Abstract
The immune system’s role in cancer development and progression is receiving increasing attention. Endometrial cancer, common gynecological malignancy, has exhibited promising responses to immunotherapies. This study aims to assess the prognostic significance of various immune cell subsets in endometrial cancer, focusing on potential novel biomarkers and therapeutic targets. A systematic literature review and meta-analysis were conducted. Eleven eligible studies, comprising 2,319 patients with endometrial cancer, were included. The primary outcome was the association between levels of immune cell types, particularly CD8+ T cells, and overall prognosis. The meta-analysis found that high levels of tumor-infiltrating lymphocytes (TILs), particularly CD8+ T cells, were significantly associated with better overall prognosis in endometrial cancer patients. These findings suggest that the tumor immune microenvironment plays a crucial role in endometrial cancer prognosis. This meta-analysis indicates that higher levels of CD8+ T cells in the tumor microenvironment are linked to improved prognosis in endometrial cancer, underscoring the immune system’s potential in prognostication and therapy.
Keywords: Immune cell infiltration, prognostic biomarkers, tumor microenvironment, personalized treatment, endometrial cancer
Introduction
Endometrial cancer (EC) is a common malignancy in women, with increasing incidence worldwide, posing a significant public health concern [1]. Originating from the uterine lining, EC is influenced by hormonal and metabolic changes typically associated with aging and obesity. The disease presents a complex challenge due to its multifactorial etiology, variable clinical manifestations, and diverse patient outcomes [2]. Despite advancements in treatment, traditional prognostic methods - mainly relying on clinical and histological parameters - often fail to accurately predict patient outcomes [3]. This underscores the need for additional prognostic factors to improve predictive models and guide personalized treatment plans.
In recent years, the role of the immune microenvironment in cancer progression and patient survival has gained significant attention in oncology [4]. The immune system plays a multifaceted role, with immune cells such as macrophages, dendritic cells, natural killer (NK) cells, and T cells either promoting or inhibiting tumor growth [5,6]. The interaction among these immune populations is critical in determining cancer prognosis, and this complexity is particularly pronounced in EC [7,8]. The advent of immunotherapy, including checkpoint inhibitors, has underscored the immune system’s central role in cancer treatment, with the effectiveness of these therapies influenced by the tumor’s immune landscape [9,10]. Thus, understanding immune cell infiltration in EC is essential, not only for scientific insight but also for identifying novel prognostic biomarkers and therapeutic strategies.
This study aims to systematically evaluate the prognostic significance of immune cell infiltration in EC, with a particular focus on the role of CD8+ T cells. Through a meta-analysis, the study seeks to identify potential prognostic biomarkers and therapeutic targets.
Methods
This study is registered with The International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY 202490006). The meta-analysis follows the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Literature search
Relevant articles were retrieved from PubMed, Medline, and Embase from the inception of these databases to May 31, 2024. The search strategy combined both free-text and subject headings, using keywords such as endometrial cancer, endometrial carcinoma, endometrial neoplasm, tumor-infiltrating lymphocytes (TILs), tumor-derived activated cells, prognosis, survival, and outcome.
Selection criteria
The inclusion criteria were as follows: 1) Patients diagnosed with endometrial cancer (stages I to IV) confirmed by postoperative pathology. 2) Patients who had not received chemotherapy or radiotherapy prior to surgery. 3) Patients without concurrent malignancies. 4) Studies that reported on the prognostic significance of total TILs or specific TIL subgroups (including CD3+ T cells, CD4+ T cells, CD8+ T cells, Forehead Box P3 (FoxP3) + lymphocytes, and others) in endometrial cancer. 5) Studies that provided complete data on hazard ratios (HRs) and 95% confidence intervals (CIs) for outcome measures.
