The prognostic value of tumor-infiltrating lymphocytes in colorectal cancer differs by anatomical subsite: a systematic review and meta-analysis.
ABSTRACT: PURPOSE:In colorectal cancer (CRC), whether the immune score can be used to predict the clinical prognosis of the patient has not been completely established. Besides, the prognostic values of tumor-infiltrating lymphocytes (TILs) in different anatomical locations, counting sites, and subtypes have been controversial. The purpose of this meta-analysis is to analyze and determine the prognostic value of TILs indices including TIL subsets, infiltrating sites, and anatomical sites. METHODS:Relevant literature was obtained by searching PubMed and Google Scholar. The pooled hazard ratio (HR) of the overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) was computed to investigate the prognostic significance of CD3+, CD8+, CD45RO+, and FOXP3+ T cells. RESULTS:A total of 22 studies involving 5108 patients were included in the meta-analysis. In CC, based on T cell subtypes analysis, the final results indicated that CD8+ and FOXP3+ infiltrating cells, but not CD3+ T cells were prognostic markers for DFS and OS. In addition, with regard to the counting location of TILs, subgroup analysis revealed that only high FOXP3+ infiltrates in the tumor stroma (ST) were significantly associated with OS (HR = 0.38, 95% confidence interval (CI) = 0.22-0.67, P = 0.0007), whereas in invasive margin (IM), high density of CD3+ infiltrating cells indicated increased DFS (HR = 0.76, 95% CI = 0.62-0.93, P = 0.008). At the tumor center (TC), high CD8+ T cells infiltration was associated with improved DFS (HR = 0.50, 95% CI = 0.38-0.65, P < 0.00001). In RC, whether CSS or OS, high-density TIL was associated with improved prognosis. CONCLUSION:In a single counting site, high-density TILs reflect favorable prognostic value in CC or RC. For CC, more prospective studies are needed to verify whether different anatomical sites affect the distribution of TILs and thus the prognosis of patients. For RC, further studies should analyze the prognostic value of the immune score.
Project description:The prognostic value of tumor-infiltrating lymphocytes (TILs) in ovarian cancer is still in controversial. This study is aimed to assess the impact of different TIL subsets on the progression free survival (PFS)/disease free survival (DSS) and overall survival (OS)/disease specific survival (DSS) in ovarian cancer. A comprehensive literature search in PubMed, ISI Web of Science, and Medline was performed to identify relevant studies evaluating the prognostic value of TILs in ovarian cancer. Reviews of each study were conducted and data were extracted. The main outcomes analyzed were PFS/DFS and OS/DSS. A total of 21 eligible studies enrolling 2903 ovarian cancer patients were included for the meta-analysis. The overall analysis revealed that intraepithelial CD3+ and CD8+ TILs were strongly associated with improved PFS/DFS (HR=0.53, for CD3+ TILs; and HR=0.50, for CD8+ TILs). Intraepithelial CD8+/Foxp3+ ratios appeared to be associated with improved PFS, though without reaching statistical significance (HR=0.73). Moreover, intraepithelial CD3+, CD8+, and CD103+ TILs were clearly associated with increased OS/DSS (HR=0.50, for CD3+ TILs; HR=0.62, for CD8+ TILs; HR=0.54, for CD103+ TILs). However, intraepithelial FoxP3+ TILs, CD8+/FoxP3+ ratios, CD8+/CD4+ ratios, and stromal TILs had no impact on the OS/DSS (HR=0.98, for FoxP3+ TILs; HR=0.69, for CD8+/FoxP3+ ratios; HR=0.48, for CD8+/CD4+ ratios; HR=0.82, for stromal TILs). In conclusion, the present meta-analysis supports the hypothesis that intraepithelial TILs are predictive biomarkers for the prognosis of ovarian cancer patients. Future randomized studies are needed to verify these observations.
