Tumour-infiltrating Lymphocytes and Radiation Therapy in Rectal Cancer: Systematic Review and Meta-analysis

Aim: Tumour-infiltrating lymphocytes (TILs) represent a promising cancer biomarker. Different TILs, including CD8+, CD4+, CD3+, and FOXP3+, have been associated with clinical outcomes. However, data are lacking regarding the value of TILs for patients receiving radiation therapy (RT). We conducted a systemic review and meta-analysis of available data evaluating TILs for patients receiving curative-intent therapy including RT. Materials and Methods: Eligible studies presented a defined cohort of patients who all received curative-intent therapy, including RT, and also reported the relationship between any TIL score and either tumour response or survival outcomes. After comprehensive search of online databases (PubMed, EMBASE, Cochrane, and Web of Science), 2 authors conducted title, abstract, and whole-text review for quality and risk of bias following Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Data from publications that met quality criteria were grouped via (1) TIL analysed, (2) pre- or post-RT TIL assessment, and (3) clinical outcome measured. Results: Initial search yielded 669 unique studies. Thirty-one studies met quality criteria, of which 20 studied rectal cancer (RC), 4 oesophageal, 3 pancreas, 2 lung, cervical/uterine 1 each. We conducted systematic review and meta-analysis of the RC publications. All except 2 were single-institutional cohort studies. After meta-analysis, the pre-RT epithelial CD8+ (p = 0.04) and stromal FOXP3+ (p = 0.01) counts were associated with survival without disease, while pre-RT epithelial (p = 0.02) and stromal (p = 0.001) FOXP3+ TILs were associated with overall survival. On post-RT analysis, epithelial (p = .04) and stromal (p = 0.02) CD8+ TILs were associated with survival without disease and epithelial CD8+ TILs were associated with overall survival (p = 0.01).Preoperative CD8+ and FOXP3+ TILs were generally associated with tumour response to RT, but meta-analysis was not conducted due to heterogeneity of response measurement techniques. Conclusion: TILs represent a useful parameter for tumour response and survival outcomes for patients receiving curative-intent therapy, including RT for RC. Future work should aim to standardise TIL measurement and quantification methods and to develop protocols to clarify clinical application of these findings.