Prognostic Impact of Tumor-Infiltrating Lymphocytes in Primary and Metastatic Colorectal Cancer: A Systematic Review and Meta-analysis

BACKGROUND: There is increasing literature emerging on the significance of tumor-infiltrating lymphocytes in colorectal cancer. However, there have been inconsistent findings, secondary to small patient numbers and varied methods for identifying these lymphocytes. OBJECTIVE: The aim of this study was to determine the prognostic and predictive power of tumor-infiltrating lymphocytes in colon, rectal (in neoadjuvant setting), and metastatic colorectal cancer. DATA SOURCES: A comprehensive search of PubMed and Embase was undertaken from January 2006 to December 2016. STUDY SELECTION: The inclusion criteria included a description of the tumor-infiltrating lymphocyte subset(s) assessed with reporting of associated short-and long-term outcomes. MAIN OUTCOME MEASURES: The main outcome measures, were disease-free and overall survival. RESULTS: A total of 25 studies were included, 15 for primary colorectal cancer (4719 patients), 7 for locally advanced rectal cancer (727 patients), and 3 studies for metastatic colorectal cancer (418 patients). High CD3(+), CD8(+), FoxP3(+), and CD45RO(+) densities were associated with improved overall survival for primary colorectal cancer, with pooled estimated HRs of 0.88, 0.81, 0.70, and 0.63 (all p < 0.001) respectively. Furthermore, in locally advanced rectal cancer, the levels of CD8(+) cells were a significant predictor of good tumor regression grade after chemoradiotherapy. LIMITATIONS: The retrospective nature of included studies and the significant interstudy heterogeneity were limitations. CONCLUSIONS: There is increasing evidence that tumor-infiltrating lymphocytes play an important role in predicting prognosis in colorectal cancer and tumor regression after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Clinical researchers are now in a unique position to build on this work to identify robust predictive markers to stratify patients not only to currently available therapies but also to immunotherapy, which has demonstrated success in improving patient outcomes.