Abstract
Background: The genetic alterations in colorectal cancer (CRC) progression are determined by two separate pathways, chromosomal and microsatellite instability (MSI). The CRCs with MSI have distinct clinicopathological characteristics with pronounced tumor-associated immune responses. The aim of our study was to investigate the intensity of host immune response in CRC tissue by comparing microsatellite stable (MSS) and instable tumors. Methods: The study was performed on CRC specimens from 28 patients with MSI and compared with 30 MSS tumors. The microsatellite status was evaluated with two markers by PCR and melting point analysis. The immunostaining with anti-CD3 pan-T cell antibody was used to quantify the number of tumor infiltrating lymphocytes. The lymphocytes in peritumoral stromal and the Crohn?s-like peritumoral reaction were counted on H&E slides. Results: No significant differences were found in the average number of lymphocytes in peritumoral stroma and in clinicopathological characteristics of CRCs. The conspicuous Crohn?s-like lymphoid reactions were present in 67.86% of CRCs with MSI versus 26.66% of MSS cases. The CRCs with MSI cases carried significantly higher numbers of tumor infiltrating T-lymphocytes (13.21 versus 7.47) (p<0.0001). Conclusion: The presences of peritumoral Crohn?s-like lymphoid and intraepithelial lymphocytic reaction were intensive markers for MSI in colorectal carcinomas in our study. The peculiar genetic instability in MSI tumors may lead to a continuous production of abnormal peptides, which act as neoantigens. They could induce specific antitumor immune responses effective in limiting tumor growth and spread. Abnormal peptides are potentially promising in immunotherapy advancing and in the design of a vaccine against colorectal tumors with MSI.
Highlights
The genetic alterations in colorectal cancer progression are determined by one of two separate and distinct underlying pathways of genomic instability
Tumors with instability in one marker are nominated as low-level instability (MSI-L), or showing no instability was designated as microsatellite stable (MSS) tumors [3]
There were no significant differences in the average number of lymphocytes in peritumoral stroma and clinicopathological characteristic of colorectal cancer (CRC)
Summary
The genetic alterations in colorectal cancer progression are determined by one of two separate and distinct underlying pathways of genomic instability. The second pathway, microsatellite instability (MSI), is characterized by an abundance of subtle DNA mutations and diploidy. The replication machinery slips more frequently on repetitive sequences, so microsatellite sequences accumulate mutations in MMR-deficient cells, which results in MSI (or replication error). Tumors with instability at two or more of these markers were defined as being high-level instability (MSI-H). In 1997, methylation of the promoter region and transcriptional silencing of mlh gene was shown to occur in CRCs [7], and caused MSI seen in 15% unselected sporadic cancers of the large bowel [1,2]. Almost every description of MSI in CRCs noted a sign of pronounced tumor-associated immune responses in form of explicit peritumoral inflammatory reaction and lymphoid nodules (the so-called Crohn's-like lymphoid reaction) and high number of intraepithelial activated cytotoxic lymphocytes [13,14]. The last updated evidence-based clinical practice guidelines of American Society of Clinical Oncology for the use of tumor www.onk.ns.ac.yu/Archive Vol 15, no 1-2, July 2007
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