Characterization of tumour‐infiltrating lymphocytes and apoptosis in colitis‐associated neoplasia: comparison with sporadic colorectal cancer

Abstract

The development of colorectal cancer is a major complication for patients with chronic idiopathic colitis. Colitis-associated tumours tend to occur at a younger age and be more aggressive than sporadic colorectal cancers. While we have previously associated the presence of tumour-infiltrating lymphocytes (TILs) and increased apoptosis in sporadic colorectal cancer with high-level microsatellite instability and improved prognosis, little is known of the relationship between these variables in colitis-associated colorectal cancer. The aim of this study was to correlate TILs and tumour cell apoptosis in colitis-associated neoplasms stratified according to microsatellite instability. Twenty tumour and 11 dysplastic samples resected from 21 patients with long-standing colitis were analysed for microsatellite instability at 10 microsatellite markers. TIL distribution (CD3, CD8) and function (granzyme B) were quantified by immunohistochemistry. Neoplastic cell apoptosis was assessed using the M30 CytoDEATH antibody. These findings were compared with 40 microsatellite stable (MSS) sporadic colorectal cancers previously evaluated for TILs and neoplastic apoptosis. Low-level microsatellite instability was found in 1/20 colitis-associated tumours. All other colitis-associated lesions were designated MSS. CD3(+) and CD8(+) TIL counts were significantly higher in colitis-associated lesions compared with MSS sporadic colorectal cancer (p < 0.0001, p = 0.001 respectively). Despite their higher TIL density, colitis-associated tumours were more likely to present late (Dukes' stage C or D) (p = 0.02). Functionally, colitis-associated TILs demonstrated significantly less granzyme B expression compared to sporadic cancers (p = 0.002). The level of tumour cell apoptosis was similar between the two groups (sporadic, 1.53%; colitis cancers, 1.45%). In conclusion, MSS colitis-associated tumours have a higher prevalence of CD3(+)/CD8(+) TILs but no associated increase in tumour cell killing by apoptosis. Unlike cytotoxic T cells in sporadic colorectal cancer, TILs do not appear to enhance the prognosis of colitis-associated colorectal cancer. This may be related to an impairment of granzyme B expression within these lesions.

Immunoprofiling of Colitis-associated and Sporadic Colorectal Cancer and its Clinical Significance

“…The only study so far that evaluated T cells in colitis-associated dysplasia compared to sporadic CRC using a quantified IHC method was conducted by Michael-Robinson et al . 16 . In that report, the counts of CD3 + and CD8 + cells were significantly higher in colitis-associated lesions than in sporadic cancer, which is contrary to our study.…”

Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability

“…While increased TILs are associated with the MSI‐H phenotype,9, 10, 11 their relationship to apoptosis, cell proliferation and the prognosis is incompletely understood. Furthermore, colitis‐associated colon tumors arising in a background of inflammation have increased TILs but no associated increase in tumor cell apoptosis 15. Production of cytokines by TILs may regulate tumor cell growth and in this regard, TIL have been shown to secrete significant amounts of IFN‐γ 16.…”

From Colitis to Cancer: An Evolutionary Trajectory That Merges Maths and Biology

“…In one revealing study, Galon et al have demonstrated that simple measurements of CD3 and CD8 cell infiltration in the tumor core and invasive margin ( 68 ) of sporadic CRCs are superior to clinical TNM staging ( 69 ) and genetic microsatellite instability status ( 70 ) in predicting patient prognosis. The aberrant immune function that is characteristic of IBD may manifest itself in cancer immune-epithelium co-evolution: for example, IBD-CRC demonstrates greater lymphocyte infiltration compared to sporadic CRC, but with no associated prognostic improvement ( 71 ). This may be explained by impaired lymphocyte cytotoxicity in IBD, as reflected by reduced cancer cell apoptosis and lower granzyme B expression in lymphocytes infiltrating IBD-CRC compared to sporadic CRC.…”