Exclusion criteria included: 1) Non-clinical primary studies such as literature reviews, conference abstracts, case reports, animal studies, and editorials. 2) When multiple studies by the same author were available, only the most recent data were considered. 3) If a study presented both univariate and multivariate Cox regression analyses, the multivariate data were preferred due to higher precision.
The literature that met these criteria was reviewed by two independent researchers, who examined the titles, abstracts, full texts, and duplicates for inclusion or exclusion. Any discrepancies were resolved through discussion.
Data extraction
Data were independently extracted by two reviewers. The extracted information included: author details, nationality of study subjects, age, sample size, clinical stage, TIL subgroups, TIL data, tumor grade, cut-off values, median follow-up time, patient cohort, and outcome measures.
Overall Survival (OS) was defined as the time from surgery to death; Progression-Free Survival (PFS) was the time from treatment initiation to disease progression or death; Disease-Free Survival (DFS) was the time from surgery to recurrence or death; Disease-Specific Survival (DSS) excluded deaths due to causes unrelated to the tumor.
In cases of disagreement during data extraction, a third author was consulted, and consensus was achieved between the two reviewers.
Quality assessment
Two reviewers independently assessed the quality of the selected studies using predefined criteria. Disagreements were resolved through consensus. Observational studies, including case-control and cohort studies, were evaluated using an adapted version of the Newcastle-Ottawa Scale (NOS). This scale assigns scores across three domains: selection (four items), comparability (two items), and outcome ascertainment (three items), based on specific criteria. Studies with a total score of 7 or more were categorized as high quality, those scoring between 4 and 6 were deemed moderate quality, and studies with scores below 4 were considered low quality.
Statistical analyses
This study assessed the prognostic significance of TILs in EC by examining HRs and their corresponding 95% CIs. The heterogeneity across studies was assessed using the χ2 test and the I2 statistic. If the I2 value was less than 50% (I2 < 50%) and the P value was greater than 0.1 (P > 0.1), indicating low heterogeneity, a fixed-effect model was applied for statistical analysis. In contrast, if heterogeneity was high, a random-effects model was used. Publication bias was evaluated using Egger’s and Begg’s tests. The data included in the final analysis were processed and visualized using Stata software, version 14.0. Trial sequential analysis (TSA) was performed using TSA Viewer software, version 0.9, to account for cumulative heterogeneity, reduce the type I error rate, and estimate the potential effect of incomplete registered studies. The information size was determined based on an alpha risk of 5% and a beta risk of 20%. Statistical significance was determined by examining the 95% CI; values not encompassing the null value (less than 1.00 or greater than 1.00) were considered significant.
Results
Search results
The literature search across the databases yielded a total of 623 articles. After excluding duplicate publications, 351 non-qualifying documents, and an additional 100 articles for various reasons, 86 articles remained. A review of the titles and abstracts led to the exclusion of 60 articles. Furthermore, 15 articles with incomplete observation data were excluded, leaving 11 articles that were ultimately selected for the meta-analysis (Figure 1).
Figure 1.
Flow chart of literature screening.
Study description
Table 1 summarizes the characteristics of the studies included in this review. A total of 2,319 patients from various countries, including Greece, the United States, the Netherlands, the Czech Republic, Japan, Canada, and Spain, were included. Of the 11 studies, 10 focused on the prognostic value of CD8+ T cells (8 studies examined their correlation with OS, 3 with DSS, and 2 with DFS), while 1 study investigated the prognostic implications of TILs in relation to DSS. Additionally, 3 studies explored the prognostic importance of CD4+ T cells, with 3 analyzing their association with OS, 1 with DSS, and 1 with DFS.
Table 1.
