The ratio of intratumoral CD15+ neutrophils to CD8+ lymphocytes predicts recurrence in gastric cancer patients after resection

doi:10.21203/rs.3.rs-2734429/v1

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The ratio of intratumoral CD15⁺ neutrophils to CD8⁺ lymphocytes predicts recurrence in gastric cancer patients after resection

https://doi.org/10.21203/rs.3.rs-2734429/v1

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An elevated neutrophil-to-lymphocyte ratio (NLR) in the peripheral blood is an independent prognostic indicator of various cancers. However, whether a similar immune cell balance in tumor tissues influences the prognosis of cancer patients is not well understood. This study aimed to investigate the prognostic relevance of the intratumoral immune cell balance in gastric cancer patients. The study included 82 consecutive patients who underwent curative resection for gastric cancer. Intratumoral Cluster of Differentiation (CD) 15- and CD8-positive cells were evaluated using immunohistochemical staining, and clinicopathological factors and prognoses were analyzed. The effects of these scores on overall survival (OS) and relapse-free survival (RFS) were estimated using Cox proportional hazards regression. Patients with high intratumoral CD15/CD8 ratios had significantly lower OS and RFS compared to those with low CD15/CD8 ratios (P ). In addition, a high CD15/CD8 ratio was associated with lymph node metastasis (P = 0.019). Patients with a high NLR had a significantly lower RFS than those with a low NLR (P = 0.0050). Multivariate analysis revealed that the intratumoral CD15/CD8 ratio was an independent prognostic indicator of RFS (Hazard ratio = 4.7, 95% confidence interval = 1.4–16.2). Therefore, an increased intratumoral CD15/CD8 ratio is an independent predictor of survival following gastric cancer resection and is associated with lymph node metastasis and microscopic lymph vessel invasion. Establishing the postoperative follow-up schedule and adjuvant therapy may be clinically advantageous.

NLR

Gastric cancer

RFS

CD15/CD8

Inflammation and the immunological milieu within tumor tissues have long been associated with tumor progression and prognosis, and the detailed mechanisms underlying this association are currently the focus of extensive research [1]. Gene expression analysis of a large cohort of cancer tissues using The Cancer Genome Atlas (TCGA) samples has validated that the expression of immune-related genes in the tumor environment is second in importance to cell cycle-related genes, and this event is prevalent across a wide range of carcinomas [2]. Furthermore, in a study that predicted the leukocyte fraction infiltrating the tumor based on elevated gene expression in tumor tissues, high gene expression derived from specific lymphocyte fractions, such as CD8 lymphocytes, was associated with a good prognosis, whereas gene expression related to myeloid leukocytes, such as neutrophils, correlated with a poor prognosis [3]. These reports suggest that the balance of representative leukocytes, CD8-positive lymphocytes and neutrophils in tumor tissue, could serve as a predictive indicator of patient prognosis. A comprehensive genetic analysis using TCGA samples revealed high leukocyte infiltration in gastric cancer tissues, suggesting that the immunological landscape in the tissue is critical for tumor growth and progression [3].

This study aimed to examine the prognostic significance of the ratio of CD15-positive neutrophils to CD8-positive lymphocytes in cancer tissues of patients with resected gastric cancer using immunohistochemistry to verify whether this ratio might be applicable in clinical practice. We also analyzed clinicopathological correlations to estimate how these factors would affect prognosis. The correlation between the local tumor and the systemic immunological landscape was evaluated by measuring the neutrophil-lymphocyte ratio (NLR) in peripheral blood, an indicator of the systemic immune state that has been shown to predict prognosis in gastric cancer.

Patient samples

This study included 82 consecutive patients who underwent curative surgery for gastric cancer at the Fukushima Medical University, Japan, from January 2009 to December 2011. Informed consent was obtained from all patients to collect and analyze specimens for this study. This study was performed in line with the principles of the Declaration of Helsinki. The experimental protocols were reviewed and approved by the Fukushima Medical University Ethics Committee (Approval number: 2022, July 2, 2014).

The study was performed in accordance with the ethical guidelines of studies on medical science for humans (Ministry of Education, Culture, Sports, Science and Technology, Ministry of Health, Labor and Welfare Notification No. 3) announced in February 2017. All patients who underwent distal gastrectomy or gastrectomy with lymph node dissection for radical cure were included in this study. Patients with other forms of primary cancer resected during the same operation were excluded. Pathological findings were evaluated based on the 8th Edition of the TNM Classification of Gastric Cancer [19].

Immunohistochemistry

Following the standard protocol, immunohistochemical staining for CD15 and CD8 was performed on 4-µm formalin-fixed paraffin-embedded tissue sections. After deparaffinization, the antigen was microwave-activated for 15 min, and endogenous peroxidase activity was inhibited for 20 min with 0.3% aqueous hydrogen peroxide. The tissue samples were subsequently treated with 5% powdered skim milk to block nonspecific reactions with antibodies. Slides were incubated for 20 min at 4°C with the following primary antibodies: CD15 (1:50 dilution, mouse monoclonal, clone MMA, BD Biosciences, San Jose, CA, USA) and CD8 (1:50 dilution, mouse monoclonal, clone C8/144B, DAKO, Santa Clara, CA, USA). Slides were then incubated with biotinylated anti-mouse secondary antibodies (rabbit polyclonal, 1:400 dilution; DAKO, Santa Clara, California, USA). Antigen visualization was performed using the VECTASTAIN Elite ABC Standard Kit (1:200 dilution; VECTOR Laboratories, San Diego, CA, USA). Five randomly selected samples from serial sections of anti-CD8 and anti-CD15 stained slides were selected and observed at 400\(\times\) magnification. Morphological characteristics were considered to exclude eosinophils that were positive for CD15 when identifying CD15-positive cells.

