Differential immune microenvironmental features of microsatellite-unstable colorectal cancers according to Fusobacterium nucleatum status

Lee, Ji Ae; Yoo, Seung Seok; Oh, Hyeon Jeong; Jeong, Seorin; Cho, Nam Yun; Kang, Gyeong Hoon; Kim, Tae-You

doi:10.1007/s00262-020-02657-x

Cited by 41 publications

(32 citation statements)

References 36 publications

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“…Quantification of the densities of tumor-infiltrating immune cells, including CD3 + T cells, CD8 + T cells, FoxP3 + T cells, CD68 + macrophages, and CD163 + macrophages, in CRCs was conducted using the QuPath-based computational image analysis method as previously described. 27…”

Section: Methodsmentioning

confidence: 99%

“…To efficiently perform IHC, tissue microarray (TMA) blocks of the 133 MSI-high CRCs, 308 MSS CRCs, 132 SSLs, 23 SSLDs, 45 TSAs, 100 HPs, 150 CALGs, and 115 CAHGs were constructed as previously described. 27 IHC using two different antibody clones against pan-TRK (EPR17341 clone, Abcam, Cambridge, UK; and A7H6R clone, Cell Signaling Technology, Danvers, MA, USA) was conducted on TMA slides of all of the 441 CRCs and 565 premalignant lesions. IHC staining using anti-MLH1 antibody (M1 clone, Ventana RTU, Roche, Basel, Switzerland) or anti-ALK antibody (D5F3 CDx Assay, Ventana RTU, Roche) was also performed on TMA slides of the 441 CRCs, 132 SSLs, and 23 SSLDs.…”

Section: Methodsmentioning

confidence: 99%

“…preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted March 30, 2021. ; https://doi.org/10.1101/2021.03.29.21253871 doi: medRxiv preprint 8 including CD3 + T cells, CD8 + T cells, FoxP3 + T cells, CD68 + macrophages, and CD163 + macrophages, in CRCs was conducted using the QuPath-based computational image analysis method as previously described. 27…”

Section: Clinicopathological Datamentioning

confidence: 99%

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NTRK oncogenic fusions are exclusively associated with the serrated neoplasia pathway in the colorectum and begin to occur in sessile serrated lesions

Kim

Hong²,

Choi

et al. 2021

Preprint

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Background: NTRK fusions are emerging tissue-agnostic drug targets in malignancies including colorectal cancers (CRCs), but their detailed landscape in the context of various colorectal carcinogenesis pathways remains to be investigated. Methods: Pan-TRK expression was assessed by immunohistochemistry in retrospectively collected colorectal epithelial tumor tissues, including 441 CRCs (133 microsatellite instability-high (MSI-high) and 308 microsatellite stable (MSS)) and 565 premalignant colorectal lesions (300 serrated lesions and 265 conventional adenomas). TRK-positive cases were subjected to next-generation sequencing and/or fluorescence in situ hybridization to confirm NTRK rearrangements. Results: TRK positivity was not observed in any of the MSS CRCs, conventional adenomas, traditional serrated adenomas, or hyperplastic polyps, whereas TRK positivity was observed in 11 of 58 (19%) sporadic MSI-high CRCs, 4 of 23 (17%) sessile serrated lesions with dysplasia (SSLDs), and 5 of 132 (4%) SSLs. The 11 TRK-positive MSI-high CRCs commonly harbored CpG island methylator phenotype-high (CIMP-high), MLH1 methylation, KRAS/BRAF wild-type, and NTRK1 or NTRK3 fusion (TPM3-NTRK1, TPR-NTRK1, LMNA-NTRK1, SFPQ-NTRK1, ETV6-NTRK3, or EML4-NTRK3). Both NTRK1 or NTRK3 rearrangement and KRAS/BRAF wild-type were detected in all nine TRK-positive SSL(D)s, seven of which demonstrated MSS and/or CIMP-low. TRK overexpression and early dysplastic changes are occasionally co-localized in the crypt base area of SSLs. Age-related occurrence patterns suggest that the progression interval from NTRK-rearranged SSLs to CRCs may be shorter than from BRAF-mutated SSLs to CRCs. Conclusion: NTRK-rearranged colorectal tumors develop exclusively through the serrated neoplasia pathway and can be initiated from non-dysplastic SSLs without KRAS/BRAF mutations prior to full occurrence of MSI-high/CIMP-high.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Clinicopathological Datamentioning

confidence: 99%

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NTRK oncogenic fusions are exclusively associated with the serrated neoplasia pathway in the colorectum and begin to occur in sessile serrated lesions

