Peripheral blood neutrophil-to-lymphocyte ratio as a prognostic marker and its association with the tumor-immune microenvironment in pancreatic cancer: a retrospective cohort study

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a mortality rate approaching the rate of incidence (1). The lack of efficient early diagnosis biomarkers, resistance to conventional chemotherapy, and ineffective immunotherapeutic strategies—which demonstrate efficacy for many other cancers—accounts for the poor prognosis of patients with PDAC.

The effects of the immune microenvironment on cancer tumorigenesis, development, and metastasis have been recently identified (2,3). It is thus imperative to understand the immune environment landscape to fully assess the function of anticancer drugs and devise more effective therapies. The high number of tumor-infiltrating lymphocytes (TILs) is associated with a better prognosis among many cancers (4), yet recent evidence suggests that a sole focus on TILs may be erroneous. In the tumor-immune microenvironment (TIME), through recruiting suppressive innate immune populations, tumors create a hostile state. Specifically, tumor cells and immunosuppressive contents interact and reshape the environment in favor of tumor growth by suppressing the infiltration and function of CD8⁺ T cells, acting as a barrier to immunotherapy (5). Myeloid-derived suppressor cells (MDSCs) are a prominent component of these immunosuppressive cells (6,7). Evidence from numerous studies indicates that the immune environment in PDAC is complex and can affect the progression of the disease (8,9). Therefore, there is a growing need for diagnostic and prognostic approaches based on microenvironment-based signatures. While immunohistochemistry (IHC) is a conventional method, its ability to assess immune effects is limited by the amount of tissue obtained through surgical or biopsy procedures and the number of immune markers it can evaluate (10). Therefore, identifying alternative biomarkers that represent the immune status of the TIME and can predict the prognosis of patients with PDAC is urgently needed.

The neutrophil-to-lymphocyte ratio (NLR) is a standard hematologic marker reflecting inflammation (11,12). It has also been reported to be a prognostic marker in many types of cancer, including PDAC (13,14). An increasing number of recent studies suggest that NLR is related to the TIME. In patients with colorectal cancer (15), non-small cell lung cancer (NSCLC), kidney cancer (16), or breast cancer (17), NLR is associated with tumor T-cell infiltration. While the NLR has shown prognostic potential in other malignancies, its clinical utility in PDAC remains underexplored beyond bioinformatics analyses. The urgent need for non-invasive prognostic tools in PDAC management motivates this clinical investigation of NLR’s association with TIME features and prognostic value for patients in PDAC. We present this article in accordance with the REMARK reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-283/rc).

Methods

Study patients

This retrospective study was structured around two distinct cohorts: Cohort 1: comparative analysis of 70 pancreatic cancer cases versus healthy controls; PDAC samples and healthy age-matched samples were collected from 2016 to 2017 at Tianjin Medical University Cancer Institute and Hospital, with the PDAC samples including stage I–IV. Cohort 2: evaluation of 68 stage I–II pancreatic cancer patients categorized by NLR thresholds (low vs. high groups). This cohort enrolled patients who underwent radical R0 resection and who were histologically diagnosed with PDAC at the Tianjin Medical University Cancer Institute and Hospital (China) between 2011 to January 2013. Until the last follow-up date of June 30, 2016, 10 patients were lost to follow-up. The NLR was measured in all patients before they received any treatment. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the Tianjin Medical University Cancer Institute and Hospital (No. bc.2019104) and informed consent was taken from all participants.

Collection of clinical data

The following data were collected: stage classified according to the eighth edition of the TNM staging system (18), age, sex, histological grade, and the NLR. We determined the NLR cutoff value to be 2.53 based on the median value. Overall survival (OS) was defined as the time from the beginning of resection to the date of death from any cause. Relapse-free survival (RFS) was defined as the interval from the beginning of resection to the date of disease progression or death, whichever occurred first.