Project description:Background - The presence of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment is associated with an improved prognosis and a better response to therapy in different types of cancer. In this systematic review and meta-analysis, we investigated the prognostic value of T cells in head and neck squamous cell carcinoma (HNSCC). Methods - In a systematic review, Pubmed and Embase were searched for publications that investigated the prognostic value of T cells in HNSCC. A meta-analysis was performed including all studies assessing the association between CD3+, CD4+, CD8+, and FoxP3+ TILs and overall survival (OS), disease-free survival (DFS), or locoregional control (LRC). Results - A pooled analysis indicated a favorable, prognostic role for CD3+ TILs (HR 0.64 (95%CI 0.47-0.85) for OS, HR 0.63 (95%CI 0.49-0.82) for DFS) and CD8+ TILs (HR 0.67 (95%CI 0.58-0.79) for OS, HR 0.50 (95%CI 0.37-0.68) for DFS, and HR 0.82 (95%CI 0.70-0.96) for LRC) in the clinical outcome of HNSCC. FoxP3+ TILs were also associated with better OS (HR 0.80 (95%CI 0.70-0.92)). Conclusion - This systematic review and meta-analysis confirmed the favorable, prognostic role of CD3+ and CD8+ T cell infiltration in HNSCC patients and found an association between FoxP3+ TILs and improved overall survival. Future studies using homogeneous patient cohorts with regard to tumor subsite, stage and treatment are necessary to provide more insight in the predictive value of TILs in HNSCC.
Project description:Background: Tumor-infiltrating lymphocytes (TILs) play a role in the anti-tumor immune response, and are often found in esophageal squamous cell carcinoma (ESCC). Methods: We performed a systematic review and meta-analysis, aiming to establish pooled estimates for survival outcomes of TILs based on their abundance and infiltrating location. A literature search of PubMed/Medline, Embase, Web of Science and the Cochrane Library was conducted. Studies that investigated the prognostic significance of generalized, CD8+, CD4+, FoxP3+, CD3+, and CD45O+ TILs in ESCC patients were included. Results: In pooled analysis, generalized TILs infiltrating the entire tumor mass were positively associated with disease-free survival (DFS), with a univariate-related hazard ratio (HR) of 0.630 [95% confidence interval (CI) 0.415-0.955], and also positively associated with overall survival (OS), with a univariate-related HR of 0.586 (0.447-0.770) and a multivariate-related HR of 0.621 (0.439-0.878). The pan-tumor, intra-tumor and peri-tumor CD8+ TILs had a favorable effect on OS, with univariate-related HRs of 0.733 (0.555-0.968), 0.797 (0.660-0.962), and 0.776 (0.635-0.948), respectively. Similar results were observed in CD8+ TILs that infiltrated the whole tumor mass, with a multivariate-related HR of 0.705 (0.524-0.947). CD4+, FoxP3+, CD3+, and CD45O+ TILs were not linked to DFS or OS. Subtypes and spatial locations of TILs seemed to influence study outcomes. Conclusions: Experimental and analytical methods of future studies should be carefully designed to avoid overestimating the effect of TILs on prognosis. Our meta-analysis confirms the prognostic efficacy of generalized TILs and CD8+ TILs in esophageal squamous cell carcinoma (ESCC) patients.
Project description:BACKGROUND:The prognostic values of tumor-infiltrating lymphocytes (TILs) and TILs subsets in breast cancer (BC) are uncertain. METHODS:A systematic literature search (MEDLINE, Web of Science, EMBASE, and the Cochrane Library to August 2014) was conducted for studies which met the eligibility criteria. The primary clinical outcome was defined as disease-free survival (DFS), overall survival (OS), and BC-specific survival (BCSS). Random or fixed-effects model was adopted to estimate the summary hazard ratio (HR). RESULTS:Twenty-five published studies comprising 22,964 patients were reviewed. Pooled analysis indicated that TILs were not prognostic markers for DFS and OS in overall population, but related to improved DFS (HR, 0.82; 95% CI, 0.76-0.88) and OS (HR, 0.79; 95% CI, 0.71-0.87) in triple negative breast cancer (TNBC) patients. For TILs subsets, CD8+ lymphocytes were associated with improved DFS (HR, 0.69; 95% CI, 0.56-0.84) and BCSS (HR, 0.78; 95% CI, 0.71-0.86) in overall population, while FOXP3+ lymphocytes were associated with reduced DFS (HR, 1.47; 95% CI, 1.01-2.05) and OS (HR, 1.50; 95% CI, 1.15-1.97). In estrogen receptor (ER) negative patients, CD8+ lymphocytes was also related to better BCSS. In addition, the high density of CD20+, CD3+ or low level of PD-1+ or ?? T lymphocytes indicated increased OS in limited studies. CONCLUSION:TILs and TILs subsets are promising prognostic biomarkers in breast cancer, especially in TNBC.