Summary of the key characteristics of the included studies
| Study | Area | TILs/TIL subgroups | Sample size | Age, mean (SD) or Median (range) | Follow up (months) | Tumor staging (I/II/III/VI) | Tumor grading (G1/G2/G3) | Cut of value | Survival outcomes |
|---|---|---|---|---|---|---|---|---|---|
| Vagios et al. [23] | Greece | CD8+ | 101 | 64.43 (10.20) | 12-178 | 52/10/30/9 | NA | Median | OS |
| Zhang et al. [24] | Japan | CD4+/CD8+ | 221 | 57 (26-84) | 132 (3-209) | 144/17/36/24 | 115/56/25 | Median | OS |
| Čermáková et al. [25] | Czech Republic | CD8+ | 124 | 66 (9) | 102 (64-145) | 90/19/13/2 | 44/63/17 | Median | OS |
| de Jong et al. [26] | Netherlands | CD8+ | 368 | 65 (32-89) | 52.8 (0-258) | 201/60/80/26 | 16/96/10 7 | Median | OS |
| Kim et al. [27] | Korea | CD8+ | 183 | 53.0 (10.4) | 30.3 | NA | NA | K-Adaptive partitioning method | OS |
| Ikeda et al. [28] | USA | CD8+ | 32 | 56.5 (35-78) | NA | 6/10/10/7 | 15/11/6 | Median | OS |
| Workel et al. [29] | Netherlands | CD8+ | 305 | NA | 29 | 158/53/72/22 | 132/82/86 | Median | DSS/DFS |
| Suemori et al. [30] | Japan | CD8+ | 123 | 57.8 (38-80) | 85.3 (1.1-149.2) | 58/6/36/9 | 55/38/31 | Median | DSS |
| Versluis et al. [31] | Netherlands | Total CTLs | 355 | 64 (56-73) | 74.4 | 169/54/69/21 | 22/91 | The lowest quartile (2.5) | DSS/DFS |
| Talhouk et al. [32] | Canada | CD8+/CD4+ | 460 | NA | NA | NA | NA | Median | DSS/DFS/OS |
| Palomero et al. [1] | Spain | CD8+/CD4+ | 47 | 70.36 (10.28) | 45.6 | 35/9/3 | 15/6/26 | Median | OS |
Notes: TILs: tumor-infiltrating lymphocytes; NK cells: Natural Killer cells; CTLs: Cytotoxic T cells; DSS: disease-specific survival; DFS: disease-free survival; OS: overall survival.
Quality assessment
The details of the quality assessment are provided in Table 2. Five studies were classified as high quality, with NOS scores of 7 or higher. Overall, the quality of the included studies was deemed acceptable.
Table 2.
Risk bias assessment of included literature (NOS scale)
| Study | Selection of objects | Group comparability | Outcome assessment | Total score | |||||
|---|---|---|---|---|---|---|---|---|---|
|
|
|
|
|||||||
| Q1 | Q2 | Q3 | Q4 | Q5 | Q6 | Q7 | Q8 | ||
| Vagios et al. [23] | 1 | 0 | 1 | 0 | 1 | 1 | 1 | 1 | 66 |
| Zhang et al. [24] | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 7 |
| Čermáková et al. [25] | 1 | 0 | 1 | 1 | 0 | 1 | 1 | 1 | 6 |
| de Jong et al. [26] | 1 | 0 | 1 | 0 | 1 | 1 | 1 | 1 | 6 |
| Kim et al. [27] | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 7 |
| Ikeda et al. [28] | 1 | 1 | 1 | 1 | 0 | 1 | 0 | 1 | 6 |
| Workel et al. [29] | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 0 | 6 |
| Suemori et al. [30] | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 7 |
| Versluis et al. [31] | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 7 |
| Talhouk et al. [32] | 1 | 1 | 0 | 1 | 1 | 1 | 0 | 1 | 6 |
| Palomero et al. [1] | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 7 |
Notes: Q: question; NOS: Newcastle-Ottawa Scale.
