Prognostic significance of SDF-1 in colorectal cancer depends on CD8+ T-cell density
Abstract Background: Since colorectal cancer (CRC) remains one of the most common malignancies, a tremendous amount of studies keep taking place in this field. Over the past 25 years, a notable part of the scientific community has focused on the association between the immune system and colorectal cancer. A variety of studies have shown that high densities of infiltrating CD8+ T cells are associated with improved disease-free and overall survival in colorectal cancer (CRC). Stromal cell-derived factor-1 (SDF-1) is a protein that regulates leukocyte trafficking and is variably expressed in several healthy and malignant tissues. There is strong evidence that SDF-1 has a negative prognostic impact on colorectal cancer (CRC). However, based on a significant correlation of SDF-1 and CD8+ T cells in a previous study (r=0.53, p<0.0001), we hypothesized that the prognostic significance of SDF-1 in CRC could depend on the immune microenvironment. Therefore, we explored the combined prognostic significance of SDF-1 expression and CD8+ T cell density in a large CRC collective. Methods: We analyzed a tissue microarray (TMA) of 613 patient specimens of primary CRCs by immunohistochemistry (IHC) for the expression of SDF-1 by tumor cells and tumor-infiltrating immune cells (TICs) and CD8+ T-cells. Besides, we analyzed the expression of SDF-1 at the RNA level in The Cancer Genome Atlas cohort (TCGA). Results: We found that the the combined high expression of SDF-1 and CD8+ T-cell infiltration shows a favorable 5-year overall survival rate (66%; 95%CI=48–79%) compared to tumors showing a high expression of CD8+ T-cells only (55%; 95%CI=45–64%; p=0.0004). High expression of SDF-1 and CD8+ T-cells infiltration was significantly associated with a favorable prognosis also in a validation group (p=0.016). Univariate and multivariate Hazard Cox regression survival analysis considering the combination of both markers revealed that the combined high expression of SDF-1 and CD8+ T cells was an independent, favorable, prognostic marker for overall survival (HR=0.34, 95%CI=0.17–0.66; p=0.002 and HR=0.45, 95%CI=0.23–0.89; p=0.021, respectively). In a spearman’s correlation analysis from the TCGA cohort, SDF-1 also correlated significantly with CD8+ T cells (r=0.28). Conclusions: SDF-1 high /CD8 high density represents an independent, favorable, prognostic condition in CRC, most likely due to an effective antigen-specific immune response.