Abstract
BackgroundHistological lymphocytic reaction is regarded as an independent prognostic marker in colorectal cancer. Considering the lack of adequate statistical power, adjustment for selection bias and comprehensive tumour molecular data in most previous studies, we investigated the strengths of the prognostic associations of lymphocytic reaction in colorectal carcinoma by utilising an integrative database of two prospective cohort studies.MethodsWe examined Crohn’s-like reaction, intratumoural periglandular reaction, peritumoural reaction and tumour-infiltrating lymphocytes in 1465 colorectal carcinoma cases. Using covariate data of 4420 colorectal cancer cases in total, inverse probability-weighted Cox proportional hazard regression model was used to control for selection bias (due to tissue availability) and potential confounders, including stage, MSI status, LINE-1 methylation, PTGS2 and CTNNB1 expression, KRAS, BRAF and PIK3CA mutations, and tumour neoantigen load.ResultsHigher levels of each lymphocytic reaction component were associated with better colorectal cancer-specific survival (Ptrend < 0.002). Compared with cases with negative/low intratumoural periglandular reaction, multivariable-adjusted HRs were 0.55 (95% CI, 0.42–0.71) in cases with intermediate reaction and 0.20 (95% CI, 0.12–0.35) in cases with high reaction. These relationships were consistent in strata of MSI status or neoantigen loads (Pinteraction > 0.2).ConclusionsThe four lymphocytic reaction components are prognostic biomarkers in colorectal carcinoma.
Highlights
Histological lymphocytic reaction is regarded as an independent prognostic marker in colorectal cancer
In 1465 cases, we examined lymphocytic reaction patterns: tumour-infiltrating lymphocytes (TIL, 1461 cases), intratumoural periglandular reaction (1462 cases), peritumoural lymphocytic reaction (1456 cases) and Crohn’s-like lymphoid reaction (1195 cases) (Table 1; Supplementary Table S1)
Utilising two US prospective cohort studies, we found that higher levels of each of four lymphocytic reaction components, and higher overall lymphocytic reaction score, were strongly associated with better colorectal cancer survival
Summary
Histological lymphocytic reaction is regarded as an independent prognostic marker in colorectal cancer. Considering the lack of adequate statistical power, adjustment for selection bias and comprehensive tumour molecular data in most previous studies, we investigated the strengths of the prognostic associations of lymphocytic reaction in colorectal carcinoma by utilising an integrative database of two prospective cohort studies. Host immune response in the tumour microenvironment plays a critical role in regulating cancer initiation and progression.[1,2,3,4] Histological lymphocytic reaction that reflects host immune response to tumour cells can be evaluated by Crohn’s-like lymphoid reaction, peritumoural lymphocytic reaction, intratumoural periglandular reaction and tumour-infiltrating lymphocytes (TIL).[5] Accumulating evidence indicates that colorectal cancer with microsatellite instability (MSI)-high status is characterised by higher lymphocytic reaction, because of potentially immunogenic neoantigens generated by frameshift mutations due to defective DNA mismatch repair.[5,6,7,8] higher neoantigen load has been positively associated with overall lymphocytic infiltration, TIL, memory T cells and better colorectal cancer-specific survival.[9,10] In addition, the specific tumour molecular alterations, including PTGS2 expression,[11] nuclear CTNNB1 expression,[12] CpG island methylator phenotype (CIMP) status[13] and long-interspersed nucleotide element-1 (LINE-1) methylation levels,[14] can modify. We examined statistical interactions between lymphocytic reaction and MSI status or neoantigen load
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