Project description:AIM:This study aimed to evaluate the presence and prognostic value of tumor-infiltrating T cells in the tumor epithelium in advanced stage, HPV-negative head and neck squamous cell carcinoma (HNSCC) patients treated with primary chemoradiotherapy using digital pathology. METHODS:Pre-treatment biopsies from 80 oropharyngeal, 52 hypopharyngeal, and 29 laryngeal cancer patients were collected in a tissue microarray (TMA) and immunohistochemically stained for T-cell markers CD3, CD4, CD8, FoxP3, and PD1, and for immune checkpoint PD-L1. For each marker, the number of positive tumor-infiltrating lymphocytes (TILs) per mm2 tumor epithelium was digitally quantified and correlated to overall survival (OS), disease-free survival (DFS), and locoregional control (LRC), as well as to clinicopathological characteristics. Differences in clinical outcome were estimated using Cox proportional hazard analysis and visualized using Kaplan-Meier curves. RESULTS:The patient cohort had a 3-year OS of 58%, with a median follow-up of 53 months. None of the T-cell markers showed a correlation with OS, DFS or LRC. A low N stage was correlated to a better prognosis (OS: HR 0.39, p?=?0.0028, DFS: HR 0.34, p?=??<?0.001, LRC: HR 0.24, p?=?0.008). High TIL counts were more often observed in PD-L1-positive tumors (p?<?0.05). CONCLUSION:This study showed an objective, digital pathology-aided method to assess TILs in the tumor epithelium. However, it did not provide evidence for a prognostic role of the presence of CD3?+?, CD4?+?, CD8?+?, FoxP3?+?, and PD1?+?TILs in the tumor epithelium of advanced stage, HPV-negative HNSCC patients treated with primary chemoradiotherapy.
Project description:BACKGROUND:Tumor-infiltrating lymphocytes (TILs) have been shown to be of prognostic value in several cancer types. In early breast cancer, TILs have a prognostic utility, as well, especially in HER2-positive and triple-negative breast cancer. TILs presence is broadly associated with improved survival; however, there is controversy regarding TILs subpopulations. PATIENTS AND METHODS:Early-stage breast cancer patients treated with anthracycline-based chemotherapy within two randomized trials were included in the study. We evaluated, by qRT-PCR, 826 tumor tissue samples for mRNA expression of CD3, CD8, and FOXP3 for potential prognostic significance in terms of disease-free survival (DFS) and overall survival (OS). RESULTS:After a median follow-up of 133.0 months, 255 patients (30.9%) had died and 314 (38.0%) had disease progression. In the univariate analysis, high CD3 and CD8 mRNA expression was found to be of favorable prognostic value for DFS (P = 0.007 and P = 0.016, respectively). In multivariate analyses, the association of high CD8 mRNA expression with increased DFS was retained (HR = 0.77, 95% CI 0.60-0.998, Wald's P = 0.048), whereas that of high CD3 mRNA expression was of marginal statistical significance (HR = 0.77, 95% CI 0.59-1.01, P = 0.059). Moreover, a significant interaction was observed between HER2 status and CD3 mRNA expression with respect to DFS (interaction P = 0.032). In the HER2-positive subgroup, the hazard ratio associated with high CD3 mRNA expression was of greater magnitude (HR = 0.48, 95% CI 0.30-0.76, P = 0.002) compared with the hazard ratio presented above, for the entire cohort. No significant findings were observed for FOXP3 in terms of DFS, while none of the studied markers were of prognostic value for OS. CONCLUSIONS:High CD3 and CD8 mRNA expression in early-stage breast cancer patients is of prognostic value for decreased risk of relapse and, in the future, could potentially be of importance in deciding the most appropriate therapeutic strategy in light of the recent immune-related treatment developments.
