Background
Cancers have become the most frequent cause of death worldwide due to rapid progress, with approximately 1650 Americans per day estimated to die in 2017. Generally, therapies including chemotherapy, radiotherapy, surgical resection and immunotherapy were applied to treat different types of cancers [
1], resulting in an overall drop of 25% in cancer death rates over 2 decades. However, the prognosis of most cancers remains poor. Recent findings have validated the importance of immunosuppressive network in the carcinogenesis and progression via suppressing antitumor immune system, thus leading to tumor invasion [
2]. And there are rising studies on the clinical significance of immunosuppressive parameters in various cancers.
Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature myeloid cells, are well-known to suppress both innate and adaptive immunity. The most common phenotype of MDSCs can be characterized as CD11b
+CD33
+HLA-DR
−/low, which include monocytic CD14
+CD15
− and granulocytic CD14
−CD15
+ subtypes [
3]. In cancer patients, MDSC expansion inhibits T cell proliferation, decreases cytokines secretion, and recruiting regulatory T cells, etc., thus hampering the host anti-tumor immune response [
3‐
7].
Currently, accumulating studies have investigated the role of MDSCs in both solid tumor and hematologic malignances, and MDSCs was found to be an independent prognostic factor in melanoma [
8,
9], gastrointestinal (GI) cancers [
10‐
12], NK/T lymphoma [
13], bladder cancer [
14] and so on. However, increasing researches referring to MDSCs and cancer questioned the reliability of MDSCs acting as a prognostic biomarker in various malignancies [
15,
16]. Here, a meta-analysis was first performed to estimate the correlation between MDSCs and the survival outcomes of cancer patients, providing a basis for the predicting role of MDSCs in the various cancers.
Methods
Search strategy
A systematic search was conducted in 3 electric databases including PubMed (Medline), ISI Web of Science, and Ovid (EMBASE) databases. All relevant publications were picked out until January 2018. The search strategies are as following: “MDSC” (e.g. “Myeloid-derived suppressor cells”), “prognosis” (e.g. “survival” “mortality” “outcome”) and “cancer” (e.g. “tumor” “carcinoma” “neoplasm” “leukemia” “lymphoma” “myeloma”). Furthermore, the reference lists of retrieved studies were also checked to find more studies.
Selection criteria
The inclusion criteria of this meta-analysis were: (1) Patients were histopathologically diagnosed with cancer; (2) Association between the pretreatment MDSCs level and clinicopathological parameters including OS, PFS, etc. was reported; (3) Studies were also allowed if we could reconstruct HRs and 95%CIs from the Kaplan-Meier survival curves or by other methods reported [
17]. Exclusion criteria of this meta-analysis were: (1) conference abstracts, case reports, reviews, etc.; (2) publications with insufficient information for meta-analysis; (3) multiple published reports. We enrolled the most recent publication concerning the same cohort in our meta-analysis.
Two reviewers (Shidai Mu and Yadan Wang) independently screened the studies for eligibility. Two reviewers (Lisha Ai and Yu Hu) evaluated the quality, and extracted the data from eligible studies. The Newcastle–Ottawa Quality Assessment Scale (NOS) was applied to assess the quality of the include studies [
18]. Studies which got ≥ 7 in the NOS were assigned as high-quality. A predefined table was used to list the following relevant data: (1) characteristics of each study, such as the first author’s name, sample size, the country in which the study was carried out, year of publication, age of patients, gender, and follow-up period; (2) survival data including OS, and DFS/RFS (OS was defined as the length of time from either the date of diagnosis or the start of treatment for a disease until the death of patient or the last follow-up. DFS / RFS was defined as the length of time after primary treatment for a cancer until the patient survived without any signs or symptoms of that cancer); (3) cut-off value defining “elevated MDSCs”.
