Compared to MSS tumors, both sporadic and hereditary MSI-H cancers from patients with Lynch syndrome (hereditary selleck chemical non-polyposis coli; HNPCC) are characterized by prolonged survival time, significantly more frequent PTL inflammation at the invasive front and by an inherent abundance of intra-epithelial TILs[87-94]. In contrast to MSS tumors which primarily arise following disruption of WNT signalling, sporadic MSI-H tumors are linked to mutations in TGF��RII[95,96]. Baker et al[97] hypothesized that retention of TILs in MSI-H cancers may be a consequence of refractoriness to normal TGF-�� signalling. In a subsequent study, these authors show in more than 1000 MSS and 223 MSI tumors that an abundant CD8+ TIL infiltrate has a beneficial effect on survival time in MSS, but not MSI cancers[71].
Other authors confirm the abundance of CD8+ TILs and granzyme-positive cells as well as improved clinical outcome in patients with MSI-H compared to MSS colorectal cancers[98-100]. In addition, a positive correlation between apoptosis rates and higher TIL number has been described, a finding which could perhaps help to explain the improved prognosis seen in patients with MSI-H compared to MSS tumors[98,101]. Studies on T-regs such as FOXP3 and CD25+ have recently been undertaken[102]. Drescher et al[102], evaluating both MSS and MSI-H cancers found that in contrast to CD8+ T-cells which may be involved in actively preventing growth and/or metastatic in MSI-H tumors, CD25+ cell counts were similar between MSS and MSI-H tumors suggesting no active immunosuppressive mechanisms in MSS cancers.
Finally, the upregulation in MSI-H cancers of a large number of genes involved in immune response and increased levels of pro-inflammatory cytokines and cytotoxic mediators indicate an activated anti-tumor immune response in these tumors[86]. THE INVASIVE FRONT OF COLORECTAL CANCER: A BALANCE OF PRO- AND ANTI-TUMOR FACTORS Several observations have led to the hypothesis that tumor progression and prognosis in patients with colorectal cancer is not based solely on the presence of pro-tumor or absence of anti-tumor factors but rather on the balance between the two. First, the presence of tumor buds is inversely correlated with the presence of PTL inflammation and intra-epithelial CD8+ TILs[9,21].
In MSI-H cancers, where intra-epithelial TILs are abundant, PTL inflammation ��encapsulating�� Entinostat the tumor at the invasive front and pushing tumor border are commonly seen, tumor budding is virtually absent[20]. When it occurs, tumor budding in the MSI-H lacks the full budding immunophenotype and the cytoplasmic podia which give budding cells a temporal dimension[20]. In a previous study on MSS colorectal cancers, we hypothesized that an intense peritumoral inflammatory reaction at the invasive front could be ��nipping colorectal cancer in the bud�� by specifically targeting budding cells for destruction[9].