Abstract
Simple SummaryThis study investigated tumor-infiltrating lymphocytes (TILs) in pretherapeutic biopsies as biomarkers of treatment response and long-term prognosis in patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy. A systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. The results indicate that it is possible to identify a sub-group of patients with improved treatment response and long-term prognosis by assessing the density of CD8+ TILs at the time of diagnosis.Neoadjuvant chemoradiotherapy (NCRT) is indicated in locally advanced rectal cancer (LARC) to downstage tumors before surgery. Watchful waiting may be a treatment option to avoid surgery in patients, obtaining a complete clinical response. However, biomarkers predictive of treatment response and long-term prognosis are lacking. Here we investigated tumor-infiltrating lymphocytes (TILs) in pretherapeutic biopsies as predictive and prognostic biomarkers. A systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. In total, 429 articles were identified, of which 19 studies were included in the systematic review and 14 studies in the meta-analysis. Patients with high pretherapeutic CD8+ TILs density had an increased likelihood of achieving a pathological complete response (RR = 2.71; 95% CI: 1.58–4.66) or a complete or near-complete pathological treatment response (RR = 1.86; 95% CI: 1.50–2.29). Furthermore, high CD8+ TILs density was a favorable prognostic factor for disease-free survival (HR = 0.57; 95% CI: 0.38–0.86) and overall survival (HR = 0.43; 95% CI: 0.27–0.69). CD3+, CD4+, and FOXP3+ TILs were not identified as predictive or prognostic biomarkers. Thus, assessing pretherapeutic CD8+ TILs density may assist in identifying patients with increased sensitivity to NCRT and favorable long-term prognosis.
Highlights
This article is an open access articleNeoadjuvant chemoradiotherapy (NCRT) is indicated in patients with locally advanced rectal cancer (LARC) to downstage tumors before surgery
The five studies ineligible in the meta-analysis were due to the following reasons: Three studies were excluded from the meta-analysis as the subgroups of tumorinfiltrating lymphocytes (TILs) were not dichotomized into high or low-density groups for each individual marker [38,39,41], whereas two were ineligible as the studies included patients that did not undergo curatively intended treatment [11,40]
CD4+ TILs density was not correlated with significant changes in pathological treatment response (pTR) (RR = 1.23; 95% confidence intervals (CIs): 0.83–1.82, p = 0.19) (Figure S2, Supplemental)
Summary
This article is an open access articleNeoadjuvant chemoradiotherapy (NCRT) is indicated in patients with locally advanced rectal cancer (LARC) to downstage tumors before surgery. NCRT, a complete clinical response is observed in 10–40% of patients [1]. Treatment response is associated with an unfavorable long-term prognosis [2]. The achievement of complete response is affected by the initial clinical UICC stage, pathological subtype, pretherapeutic carcinoembryonic antigen levels, and other currently unidentified factors [1,4]. Some studies have identified the density of tumorinfiltrating lymphocytes (TILs) as a predictive marker of treatment response and long-term prognosis in patients with LARC undergoing NCRT [5,6]. High levels of FOXP3+ TILs have been associated with an immunosuppressive tumor microenvironment [8,9,10,11]. Infiltration of TILs, especially CD8+ T cells, in pretherapeutic tumor tissue has been correlated with improved survival in different gastrointestinal cancers, including gastric cancer, hepatocellular carcinoma, and pancreatic cancer [12,13,14]
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