Abstract
Tumor-infiltrating lymphocytes (TILs) are an important histopathologic feature of colorectal cancer that confer prognostic information. Previous clinical and epidemiologic studies have found that the presence and quantification of tumor-infiltrating lymphocytes are significantly associated with disease-specific and overall survival in colorectal cancer. We performed a systematic review and meta-analysis, establishing pooled estimates for survival outcomes based on the presence of TILs in colon cancer. PubMed (Medline), Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched from inception to April 2017. Studies were included, in which the prognostic significance of intratumoral tumor infiltrating lymphocytes, as well as subsets of CD3, CD8, FOXP3, CD45R0 lymphocytes, were determined within the solid tumor center, the invasive margin, and tumor stroma. Random-effects models were calculated to estimated summary effects using hazard ratios. Forty-three relevant studies describing 21,015 patients were included in our meta-analysis. The results demonstrate that high levels of generalized TILS as compared to low levels had an improved overall survival (OS) with a HR of 0.65 (p = <0.01). In addition, histologically localized CD3+ T-cells at the tumor center were significantly associated with better disease-free survival (HR = 0.46, 95% CI 0.36–0.61, p = 0.05), and CD3 + cells at the invasive margin were associated with improved disease-free survival (HR = 0.57, 95% CI 0.38–0.86, p = 0.05). CD8+ T-cells at the tumor center had statistically significant prognostic value on cancer-specific survival and overall survival with HRs of 0.65 (p = 0.02) and 0.71 (p < 0.01), respectively. Lastly, FOXP3+ T-cells at the tumor center were associated with improved prognosis for cancer-specific survival (HR = 0.65, p < 0.01) and overall survival (HR = 0.70, p < 0.01). These findings suggest that TILs and specific TIL subsets serve as prognostic biomarkers for colorectal cancer.
Highlights
Among the 3,789 studies identified for initial evaluation, 1,963 studies were eligible for further assessment based on pre-specified criteria
Systematic literature search of Medline, Embase, Web of Science, and Scopus databases using pre-determined inclusion criteria, we identified 43 studies published between August 1997 and April 2017 that evaluate specific marker subset populations of tumor infiltrating lymphocytes in CRC and survival outcomes
We separately considered Generalized TIL density, CD3, CD8, FOXP3, CD45R0 as the focus of our meta-analysis, recognizing that there are other systems of scoring the host immune response that are beyond the scope of the current meta-analysis
Summary
We developed a protocol based on standard guidelines for the systematic review of prognostic studies and followed suggestions on updating systematic reviews as outlined by Moher et al.. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements for reporting our systematic review. A librarian (LK) developed searches using a combination of keywords and controlled vocabulary (when available) in the following databases: PubMed (Appendix 1), Embase (Appendix 2 & 3), initially through OvidSP and later via Elsevier, Cochrane Library (Appendix 4), Web of Science (Appendix 5), and ClinicalTrials.gov (1997 to April 2017). We search grey literature sources (https// www.usa.gov, https://scholar.google.com) to identify relevant publications. We evaluated reference lists of previously published systematic reviews and meta-analysis
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