Abstract
Tumour-infiltrating FoxP3+ regulatory T cells have been identified as both positive and negative prognostic factors in colorectal cancer (CRC) and rectal cancer (RC). In this study we investigated whether immune phenotypes, defined by CD8+ cytotoxic T cell density, may influence the prognostic association of FoxP3+ T cell densities in RC. Tissue microarrays from 154 rectal cancer resections were immunohistochemically double stained for CD8 and FoxP3. CD8+ and FoxP3+ cell densities were measured in the stromal and intraepithelial compartment. Stromal FoxP3+ cell densities were not associated with 10-year overall survival (OS). In the “immune-desert” phenotype, defined by very low stromal CD8+ cell density, a high density of stromal FoxP3+ T cells displayed a tendency towards an association with decreased 10-year OS (p = 0.179). In “inflamed” tumours, defined by high intraepithelial CD8+ T cell infiltration, the opposite was the case and high stromal FoxP3+ T cell densities were a positive prognostic factor (p = 0.048). Additionally, patients with an increased FoxP3/CD8 cell density ratio demonstrated a strong trend towards decreased 10-year OS (p = 0.066). These contrasting findings suggest functional heterogeneity within the group of FoxP3+ T cells. They are consistent with experimental studies which reported suppressive and non-suppressive populations of FoxP3+ T cells in CRC. Furthermore, our study demonstrates that CD8 immunohistochemistry may act as an instrument to identify tumours infiltrated by possibly functionally differing FoxP3+ T cell subtypes.
Highlights
The relevant relationship of immune cell infiltration in colorectal and rectal carcinomas (CRC) and patient prognosis has been established in numerous studies [1–4]
Cut-off values of these groups were defined by serial comparison of different CD8+ cell density thresholds for their impact on the prognostic significance of stromal forkhead box protein P3 (FoxP3)+ cell densities on overall survival (OS) and no-evidence-ofdisease survival rates (NED)
Tumours with stromal CD8+ cell densities of equal to or more than 40 cells/mm2 in combination with intraepithelial CD8+ cell densities of less than 170 cells/mm2 were assigned to the “immune-excluded” group, indicating a phenotype characterized by stromal accumulations of cytotoxic T cells with a simultaneous lack of intraepithelial infiltration (Figure 3D). 10-year OS was not associated with FoxP3+ cell densities in this group (Figure 3E)
Summary
The relevant relationship of immune cell infiltration in colorectal and rectal carcinomas (CRC) and patient prognosis has been established in numerous studies [1–4]. Treg are an important element of immunological tolerance, both for selftolerance in healthy tissue and locally in tumours [9, 10] Targeting this cell type is regarded as a promising approach for improving the response rate of current immunotherapies [11]. Even the fundamental question of whether increased Treg infiltration in CRC is a favourable or unfavourable prognostic factor is still undecided and several studies have reported conflicting results [13, 14]. In this immunohistochemical study we investigated the prognostic relevance of FoxP3+ T cell density in the context of different degrees of intratumoural inflammation as signified by CD8+ T cell infiltration. Our results offer a possible explanation for inconsistent findings on the role of Treg in previous studies and give insights into the intricacies of Treg functionality in cancers
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