Tissue immunofluorescence (IF)

Two sets of PDAC tissues were used for the immunologic assessment of CD8 and CD33 expression: (I) deparaffinization & antigen retrieval: FFPE sections (4 µm) were deparaffinized, rehydrated, and subjected to heat-induced epitope retrieval (citrate buffer, pH 6.0, 95 ℃, 20 min); (II) blocking & staining: after permeabilization (0.3% Triton X-10), sections were blocked (10% goat serum) and incubated overnight at 4 ℃ with mouse anti-CD33 (ab11032, Abcam, Cambridge, UK; 1:100) and rabbit anti-CD8 (ab199016, Abcam; 1:100); (III) secondary antibodies: Alexa Fluor 594 (anti-mouse) and 488 (anti-rabbit) were applied (1 h, RT, dark). Nuclei were stained with 4',6-diamidino-2-phenylindole (DAPI) (SouthernBiotech, Birmingham, AL, USA; 1 µg/mL, 5 min); (IV) imaging: slides were mounted with ProLong Gold and imaged by confocal microscopy (DAPI: blue; CD8: green; CD33: red). Controls: no-primary-antibody and isotype controls were included.

Evaluation of TILs

To evaluate the immune status, tissue IF scores were determined by two observers who were blinded to clinical data. CD33⁺ and CD8⁺ cells were used to indicate the abundance of MDSCs and CD8⁺ T cells in tumor stroma. CD8⁺ T cells >20 per high-power field (HPF) and MDSCs >10 per HPF were defined as high CD8⁺ T cell and high MDSC infiltration, respectively. The stained specimens were digitally scanned using a Leica microscope (Wetzlar, Germany). TILs were assessed under 200× magnification, with evaluation across multiple HPFs (typically 3–10 fields), and the final TIL density was calculated as the average value.

Statistical analyses

Statistical analyses were performed using SPSS 21.0 (The R Foundation for Statistical Computing). The Kaplan-Meier method was used for OS and RFS analysis, and the difference between survival curves was tested via the log-rank test. Cox regression Model Specification: We employed multivariable Cox proportional hazards regression to assess associations between age, tumor size, e.g., and OS and RFS. The proportional hazards assumption was verified using Schoenfeld residuals (all P>0.05). Variable selection: covariates were chosen a priori based on clinical relevance and prior literature. A stepwise selection approach (backward elimination with P<0.10 for retention) was also applied to confirm robustness. Statistical significance: all reported P values are two-sided, with P<0.05 considered statistically significant. Hazard ratios (HRs) and 95% confidence intervals (CIs) are reported for each predictor.

Adjustments: the final model adjusted for [list covariates, e.g., age, sex, tumor size].

Spearman rank correlation analysis was used to determine the correlation of two continuous variables. A P value <0.05 was considered statistically significant.

Results

Efficacy of peripheral blood NLR as a biomarker in PDAC

The characteristics of samples from healthy controls and patients with PDAC are presented in Table S1. We compared the level of peripheral blood NLR in the two groups. The level of peripheral blood NLR in PDAC samples was significantly higher than that in healthy controls (Figure 1A). Based on receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) for peripheral blood NLR was 0.722 (P<0.001; Figure 1B). The maximum Youden index was acquired when the ratio was at 2.225, and the sensitivity and specificity were 64.3% and 85%, respectively. More importantly, the level of NLR in patients with stage I–II PDAC (early PDAC) was higher than that in samples from healthy controls (Figure 1C). Based on ROC curve analysis, the area under the curve (AUC) was 0.702 (P<0.001; Figure 1D). The maximum Youden index was acquired when the ratio was 2.325, and the sensitivity and specificity were 64% and 86.7%, respectively.

Figure 1 Peripheral blood NLR as a potential biomarker in PDAC. (A) The NLR in healthy controls (n=60) and patients with PDAC (n=70). (B) According to ROC analysis, NLR was a diagnostic biomarker for PDAC, and an area under the ROC curve of NLR was 0.722 (P<0.05). (C) The NLR in healthy controls (n=60) and patients with stage I–II PDAC (n=25). (D) According to ROC analysis, NLR was a diagnostic biomarker for early-stage PDAC, and the area under the ROC curve of NLR was 0.702 (P<0.05). **, P<0.01. AUC, area under the curve; NLR, neutrophil-to-lymphocyte ratio; PDAC, pancreatic ductal adenocarcinoma; ROC, receiver operating characteristic.

Peripheral blood NLR in PDAC was associated with poor OS and RFS

There were 68 patients with the histologically proven PDAC included in the study. Peripheral blood NLR was divided into two grades according to the median value: a low-ratio group (NLR <2.53) and a high-ratio group (NLR ≥2.53). The number of participants in the NLR-low group and NLR-high group was 34 and 34, respectively. The median OS of all patients was 16.9 months (range, 3.8–47 months). Patients with PDAC and a high NLR had a significantly poorer OS (P<0.05) [12.3 months (range, 4.6–26 months) vs. 18.0 months (range, 3.8–47 months)] (Figure 2A). The median RFS of the patients with PDAC was 10.03 months (range, 1.27–41 months), and the patients with a low NLR tended to have a better RFS than did those with a high NLR (P<0.001) [14 months (range, 1.83–41 months) vs. 6 months (range, 1.27–16 months)] (Figure 2B).

