Association of Fusobacterium nucleatum with Specific T-cell Subsets in the Colorectal Carcinoma Microenvironment

Abstract

Purpose: While evidence indicates that Fusobacterium nucleatum (F. nucleatum) may promote colorectal carcinogenesis through its suppressive effect on T-cell-mediated antitumor immunity, the specific T-cell subsets involved remain uncertain.Experimental Design: We measured F. nucleatum DNA within tumor tissue by quantitative PCR on 933 cases (including 128 F. nucleatum-positive cases) among 4,465 incident colorectal carcinoma cases in two prospective cohorts. Multiplex immunofluorescence combined with digital image analysis and machine learning algorithms for CD3, CD4, CD8, CD45RO (PTPRC isoform), and FOXP3 measured various T-cell subsets. We leveraged data on Bifidobacterium, microsatellite instability (MSI), tumor wholeexome sequencing, and M1/M2-type tumor-associated macrophages [TAM; by CD68, CD86, IRF5, MAF, and MRC1 (CD206) multimarker assay]. Using the 4,465 cancer cases and inverse probability weighting method to control for selection bias due to tissue availability, multivariable-adjusted logistic regression analysis assessed the association between F. nucleatum and T-cell subsets.Results: The amount of F. nucleatum was inversely associated with tumor stromal CD3 þ lymphocytes [multivariable OR, 0.47; 95% confidence interval (CI), 0.28-0.79, for F. nucleatum-high vs.-negative category; P trend ¼ 0.0004] and specifically stromal CD3 þ CD4 þ CD45RO þ cells (corresponding multivariable OR, 0.52; 95% CI, 0.32-0.85; P trend ¼ 0.003). These relationships did not substantially differ by MSI status, neoantigen load, or exomewide tumor mutational burden. F. nucleatum was not significantly associated with tumor intraepithelial T cells or with M1 or M2 TAMs.Conclusions: The amount of tissue F. nucleatum is associated with lower density of stromal memory helper T cells. Our findings provide evidence for the interactive pathogenic roles of microbiota and specific immune cells.

Intratumor Microbiome Analysis Identifies Positive Association Between Megasphaera and Survival of Chinese Patients With Pancreatic Ductal Adenocarcinomas

“…If the Megasphaera sp. XA511 translocated to the tumor microenvironment, the intra-tumor bacteria could play a role in either the differentiation or proliferation of multiple tumor-infiltrating immune cells thus affecting the anti-cancer immune responses ( 48 – 50 ). Besides, the microbiota-derived STING agonists can also induce IFN-I production through monocytes in tumors, thereby making the tumor microenvironment more conducive for immune response ( 42 ).…”

Fusobacterium nucleatum Acts as a Pro-carcinogenic Bacterium in Colorectal Cancer: From Association to Causality

“…(3) Regarding its relationship with molecular features, intratumoral F. nucleatum is associated with high microsatellite instability, the CpG island methylator phenotype (CIMP) status, and certain gene mutations ( Tahara et al, 2014 ). In addition to the cancer cells, F. nucleatum is also associated with low CD3 + T cells ( Mima et al, 2015 ; Borowsky et al, 2021 ).…”

“…Epidemiological studies have revealed that a high abundance of F. nucleatum is associated with a low level of CD3 + T cells ( Mima et al, 2015 ), specifically CD3 + CD4 + CD45RO + cells ( Borowsky et al, 2021 ). This may be because F. nucleatum has a direct or indirect inhibitory effect on CD3 + T cells.…”

Tumor-Immune Partitioning and Clustering (TIPC): an algorithm for identifying tumor-immune cell spatial interaction signatures within the tumor microenvironment

“…Each slide was then treated with a nuclear counterstain 14',6-diamidino-2-phenylindole (DAPI) (FP1490, PerkinElmer). 36 Digital images were acquired using a Vectra 3.0 quantitative pathology imaging system (PerkinElmer) equipped with a 20× objective. Large areas with necrosis, artefact, or excessive tissue folding were excluded from analysis.…”