Abstract
BackgroundT-lymphocyte infiltration into colon carcinomas can influence clinical outcome, and interactions among T cell subsets may be more informative than either subset alone. Our objective was to examine the prognostic impact of tumor-infiltrating FoxP3+ regulatory T cells (Tregs) in relation to cytotoxic CD8+ T lymphocytes in patients with colon carcinomas characterized by DNA mismatch repair (MMR) status who participated in adjuvant chemotherapy trials.MethodsFoxP3+ and CD8+ densities in tumor epithelial and stromal compartments were analyzed by immunohistochemistry and quantified in resected, stage II and III colonic carcinomas (N = 216). Immune marker density was dichotomized at the median and categorized as high vs low. MMR status was classified as MMR deficient (dMMR) or proficient (pMMR). Cox models were adjusted for age, stage, and tumor grade.ResultsThe density of FoxP3+ infiltration was similar in tumor stroma and epithelia, whereas CD8+ was higher in stroma. The prognostic impact of FoxP3+ and CD8+ T cell infiltration was stronger in stroma vs epithelia, and the density of each marker in stroma was independently associated with improved overall survival (OS). However, the impact of FoxP3+ on survival was dependent upon CD8+ density (P interaction = .040). Among CD8+low tumors, FoxP3+high cases had significantly improved OS compared to FoxP3+low cases after adjustment for covariates (hazard ratio 0.43; 95% confidence interval 0.19 to 0.95; P = .030). In contrast, FoxP3+ was not prognostic among CD8+high tumors. FoxP3+ remained prognostic in CD8+low tumors after further adjustment for MMR or BRAF V600E mutation status. Additionally, these immune markers identified a pMMR subgroup with a similarly favorable OS as for dMMR tumors.ConclusionsThe prognostic impact of FoxP3+ and CD8+ T cell density are inter-dependent, whereby FoxP3+ exerts a favorable influence on survival only in colon cancers with low CD8+ infiltration.
Highlights
Studies in patients with colorectal cancer (CRC) suggest that the density of tumor infiltrating lymphocytes (TILs) strongly influences clinical outcome [1,2,3]
We previously found that a high density of TILs in colon cancers is associated with increased tumor cell apoptosis [6]
In the overall study cohort, we found that 19 cases carried the BRAFV600E mutation (15.2%)
Summary
Studies in patients with colorectal cancer (CRC) suggest that the density of tumor infiltrating lymphocytes (TILs) strongly influences clinical outcome [1,2,3]. High intratumoral density of CD3+ and cytotoxic CD8+ lymphocytes, as well as CD45RO+ memory T cells, has been associated with reduced incidence of tumor metastasis and favorable prognosis [1,2]. This finding suggests that clinical outcome could be governed, in large part, by the status of the local adaptive immune response. Our objective was to examine the prognostic impact of tumorinfiltrating FoxP3+ regulatory T cells (Tregs) in relation to cytotoxic CD8+ T lymphocytes in patients with colon carcinomas characterized by DNA mismatch repair (MMR) status who participated in adjuvant chemotherapy trials
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