Lymphocytic Reaction to Colorectal Cancer Is Associated with Longer Survival, Independent of Lymph Node Count, Microsatellite Instability, and CpG Island Methylator Phenotype

Abstract

Purpose: Host immune response to tumor may be an important prognostic factor for colon cancer patients. However, little is known on prognostic significance of histopathologic lymphoid reaction to tumor, independent of the number of lymph nodes examined and tumoral molecular alterations, including microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP), both of which are associated with lymphocytic reaction and clinical outcome. Experimental Design: Using 843 colorectal cancer patients in two independent prospective cohorts, we examined patient prognosis in relation to four components of lymphocytic reaction (i.e., Crohn's-like reaction, peritumoral reaction, intratumoral periglandular reaction, and tumor-infiltrating lymphocytes) and overall lymphocytic score (0-12). CIMP was determined using eight markers including CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1. Cox proportional hazard models computed hazard ratio for mortality, adjusted for covariates including tumor stage, body mass index, lymph node count, KRAS, BRAF, p53, cyclooxygenase-2 (PTGS2), MSI, CIMP, and LINE-1 methylation. Results: Increasing overall lymphocytic reaction score including tumor-infiltrating lymphocytes was associated with a significant improvement in colorectal cancerspecific and overall survival (log-rank P < 0.003). These findings remained significant (adjusted hazard ratio estimates, 0.49-0.71; P trend < 0.009) in multivariate models that adjusted for covariates, including body mass index, MSI, CIMP, LINE-1 hypomethylation, and cyclooxygenase-2. The beneficial effect of tumoral lymphocytic reaction was consistent across strata of clinical, pathologic, and molecular characteristics. Conclusions: Lymphocytic reactions to tumor were associated with improved prognosis among colorectal cancer patients, independent of lymph node count and other clinical, pathologic, and molecular characteristics. (Clin Cancer Res 2009;15(20): 6412-20)

Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor

“…[24][25][26][27][28][29][30][31][32][33] As in this study, MSI tumors have previously been reported to have a higher degree of T-cell infiltration than MSS tumors. [35][36][37] Yet the potential confounding effect of MSI screening status on the prognostic importance of T-cell infiltration has been considered in only a minority of reports, of which most, 32,36,[39][40][41]46,53,54 but not all, 30,55 found that the better prognosis associated with dense T-cell infiltration was independent of MSI screening status. In this study, a better prognosis was seen in patients with MSS tumors densely infiltrated by T cells compared with poorly or intermediately infiltrated MSI tumors, whereas MSI screening status was not significantly related to prognosis in subgroups of highly and poorly infiltrated tumors separately.…”

“…Presence of peri-and intratumoral inflammatory cells has consistently been associated with a better prognosis in colorectal cancer. [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] Many of these reports have been based on routine hematoxylin and eosin stained tissue sections, but an increasing number of studies have used immunohistochemical markers such as the pan T-cell marker CD3. CD3 is a cell surface protein associated with the T-cell receptor.…”

“…34 CIMP-high and MSI tumors are frequently infiltrated by a large number of T cells. 4,[35][36][37][38] However, few large studies of tumor infiltrating T cells and colorectal cancer patient survival have taken into account the potentially confounding effect of MSI screening status, 30,32,[39][40][41][42] and only one other research group has considered CIMP. 32,42 Furthermore, T-cell infiltration can be assessed in various locations within the tumor, such as the tumor front, tumor center, and the intraepithelial compartment, but few studies have evaluated these separately.…”

“…4,[35][36][37][38] However, few large studies of tumor infiltrating T cells and colorectal cancer patient survival have taken into account the potentially confounding effect of MSI screening status, 30,32,[39][40][41][42] and only one other research group has considered CIMP. 32,42 Furthermore, T-cell infiltration can be assessed in various locations within the tumor, such as the tumor front, tumor center, and the intraepithelial compartment, but few studies have evaluated these separately. 32,33,37,[42][43][44][45][46][47] Although a beneficial effect on survival has generally been observed with higher degrees of infiltrating T cells, the prognostic value has varied in reports depending on the T-cell marker used, the compartment evaluated, and the confounders considered.…”

“…32,42 Furthermore, T-cell infiltration can be assessed in various locations within the tumor, such as the tumor front, tumor center, and the intraepithelial compartment, but few studies have evaluated these separately. 32,33,37,[42][43][44][45][46][47] Although a beneficial effect on survival has generally been observed with higher degrees of infiltrating T cells, the prognostic value has varied in reports depending on the T-cell marker used, the compartment evaluated, and the confounders considered.…”