Figure 2 Peripheral blood NLR in PDAC was associated with poor OS and RFS. Kaplan-Meier curves of (A) OS and (B) RFS in patients with PDAC according to the different levels of the NLR. P values were determined using the log-rank test. PDAC, pancreatic ductal adenocarcinoma; NLR, neutrophil-to-lymphocyte ratio; RFS, relapse-free survival; OS, overall survival.

Survival analyses with consideration of the clinicopathological characteristics

We used a Cox proportional hazard model, and univariate analysis (Table 1) indicated that lymph node metastasis, TNM stage, CD8⁺ T cells, MDSCs, and the NLR were related to OS and RFS. However, multivariate analysis (Table 2) indicated that TNM stage and CD8⁺ cells were independent prognostic factors for OS in PDAC patients, while MDSC served as an independent prognostic factor for RFS.

NLR was positively correlated with the clinicopathologic parameters of patients with PDAC

To assess the association between NLR and clinicopathological parameters in patients with PDAC, we divided the patients into two groups based on the median NLR and analyzed its correlation with prognostic factors. As shown in Table 3, NLR was not associated with age, gender, tumor size, and histological grade. However, NLR expression was positively correlated with TNM stage (χ²=4.533; P=0.03; r=0.258), lymph node metastasis (χ²=4.769; P=0.03; r=0.265), CD8⁺ T cell (χ²=7.950; P=0.005; r=−0.342) and MDSC (χ²=8.500; P=0.004; r=0.354) in patients with PDAC (Table 3).

Association between NLR and the TIME

To evaluate whether the NLR values in the preoperative blood sample were correlated with the TIL status in the TIME, we performed IF for CD8 and CD33 (Figure 3). Our results indicated a negative correlation between CD8⁺ T cells and CD33⁺ cells (MDSCs). A high density of CD8⁺ T cells was observed concurrently with a low density of CD33⁺ cells (MDSCs) (Figure 3A). A low density of CD8⁺ T cells was observed concurrently with a high-density of CD33⁺ cells (MDSCs) (Figure 3B). At the same time, CD8⁺ T-cell infiltration was significantly correlated with increased OS (P=0.01) and RFS (P=0.03). Meanwhile, high MDSC infiltration was significantly correlated with decreased OS (P=0.02) and RFS (P=0.007) (Figure S1A-S1D).

Figure 3 Expression of CD8⁺ T cells and MDSCs in PDAC. Representative images of pathology slides (with DAPI staining) showed a negative correlation between CD8⁺ T cells and CD33⁺ cells (MDSCs). (A) A high density of CD8⁺ T cells was observed concurrently with a low density of CD33⁺ cells (MDSCs). (B) A low density of CD8⁺ T cells was observed concurrently with a high-density of CD33⁺ cells (MDSCs). DAPI, 4',6-diamidino-2-phenylindole; MDSC, myeloid-derived suppressor cell; PDAC, pancreatic ductal adenocarcinoma.

The correlations between baseline NLR values and TIL status in patients with PDAC are shown in Figure 4. Compared to a low NLR, a high NLR was significantly and negatively correlated with tumoral CD8⁺ TIL abundance (r=−0.345, P=0.004). Additionally, NLR was positively correlated with stromal CD33⁺ cell density (r=0.407; P=0.001).

Figure 4 Association between the NLR and the TIME. Relation between the NLR value in preoperative blood tests and the density of stromal (A) CD8⁺ and (B) CD33⁺ cells in the TIME. MDSC, myeloid-derived suppressor cell; NLR, neutrophil-to-lymphocyte ratio; TIL, tumor-infiltrating lymphocytes; TIME, tumor-immune microenvironment.

Discussion

Patients with PDAC have an extremely poor prognosis due to the lack of early symptoms, often resulting in metastasis at the time of diagnosis (19). Conventional biomarkers have limitations; therefore, it is urgent to identify reliable sensitive serum biomarkers that can represent the different phenotypes of PDAC (20).

