Prognostic value of tumor-infiltrating immune cells in primary colorectal cancer and metastases

Abstract

Background Precise prognostic biomarkers are urgently needed to improve treatment and hence prognosis for patients with metastasized colorectal carcinoma. Tumor-infiltrating CD3 and CD8 positive lymphocytes have been shown to robustly predict survival of colorectal cancer in stages I-III in retro- and prospective studies. Their clinical value in metastasized tumors or the role of other types of immune cells is not well known. Methods We performed a detailed characterization of tumor infiltrating immune cells of primary colorectal cancer and metastases of 55 patients. Immune infiltrates were assessed visually and digitally. Results High densities of CD3, CD8, CD20, CD4, CD45R0, CD68, FOXP3, PD1 and PD-L1- positive cells in both primary colorectal cancer and metastases were significantly associated with prolonged survival in univariate and multivariate analysis. For CD3-CD8 immunoscore, CD8-CD20 TB cell score, CD45R0, CD68 and PD1 the evaluation of metastatic immune infiltrates showed superior hazard ratios, compared to evaluation of primary tumor-infiltrating immune cells (hazard ratio = 9.2; 5.7; 8.9; 5.7; 6.0, respectively). In case of FOXP3, CD4 and PD-L1 the combined evaluation of primary and metastatic immune infiltrates increased prognostic precision even further (hazard ratio = 5.7; 19.6 and 8.5, respectively). Visual analysis confirmed digital image analysis, but showed inferior hazard ratios. Conclusions A broad range of types of immune infiltrates predicts longer survival in metastasized colorectal cancer patients. Of all immune infiltrates, CD4 showed the highest prognostic precision. The combined assessment in primary colorectal cancer and metastases is valuable in most cases. Thus, automated digital analysis of immune infiltrates in colorectal metastases could improve the prognostic stratification of patients.