Project description:Previous clinical studies have found that the levels of tumor-infiltrating lymphocytes (TILs) significantly correlated with prognosis in hepatocellular carcinoma (HCC). However, these conclusions and data remain controversial. We performed a systematic review and meta-analysis to assess the prognostic value and clinical utilization of TILs in patients with HCC. A total of 23 relevant studies of 3173 patients were included into our meta-analysis. The results demonstrated that high levels of CD8 + and CD3 + TILs had a better prognostic value on overall survival (OS), with HRs of 0.71 (P?=?0.04) and 0.63 (P?=?0.03), respectively, compared to low levels, as did high levels of CD8 + , CD3 + and CD4 + TILs on disease/recurrence-free survival (DFS/RFS), with HRs of 0.66 (P?=?0.01), 0.60 (P?=?0.01) and 0.79 (P?=?0.04), respectively. In contrast, high levels of FoxP3 + TILs had a worse prognostic value on OS and DFS/RFS, with HRs of 2.06 (P?<?0.00001) and 1.77 (P?<?0.00001), respectively. The FoxP3+/CD4+ and FoxP3+/CD8+ ratios negatively correlated with OS and DFS/RFS. These findings suggest that TILs may serve as a prognostic biomarker in HCC. However, further research should be performed to clarify the clinical value of TILs in HCC.
Project description:BACKGROUND:T cell density in colorectal cancer (CRC) has proven to be of high prognostic importance. Here, we evaluated the influence of a hyperfractionated preoperative short-term radiation protocol (25 Gy) on immune cell density in tumor samples of rectal cancer (RC) patients and on patient survival. In addition, we assessed spatial tumor heterogeneity by comparison of analogue T cell quantification on full tissue sections with digital T cell quantification on a virtually established tissue microarray (TMA). METHODS:A total of 75 RC patients (60 irradiated, 15 treatment-naïve) were defined for retrospective analysis. RC samples were processed for immunohistochemistry (CD3, CD8, PD-1, PD-L1). Analogue (score 0-3) as well as digital quantification (TMA: 2 cores vs. 6 cores, mean T cell count) of marker expression in 2 areas (central tumor, CT; invasive margin, IM) was performed. Survival was estimated on the basis of analogue as well as digital marker densities calculated from 2 cores (Immunoscore: CD3/CD8 ratio) and 6 cores per tumor area. RESULTS:Irradiated RC samples showed a significant decrease in CD3 and CD8 positive T cells, independent of quantification mode. T cell densities of 6 virtual cores approximated to T cell densities of full tissue sections, independent of individual core density or location. Survival analysis based on full tissue section quantification demonstrated that CD3 and CD8 positive T cells as well as PD-1 positive tumor infiltrating leucocytes (TILs) in the CT and the IM had a significant impact on disease-free survival (DFS) as well as overall survival (OS). In addition, CD3 and CD8 positive T cells as well as PD-1 positive TILs in the IM proved as independent prognostic factors for DFS and OS; in the CT, PD-1 positive TILs predicted DFS and CD3 and CD8 positive T cells as well as PD-1 positive TILs predicted OS. Survival analysis based on virtual TMA showed no impact on DFS or OS. CONCLUSION:Spatial tumor heterogeneity might result in inadequate quantification of immune marker expression; however, if using a TMA, 6 cores per tumor area and patient sample represent comparable amounts of T cell densities to those quantified on full tissue sections. Consistently, the tissue area used for immune marker quantification represents a crucial factor for the evaluation of prognostic and predictive biomarker potential.