Meta-analysis of the impact of TILs and TIL subgroups on the prognosis of EC
The meta-analysis indicated that the levels of TILs and their subgroups in EC were positively associated with prognosis (HR = 0.484, 95% CI = 0.411-0.556, P < 0.05, Figure 2), with significant heterogeneity across the studies (P = 0.003; I2 = 91.7%). These results suggest that higher levels of TILs and TIL subgroups in EC may significantly prolong survival rates. This conclusion was further validated through trial sequential analysis (TSA), which confirmed that the required information size had been reached (Figure 3).
Figure 2.
The forest plot of the impact of TILs and TIL subgroups on the prognosis of EC. TILs, tumor-infiltrating lymphocytes; EC, endometrial cancer.
Figure 3.
Trial sequential analysis of the impact of TILs and TIL subgroups on the prognosis of EC. TILs, tumor-infiltrating lymphocytes; EC, endometrial cancer.
Subgroup analyses
Subgroup analyses were performed on intratumoral CD8+ T cells and CD4+ T cells in EC to assess their prognostic significance. As shown in Figure 4, there was no heterogeneity within the CD8+ T cell group (P = 0.0001, HR = 0.507, 95% CI = 0.450-0.563), indicating a statistically significant association between CD8+ T cell infiltration and survival outcomes in EC patients. Similarly, no heterogeneity was observed within the CD4+ T cell group (P = 0.45, HR = 0.568, 95% CI = 0.390-0.745), suggesting that CD4+ T cells do not significantly affect survival rates in EC patients (Figure 5).
Figure 4.
Subgroup analysis of the impact of CD8+ T cell infiltration on the prognosis of EC. EC, endometrial cancer.
Figure 5.
Subgroup analysis of the impact of CD4+ T cell infiltration on the prognosis of EC. EC, endometrial cancer.
Sensitivity analysis
Given the notable heterogeneity in the effects of TILs and TIL subgroups on EC prognosis, a sensitivity analysis was conducted (Figure 6). No significant changes were observed when individual studies were removed and the remaining studies were pooled, suggesting that the primary findings of this meta-analysis are stable and reliable.
Figure 6.
Sensitivity analysis for the impact of TILs and TIL subgroups on the prognosis of EC. TILs, tumor-infiltrating lymphocytes; EC, endometrial cancer.
Publication bias
A funnel plot was used to assess potential publication bias (Figure 7). No significant publication bias was detected, as confirmed by Egger’s regression test (t = 0.33, P = 0.71).
Figure 7.
The funnel plot for assessing publication bias for the impact of TILs and TIL subgroups on the prognosis of EC. TILs, tumor-infiltrating lymphocytes; EC, endometrial cancer.
Discussion
Predicting clinical outcomes in EC typically involves histopathological evaluation of tissue samples obtained after surgical resection of the primary tumor [11]. However, it is recognized that even within the same disease stage, significant variability exists in the prognosis of different EC patients. For example, patients with identical histological stages of EC can have vastly different outcomes, highlighting the limitations of conventional tumor staging in providing precise prognostic information and guiding treatment decisions [12]. In recent years, studies have demonstrated that immune cell infiltration within the tumor stroma is associated with prognosis in various cancers, including breast, gastric, colorectal, lung, and ovarian cancers [13,14]. Additionally, growing evidence suggests that the immune score could serve as a predictive tool for cancer prognosis and treatment response, supplementing traditional tumor staging methods to enhance the accuracy of disease prediction [15].
Despite these advancements, inconsistencies remain regarding the prognostic value of specific subsets of TILs in EC [16]. Therefore, we conducted a comprehensive analysis and integration of existing literature to clarify the prognostic significance of TILs through a larger sample size, thus enhancing the reliability of its predictive value.
