Microsatellite Instability, EMAST, and Morphology Associations with T Cell Infiltration in Colorectal Neoplasia

Abstract

Background and Objectives Colorectal tumors are often observed with tumor infiltrating lymphocytes, presumably as a host-immune response, and patterns may segregate by types of genomic instability. Microsatellite unstable (MSI) colorectal cancers contain a pronounced lymphocyte reaction that can pathologically identify these tumors. Colorectal tumors with elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) have not been examined for lymphocyte patterns. Methods We evaluated a 108-person cohort with 24 adenomas and 84 colorectal cancers for MSI and EMAST. Immunohistochemical detection of CD4+ and CD8+ T cell infiltration were performed. Prognostic relevance was assessed by survival analysis. Results CD8+ T cell infiltration in the tumor cell nest (p=0.013) and tumor stroma (p=0.004) were more prominent in moderately- and poorly-differentiated adenocarcinoma than in adenoma and well-differentiated adenocarcinoma. CD8+ T cells in the tumor cell nest (p=0.002) and tumor stroma (p=0.009) were at higher density in tumors with ulcerating features compared with tumors with a sessile or polypoid appearance. MSI-H tumors showed a higher density of CD8+ T cell infiltrations in tumor cell nests (p=0.003) and tumor stroma (p=0.001). EMAST-positive tumors showed higher density of CD8+ T cell infiltrations than EMAST-negative tumors both in tumor cell nest (p=0.027) and in tumor stroma (p=0.003). These changes were not observed with CD4+ T lymphocytes. There was no difference in cancer patient survival based on density of CD8+ cells. Conclusions CD8+ T lymphocytes, but not CD4+ cells, were increased in tumor cell nests and the tumor stroma in both MSI and EMAST tumors, and showed higher infiltration in ulcerated tumors. CD8+ T lymphocyte infiltration is associated with both EMAST and MSI patterns, and increases with histological advancement.

<i>Fusobacterium nucleatum</i> Infection in Colorectal Cancer: Linking Inflammation, DNA Mismatch Repair and Genetic and Epigenetic Alterations

“…However, cumulative evidence shows that Fn infection affects the course of CRC carcinogenesis linked to DNA repair and genetic/epigenetic alterations. In conclusion, Fn -associated CRCs are located on the right side of the colon, are inflamed by ROS, and are associated with CIMP/MSI-H and MSI-L/EMAST (10,82,83). Fn -associated CRCs exhibit shorter RFS.…”

Correlation of Blood T-Cells to Intratumoural Density and Location of CD3+ and CD8+ T-Cells in Colorectal Cancer

“…However, there is a link between MSI and immune response in that previous studies have found that patients with MSI have a higher percentage of CD8 + T-cells, but a lower percentage of CD4 + T-cells in tumour compared to those with microsatellite stable (MSS) disease (16). Another form of MSI includes elevated microsatellite instability at selected tetranucleotide repeats (EMAST) (17), which has been associated with a higher density of CD8 + at tumour nests (18) and was included together with MSI in this study for comparison.…”

Colorectal Cancer: Sailing with a T-Cell EMAST

“…Interestingly in this study, EMAST best correlated in CRCs with ulcerated features, and the authors suggested that inflammation may help drive EMAST [12]. Along this same line, in this issue of Digestive Diseases and Sciences, Lee and colleagues provide intriguing new insights into this issue, which may help unravel the mystery surrounding the role of EMAST in colorectal neoplasia [15]. Based on the evidence for the presence of tumor infiltrating lymphocytes (TILs) in CRC, the authors asked the logical question whether there was any correlation between the pattern of cytotoxic lymphocytes infiltration and EMAST in CRC.…”

“…The present study by Lee et al [15] is not only first of its kind to evaluate the association between T cells and EMAST in CRC, but it is very timely, considering the increased recognition that disease progression in cancer patients is not solely determined by tumor characteristics alone, but is significantly influenced by the host response as well. Indeed, accumulating evidence suggests that both local and systemic inflammatory responses play an important role in the progression of a variety of solid tumors, including CRC [16,17].…”

“…T lymphocytes, but not CD4? cells, in tumor cell nests and tumor stroma are associated with moderately or poorlydifferentiated colorectal cancers, ulcerated lesions, MSI-H cancers and EMAST-positive CRCs [15].…”