Project description:BACKGROUND:The objective of this systematic review and meta-analysis was to determine the prognostic value of total tumor-infiltrating lymphocytes (TILs) and subtypes of TILs (CD4+, CD8+, and FOXP3+) in triple-negative breast cancer (TNBC). METHODS:A systematic search of the MEDLINE, EMBASE, and Web of Science databases was conducted to identified eligible articles published before August 2019. Study screening, data extraction, and risk of bias assessment were performed by two independent reviewers. Risk of bias on the study level was assessed using the ROBINS I tool and Quality in Prognosis Studies (QUIPS) tool. We performed a meta-analysis to obtain a pooled estimate of the prognostic role of TILs using Review Manager 5.3. RESULTS:In total, 37 studies were included in the final analysis. Compared to TNBC patients with low TIL levels, TNBC patients with high TIL levels showed a higher rate of pathological complete response (pCR) to treatment (odds ratio [OR] 2.14, 95% confidence interval [CI] 1.43-3.19). With each 10% increase in percentage of TILs, patients with TNBC had an increased pCR (OR 1.09, 95% CI 1.02-1.16). Compared to TNBC patients with low TIL levels, patients with high TIL levels had better overall survival (OS; hazard ratio [HR] 0.58, 95% CI 0.48-0.71) and disease-free survival (DFS; HR 0.66, 95% CI 0.57-0.76). Additionally, with a continuous increase in TIL levels, patients with TNBC had improved OS (HR 0.90, 95% CI 0.87-0.93) and DFS (HR 0.92, 95% CI 0.90-0.95). A high CD4+ TIL level was associated with better OS (HR 0.49, 95% CI 0.32-0.76) and DFS (HR 0.54, 95% CI 0.36-0.80). A high CD8+ TIL level was associated better DFS only (HR 0.55, 95% CI 0.38-0.81), as no statistical association was found with OS (HR 0.70, 95% CI 0.46-1.06). A high FOXP3+ TIL level also was associated with only DFS (HR 0.50, 95% CI 0.33-0.75) and not OS (HR 1.28, 95% CI 0.24-6.88). CONCLUSIONS:TNBC with a high level of TILs showed better short-term and long-term prognoses. High levels of specific phenotypes of TILs (CD4+, CD8+, and FOXP3+) were predictive of a positive long-term prognosis for TNBC.
Project description:BACKGROUND: The role of tumour-infiltrating inflammation in the prognosis of patients with colorectal cancer (CRC) has not been fully evaluated. The primary objective of our meta-analysis was to determine the impact of tumour-infiltrating inflammation on survival outcomes. METHODS: Ovid MEDLINE and EMBASE were searched to identify studies reporting the prognostic significance of tumour-infiltrating inflammation for patients with CRC. The primary outcome measures were overall survival (OS), cancer-specific survival (CS) and disease-free survival (DFS). RESULTS: A total of 30 studies involving 2988 patients were identified. Studies were subdivided into those considering the associations between CRC survival and generalised tumour inflammatory infiltrate (n=12) and T lymphocyte subsets (n=18). Pooled analyses revealed that high generalised tumour inflammatory infiltrate was associated with good OS (HR, 0.59; 95% CI, 0.48-0.72), CS (HR, 0.40; 95% CI, 0.27-0.61) and DFS (HR, 0.72; 95% CI, 0.57-0.91). Stratification by location and T lymphocyte subset indicated that in the tumour centre, CD3+, CD8+ and FoxP3+ infiltrates were not statistically significant prognostic markers for OS or CS. In the tumour stroma, high CD8+, but not CD3+ or FoxP3+ cell infiltrates indicated increased OS. Furthermore, high CD3+ cell infiltrate was detected at the invasive tumour margin in patients with good OS and DFS; and high CCR7+ infiltrate was also indicated increased OS. CONCLUSION: Overall, high generalised tumour inflammatory infiltrate could be a good prognostic marker for CRC. However, significant heterogeneity and an insufficient number of studies underscore the need for further prospective studies on subsets of T lymphocytes to increase the robustness of the analyses.