet K. and Bilchik, Anton J. and Lee, Delphine J.},
abstractNote = {Background: 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) associated with a higher expression of CD8+ T cells. Additionally, numerous studies indicate the gut microbiota is linked to colon cancer and clinical outcomes. Therefore, we hypothesized a microbial signature might be associated with both the intratumoral immune cells as well as DFS. Results: Ninety-one patients were randomly selected from a prospective NCI-sponsored multicenter trial evaluating ultrastaging in CC to investigate the intratumoral microbiota by 16S rRNA gene amplicon sequencing. Operational taxonomic units (OTUs) were grouped by 97% sequence similarity. A series of clinical, immunohistochemical, and microbiota-related data were first evaluated by univariable cox regression to determine candidate variables associated with DFS. DFS was influenced by three parameters: N-stage, CD8+ labeling, and one microbiota principal component by multivariate analysis (MVA). Not only were the microbiota and CD8 significant contributors to the DFS model, but they were also significantly associated with each other. Alpha diversity showed an inverse correlation to CD8+ T cells (p=0.010, R=-0.278) and beta diversity showed an association with the CD8+ T cells (u-UniFrac p=0.026, w-UniFrac p=0.034). Further analysis at the OTU level with false discovery correction revealed one OTU, OTU_104, belonging to the order Clostridiales to be associated with increased recurrence (HR 1.21, CI 1.08 to 1.36). This OTU_104 was then found to be inversely correlated to CD8+ T cells (p=0.031, R=-0.35). Conclusions: This study is the first to demonstrate an association between the intratumoral microbiota, CD8+ T cells, and recurrence in CC. An increased relative abundance of a specific OTU_104 was inversely associated with CD8+ T cells and increased CC recurrence. The link between this microbe, CD8+ T cells and DFS has not been previously shown. Further studies are warranted to examine the role of infiltrating immune cells and the microbiota on colon cancer.},
doi = {10.18632/oncotarget.25276},
journal = {Oncotarget},
issn = {1949-2553},
number = 9,
volume = 2018,
place = {United States},
year = {2018},
month = {5}
}