The findings of this study indicate that the presence and activity of immune cells in the tumor microenvironment significantly influence the prognosis of EC patients. This highlights the potential role of immune-based biomarkers and therapeutic interventions in managing this disease. The positive correlation between the level of TILs and improved prognosis in EC patients is consistent with previous studies, suggesting that T cell infiltration into the tumor microenvironment may represent an effective anti-tumor immune response [17]. Of particular interest is the strong association between the level of CD8+ T cells and improved survival in EC patients. CD8+ T cells, known for their cytotoxic potential, are essential in eliminating tumor cells [17]. Numerous studies have emphasized the critical role of these cells in the body’s immune response to cancer [18,19]. For instance, CD8+ T cells can secrete cytotoxic molecules such as perforin and granzymes, inducing apoptosis in tumor cells [20]. They can also activate other immune cells, such as macrophages, to further enhance the anti-tumor response. Furthermore, the suppression of CD8+ T cells has been shown to promote tumor growth and metastasis in animal models [21]. These findings underscore the importance of CD8+ T cells in monitoring and controlling tumor progression, making them promising biomarkers for predicting patient outcomes in cancer therapy. Our meta-analysis suggests that higher CD8+ T cell infiltration is associated with a reduced risk of mortality in EC, reinforcing the prognostic relevance of this immune cell subset.
In contrast to the findings for CD8+ T cells, we did not observe a significant association between CD4+ T cell infiltration and EC prognosis. This discrepancy may be due to the diverse functions of CD4+ T cells, which can either promote or inhibit tumor progression depending on the context. The functional diversity of CD4+ T cells could offset their prognostic impact in EC [22]. Moreover, differences in study populations, methodologies, and the classification of immune cell subgroups may contribute to the inconsistent results across studies.
One of the primary limitations of this meta-analysis is the notable heterogeneity observed across the included studies. Potential sources of this heterogeneity include variations in study design, patient characteristics, methodologies for assessing immune cell infiltration, and the criteria used to define outcome measures. This heterogeneity complicates the interpretation of the pooled results and requires caution when extrapolating the findings to clinical settings. Additionally, publication bias, a common concern in meta-analyses, represents another potential limitation. Although the funnel plot and Egger’s regression test did not reveal significant publication bias in this analysis, they cannot entirely exclude its possibility, particularly given the limited number of studies in this field.
Another limitation is the reliance on retrospective data, which may not fully capture the complexity of tumor-immune interactions over time. Furthermore, the retrospective nature of the data may overlook confounding variables that could influence the relationship between TILs and patient prognosis.
Despite these limitations, the meta-analysis has several strengths. By including studies from diverse geographical locations and patient cohorts, this analysis offers a comprehensive evaluation of the prognostic significance of immune cells in EC. The systematic search strategy and strict selection criteria ensured the inclusion of high-quality studies with reliable data. Moreover, the rigorous quality assessment and comprehensive data extraction process contribute to the validity of the findings.
The findings of this meta-analysis have important clinical and research implications for EC. The positive prognostic role of TILs, especially CD8+ T cells, suggests that immune-based biomarkers could be used to predict the prognosis of EC patients. This could, in turn, inform tailored treatment strategies that consider individual immune cell profiles.
In conclusion, this meta-analysis has clarified the prognostic role of TILs in EC, confirming that the presence and activity of immune cells within the tumor microenvironment significantly impact patient prognosis. The study highlights the potential predictive value of immune cell infiltration, particularly CD8+ T cells, which are associated with improved survival outcomes in EC patients.
Future research should focus on rigorous validation of the prognostic significance of immune cell subsets across diverse patient populations, considering the heterogeneity of EC. Establishing uniform criteria for sample collection, processing, and immune cell quantification will be crucial to ensure the reliability and comparability of results across studies. Additionally, investigating potential interactions between immune cells and other molecular factors in the tumor microenvironment will be essential for a more comprehensive understanding of EC pathogenesis and progression.
Acknowledgements
This study was supported by Joint Funds for the Innovation of Science and Technology, Fujian province, number: (2023Y9454), and Fujian Clinical Research Center for Radiation and Therapy of Digestive, Respiratory and Genitourinary Malignancies, number: (2021Y2014).
Disclosure of conflict of interest
None.
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