Kim

Hong²,

Choi

et al. 2021

Preprint

Self Cite

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“…It was revealed that F. nucleatum -high tumors are characterized by increased tumor growth and invasion, an immune microenvironment with decreased FoxP3 + T cells through the tumor and a high proportion of M2-macrophages in the tumor center. These findings correlate the presence of F. nucleatum with pro-cancerous immune responses in dMMR CRC tumors [ 100 ]. Other microorganisms of the gut microbiota, such as Bacteroides spp.…”

Section: Immunotherapy and Microbiota In Crcmentioning

confidence: 65%

Immunotherapy in Solid Tumors and Gut Microbiota: The Correlation—A Special Reference to Colorectal Cancer

Koulouridi

Messaritakis

Gouvas

et al. 2020

Cancers

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Over the last few years, immunotherapy has been considered as a key player in the treatment of solid tumors. Immune checkpoint inhibitors (ICIs) have become the breakthrough treatment, with prolonged responses and improved survival results. ICIs use the immune system to defeat cancer by breaking the axes that allow tumors to escape immune surveillance. Innate and adaptive immunity are involved in mechanisms against tumor growth. The gut microbiome and its role in such mechanisms is a relatively new study field. The presence of a high microbial variation in the gut seems to be remarkably important for the efficacy of immunotherapy, interfering with innate immunity. Metabolic and immunity pathways are related with specific gut microbiota composition. Various studies have explored the composition of gut microbiota in correlation with the effectiveness of immunotherapy. Colorectal cancer (CRC) patients have gained little benefit from immunotherapy until now. Only mismatch repair-deficient/microsatellite-unstable tumors seem to respond positively to immunotherapy. However, gut microbiota could be the key to expanding the use of immunotherapy to a greater range of CRC patients.

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“…nucleatum is associated with a high degree of microsatellite instability (MSI-high) and CpG island methylator phenotype in colorectal carcinoma, suggesting that this bacteria is involved in a molecular specific CRC subtype (113,114). MSI-high CRCs tumors with high F. nucleatum load are more invasive, show low FOXP3 + density and elevated CD163 + cells (M2 macrophages), supporting the bacterial pro-tumoral role (115).…”

Section: Enterococcus Faecalismentioning

confidence: 89%

Immune System, Microbiota, and Microbial Metabolites: The Unresolved Triad in Colorectal Cancer Microenvironment

et al. 2021

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Colorectal cancer (CRC) is one of the most common cancers worldwide. As with other cancers, CRC is a multifactorial disease due to the combined effect of genetic and environmental factors. Most cases are sporadic, but a small proportion is hereditary, estimated at around 5-10%. In both, the tumor interacts with heterogeneous cell populations, such as endothelial, stromal, and immune cells, secreting different signals (cytokines, chemokines or growth factors) to generate a favorable tumor microenvironment for cancer cell invasion and metastasis. There is ample evidence that inflammatory processes have a role in carcinogenesis and tumor progression in CCR. Different profiles of cell activation of the tumor microenvironment can promote pro or anti-tumor pathways; hence they are studied as a key target for the control of cancer progression. Additionally, the intestinal mucosa is in close contact with a microorganism community, including bacteria, bacteriophages, viruses, archaea, and fungi composing the gut microbiota. Aberrant composition of this microbiota, together with alteration in the diet‐derived microbial metabolites content (such as butyrate and polyamines) and environmental compounds has been related to CRC. Some bacteria, such as pks+ Escherichia coli or Fusobacterium nucleatum, are involved in colorectal carcinogenesis through different pathomechanisms including the induction of genetic mutations in epithelial cells and modulation of tumor microenvironment. Epithelial and immune cells from intestinal mucosa have Pattern-recognition receptors and G-protein coupled receptors (receptor of butyrate), suggesting that their activation can be regulated by intestinal microbiota and metabolites. In this review, we discuss how dynamics in the gut microbiota, their metabolites, and tumor microenvironment interplays in sporadic and hereditary CRC, modulating tumor progression.

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Differential immune microenvironmental features of microsatellite-unstable colorectal cancers according to Fusobacterium nucleatum status

Cited by 41 publications

References 36 publications

NTRK oncogenic fusions are exclusively associated with the serrated neoplasia pathway in the colorectum and begin to occur in sessile serrated lesions

NTRK oncogenic fusions are exclusively associated with the serrated neoplasia pathway in the colorectum and begin to occur in sessile serrated lesions

Immunotherapy in Solid Tumors and Gut Microbiota: The Correlation—A Special Reference to Colorectal Cancer

Immune System, Microbiota, and Microbial Metabolites: The Unresolved Triad in Colorectal Cancer Microenvironment

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