The NLR is a standard hematologic marker reflecting inflammation (11,12). It has also been reported to be a prognostic marker in many types of cancer (13,14). Specific cancers, including breast, prostate, non-melanoma skin, colon and melanoma, experience increased all-cause and cardiovascular mortality in the higher NLR group compared to the lower NLR group (15,16). However, whether NLR is also associated with the TIME or has prognostic value for patients with PDAC remains unclear.

In our study, we compared the level of NLR in patients with PDAC and healthy controls, and we found the NLR in patients with PDAC was significantly higher than that in healthy controls. Next, the NLR was negatively associated with OS and RFS in patients with PDAC. Third, NLR was found to be a prognostic factor for PDAC and early-stage PDAC.

Inflammation and immune microenvironment of cancer are essential to gaining a comprehensive understanding of the TIME and devising new cancer therapies (21,22). In the TIME, immunosuppressive cells inhibit cytotoxic T lymphocytes (CTLs) and create a “sanctuary” for tumor cell proliferation and metastasis (23). The TIME is crucial for tumor recurrence, prognosis, and therapeutic responses (24). Assessing the status of the immune microenvironment can provide a more complete picture of the patient’s condition, particularly if done noninvasively.

An increasing number of recent studies suggest that NLR is related to TIME. The interaction between neutrophils and lymphocytes plays an important role in the TIME (25,26). Neutrophils promote tumor progression and directly suppress tumor cytotoxicity (27,28). The ratio of CD10⁺ to CD20⁺ B lymphocytes in the TIME has been identified to be a prognostic marker in lung squamous cell carcinoma (29). CD163⁺/CD206⁺ cells M2 macrophages play a significant role in the tumor microenvironment of bladder cancer (30). However, Mishalian et al. reported that the functions of neutrophils vary across different TIMEs. In early-stage tumor development, neutrophils exert greater cytotoxic effects on tumor cells, while in the later stage, they exert obvious immune-suppressing effects (31). Tesi refers to the MDSC as the “queen bee” of the TIME (32). Granulocytic MDSCs (Gr-MDSCs) and monocytic MDSC (Mo-MDSCs) are two distinct subsets of MDSCs. Mo-MDSCs have been shown to be a phenocopy of macrophages in the TIME (33), and the phenotype of Gr-MDSCs overlap with those of neutrophils due to Gr-MDSCs secreting arginase-1 and reactive oxygen species (ROS) to suppress T cells (34,35). PDAC is characterized by the presence of multiple immune-suppressive elements (36). Therefore, it is necessary to develop reliable immune signatures that reflect the immune status of the TIME in PDAC.

In our study, we examined the expression of CD8⁺ T cells and MDSCs in PDAC tissues: patients with PDAC and high CD8⁺ T-cell infiltration had a significantly better OS and RFS than did those with low CD8⁺ T-cell infiltration, while the opposite was observed for MDSCs (Figure S1). More importantly, we found an inverse correlation between the NLR and the abundance of CD8⁺ T cells in patients with PDAC and a positive correlation between the NLR and the abundance of MDSCs (Figure 4). These results suggest that the level of NLR can reflect the status of the TIME in PDAC, with a high NLR indicating an immunosuppressive state and a low NLR indicating an immune-stimulated state.

Our studies suggest that NLR could be a biomarker that can inform treatment selection. However, due to the study’s retrospective nature, prospective, studies with larger, more diverse cohorts incorporating NLR’s temporal dynamics are required to validate the value of the NLR as a predictor of outcomes for patients affected by PDAC and early-stage PDAC and in reflecting their specific TIME.

Conclusions

We assessed the value of peripheral blood NLR in predicting the prognosis of patients with PDAC and early-stage PDAC. Our results indicated that the NLR may be a prognostic factor. This study is the first to examine the correlation between peripheral blood NLR and the TIME, and we found that the NLR was inversely correlated with the abundance of tumoral CD8⁺ T cells and positively correlated with that of CD33⁺ cells (MDSCs). In the TIME of patients with PDAC, prospective multicenter trials and large-sample studies are necessary to ascertain the clinical value of peripheral blood NLR in PDAC treatment.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-283/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-283/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-283/prf

Funding: This study was partially supported by funds from Tianjin Education Commission Research Project (No. 2023ZD022).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-283/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.The study was approved by the Ethics Committee of the Tianjin Medical University Cancer Institute and Hospital (No. bc.2019104) and informed consent was taken from all participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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