Statistical analysis
Hazard ratio (HR) and 95% confidence intervals (95%CIs) were mostly extracted from the reports of studies, otherwise we estimates HRs and 95CIs according to the methods published by Parmer et al. [
17]. The χ
2-based Q test and I
2 test were used to check the heterogeneity among included studies [
19]. We used the fixed-effect model for analysis if no significant heterogeneity was found between studies (
p > 0.10, I
2 < 30%). The source of heterogeneity was further explored by subgroup analysis and galbraith plots.
A sensitivity analysis was performed to to determine which parameters have the greatest impact on the overall results. Result was regarded to be significant when p < 5%. The Begg’s funnel plot was used to assess publication bias. And the trim and fill analysis was performed when the possibility of publication bias was significant. All analyses were carried out using STATA statistical software 14.0 (STATA, College Station, TX).
Discussion
Numerous studies have stressed the biological importance of tumor microenvironment in carcinogenesis and progression. Previous studies have lay solid foundation on the association between increased MDSCs level and poor prognosis in various types of tumor, including melanoma [
8,
9], GI cancers [
10‐
12], NK/T lymphoma [
13], bladder cancer [
14], small cell lung cancer [
20], etc. However, results of these studies are not comparable, owing to the different design, patient population, and therapeutic strtegies, and the diversity in cut-off value defining “elevated MDSCs”. Our meta-analysis presented here was the first study assessing the association between elevated MDSCs level and prognosis in cancers, including solid tumors, as well as hematological malignancies. Sixteen trials with a total of 1864 patients were included in this meta-analysis. The combined data indicated that elevated MDSCs level was significantly associated with shorter OS, and poor DFS/RFS of patients with various cancers.
Obvious heterogeneity existed among the included studies in our meta-analysis (I2 = 61.3%, P < 0.01). Subgroup analyses were conducted to find out the source of heterogeneity. The heterogeneity for OS decreased in the subgroup analysis based on cancer types. It implied that cancer types might contribute to heterogeneity to some extent. Moreover, the sensitivity analysis identified the study of Gabitass, R.F et al., 2011 affecting the results obviously. And the heterogeneity decreased after excluding the outlier study.
The complex association between chronic inflammation and tumor development has commenced to be investigated during the last decade [
21]. Chronic inflammation is considered to mediate tumor progression via immunosuppression, releasing various cytokines and recruiting several immunosuppressive cells, particularly MDSCs [
2,
22]. Recently, several studies have shown that MDSCs are associated with poor progression in solid tumor and hematologic malignancies [
8,
11,
23‐
25]. Mechanically, MDSCs expansion inhibits T cell proliferation, decreasing cytokine secretion, recruiting regulatory T cells, as well as prohibiting natural killer cells (NK cells) activation, thus hampering the host anti-tumor immune response [
5,
26,
27]. In addition, MDSCs also exert non-immunological functions by promoting angiogenesis, accelerating tumor invasion, and metastasis [
28,
29]. Recently, some studies have explored the direct interaction between MDSCs and tumor cells [
7]. Therefore, increased MDSCs frequency might generate a favorable immune microenvironment, contributing to poor prognosis in cancer patients.
It is notable that this meta-analysis has some limitations; therefore cautions are called for interpreting the results. First, only 16 studies were included in this meta-analysis. Besides, the result of Begg’s test indicated the possibility of publication bias. Second, the diversity of cut-off values defining high MDSCs frequency in each study might contribute to heterogeneity among the enrolled studies. Third, some studies did not directly report HR or 95%CI, possibly leading to inaccurate estimation of HR and 95%CI. Forth, differences in paper quality and study design might cause bias to some extent. Fifth, our results might overestimate the prognostic role of MDSCs with positive results from most of the included studies.
Conclusion
Here, several electronic databases, including Pubmed, Embase and Web of Science, were searched for related studies, and 16 studies with 1864 patients were enrolled in the first meta-analysis estimating the association between elevated MDSCs level and survival outcomes of patients with various types of cancers. Taken together, we can draw a conclusion that MDSCs gains a prognostic value for cancer patients. More multi-center prospective cohorts and longer follow-up period are warranted to further validate the prognostic role of the MDSCs in cancer patients.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (
http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.