Immune system and prognosis in colorectal cancer: a detailed immunohistochemical analysis

Abstract

The efficacy of tumor cell-immune cell interactions depends on a number of factors, for example, the expression of HLA-I on tumor cells, the type of immune cell, the accessibility of tumor cells for immune cells and the expression of immunogenic epitopes. We assessed infiltration of CD4 þ , CD8 þ , CD56 þ and CD57 þ cells in the tumor epithelium, tumor stroma and advancing tumor margin of 93 colorectal carcinomas and correlated this to clinicopathological parameters, the expression of HLA-A and HLA-B/C on tumor cells, the presence of a basal membrane (BM)-like structure surrounding tumor nodules and the presence of microsatellite instability/ mutator phenotype (absent MLH-1 expression). The median intraepithelial CD4 þ , CD8 þ , CD56 þ and CD57 þ cell infiltrations were 3, 23, 0 and 0 cells/mm 2 tumor, respectively. HLA-A/BC expression by tumor cells was normal in 28/43%, heterogeneous in 59/48% and absent in 13/9% of the cases. A BM-like structure surrounding the tumor nodules was absent, present and thick in 47, 38 and 15% of the cases. Six cases lost MLH1 expression. There was a positive correlation between leukocyte infiltration in the three compartments for CD4 þ , CD8 þ , CD56 þ (partly) and CD57 þ (all Po0.05) cell infiltration. Intraepithelial CD8 þ cell infiltration inversely correlated with HLA-A (P ¼ 0.04) and HLA-B/C expression (P ¼ 0.04). Intraepithelial CD57 þ cell infiltration inversely correlated with HLA-B/C expression (P ¼ 0.04). Moreover, intraepithelial infiltration of CD8 þ and CD57 þ cells was inversely correlated to the presence of a BM-like structure (P ¼ 0.003 and 0.04, respectively). Uni-and multivariate analyses showed that a lower tumor stage (P ¼ 0.004) and marked infiltration of CD8 þ (P ¼ 0.04) and CD57 þ cells (P ¼ 0.05) at the advancing tumor margin were independent prognostic factors for a longer diseasefree survival. Loss of MLH1 expression was correlated with a significantly higher intraepithelial CD8 þ and CD57 þ cell infiltration. We conclude that infiltration of CD8 þ and CD57 þ cells are important prognostic factors in colorectal cancer. However, their interaction with tumor cells is inversely correlated to the presence of HLA-I on tumor cells and a thick BM-like structure around tumor islets. Our data indicate that NK cells might play an important role in the immune surveillance in colorectal cancer patients.

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

“…58 T-cell infiltration is not homogeneous in colorectal cancer, and attention has therefore also been focused on the predictive values of T cells in different tumor compartments. 32,33,37,[42][43][44][45][46][47] In this study, the separate measurements of T-cell infiltration in the tumor front, center, and intraepithelial compartment were closely correlated and were all positively associated with cancer-specific survival. Two previous studies found that a high total lymphocyte score, similar to that used in this study, more accurately predicted cancer-specific survival compared with any single score separately.…”

“…[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.…”

“…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.…”

“…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.…”

Evaluating immune responses after sipuleucel-T therapy

“…Using IHC techniques, Menon et al 9 analyzed resected colorectal cancer samples from 93 patients with stage II/III colon cancer, and found that both higher CD 8 C (P D 0.04) and CD 57C (P D 0.05) cell infiltration within the tumor margin correlated with prolonged disease free survival in multivariate analysis. After an immunohistochemical analysis of 843 colorectal cancer specimens, Ogino et al 10 found that intra-tumor as well as peri-tumor lymphocytic infiltration were both associated with longer OS (P D 0.005 and P D 0.014 respectively).…”