Nlr Of Peripheral Blood

A blood test was performed on peripheral blood collected within 4 weeks before the surgery. The total white blood cell count and percentages of neutrophils and lymphocytes were calculated using electronic records from hospital laboratory. The NLR was defined as the absolute neutrophil count divided by the absolute lymphocyte count.

Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics version 23 (IBM, Armonk, NY, USA) and GraphPad Prism, version 7.03 (GraphPad Software, San Diego, CA, USA). Overall survival (OS) was defined as the period between the date of surgery and death, while relapse-free survival (RFS) was defined as the period between the date of surgery and recurrence. The cutoff values for low and high NLR and CD15/CD8 ratio were determined using receiver operating characteristic (ROC) curve analysis. The survival curve was prepared using the Kaplan–Meier method, and statistical differences were examined using the log-rank test. The correlation between the immune balance in tissue and clinicopathological factors was evaluated using the chi-square or Fisher’s exact test. Univariate and multivariate analyses were performed using the Cox proportional hazard model. For all statistical analyses, the statistical significance (P-value) was set at 0.05.

Patient background

The patient demographics and clinical characteristics are presented in Table 1. The median age of patients was 69 years. Although patients were predominantly male, neither age nor sex affected the prognosis. None of the patients were treated with preoperative adjuvant chemotherapy. The median follow-up time after surgery was 61 months (range: 4–94 months). In total, 21 patients died at the end of the follow-up period. Among them, 14 patients died from cancer-unrelated diseases, and 11 patients experienced tumor relapse. The median time to relapse was 17 months (range: 6–29 months). Twenty-four patients received postoperative adjuvant chemotherapy (Table 1).

Table 1

Patient demographic and clinical characteristics.
Factors	Number or period
All cases	82
Median follow-up time	61 months (4–94)
Tumor relapse	11 (12.6%)
Median time to relapse	17 months (6–29)
Adjuvant chemotherapy	24 (27.5%)
Age < 69	40 (48.7%)
(median; 69, 31–89) ≧ 69	42 (51.2%)
Gender Male	63 (76.8%)
Female	19 (23.1%)
Depth of invasion T1a	26 (31.7%)
T1b	29 (35.4%)
T2	6 (7.3%)
T3	7 (8.5%)
T4a	14 (17.1%)
LN metastasis N0	56 (68.3%)
N1	8 (9.8%)
N2	6 (7.3%)
N3	12 (14.6%)
Staging Ⅰ	54 (65.9%)
Ⅱ	12 (14.6%)
Ⅲ	16 (19.5%)
Histological grade differentiated	39 (47.6%)
undifferentiated	43 (52.4%)
Lymphatic invasion ly0	32 (39.0%)
ly1	23 (28.0%)
ly2	8 (9.8%)
ly3	19 (23.2%)
Venous invasion v0	41 (50.0%)
v1	15 (18.3%)
v2	10 (12.2%)
v3	16 (19.5%)
CEA (ng/ml) < 5.0	67 (89.3%)
≧5.0	8 (10.7%)
CA19-9 (U/ml) < 37.0	68 (91.9%)
≧37.0	6 (8.1%)
ALB (g/dl) < 3.8	32 (39.0%)
≧3.8	50 (61.0%)

LN, lymph node; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19 − 9; ALB, albumin.

Gastric Cancer Tissue With High Intratumoral Cd15-positive Cells Has A Worse Prognosis

Figure 1a shows representative cases with high and low CD15-positive and CD8-positive cells. The median number of CD15-positive and CD8-positive cells per field of view were 11 (range: 0–209) and 16 (range: 1–88), respectively. The median intratumoral CD15/CD8 ratio was 0.8 (range: 0–18.2). According to ROC curve analysis, the cutoff values for the CD15 positive and CD8 positive cells were 18 and 15, respectively, based on an RFS of 5 years. Patients were divided into two groups: one group with high CD15- and CD8-positive cells and the other with low CD15- and CD8-positive cells (Fig. 1b, c). Patients with high intratumoral CD15-positive cells in gastric cancer tissue had worse RFS than those with low intratumoral CD15-positive cells. However, the quantity of intratumoral CD8-positive cells did not affect the prognosis.

High Intratumoral Cd15/cd8 Ratio Worsen Prognosis

ROC curve analysis revealed that the cutoff value for the CD15/CD8 ratio was 2.25 based on an RFS of 5 years, as depicted in Fig. 2a. Patients were divided into two groups: one group included patients with a high CD15/CD8 ratio, and the other included patients with a low CD15/CD8 ratio. Patients with a high intratumoral CD15/CD8 ratio had worse RFS and OS than those with a low intratumoral CD15/CD8 ratio. The five-year RFS in the low and high CD15/CD8 groups were 93.9% and 56.3%, respectively (P < 0.0001). The hazard ratio (HR) for RFS was 10.8 (HR:3.2–37.2, P < 0.0001). The five-year OS in the low and high CD15/CD8 groups were 77.3% and 43.8% (P = 0.003), respectively. The HR for OS was 3.3 (HR: 1.4–7.6, P = 0.005).

A high intratumoral CD15/CD8 ratio is associated with lymph node metastasis and lymphatic invasion in gastric cancer tissue

The demographic characteristics of each patient group are presented in Table 2. Patients with a higher intratumoral CD15/CD8 ratio had a significantly higher incidence of lymph node metastasis (P = 0.019) and lymphatic invasion (P = 0.005).

In contrast, the incidence of the depth of invasion (P = 0.024), lymph node metastasis (P < 0.001), staging (P = 0.013), and lymphatic invasion (P < 0.001) was considerably elevated in patients with a higher NLR.

Table 2

Correlation between intratumoral CD15/CD8 ratio and clinicopathological factors.
Clinicopathological factors	CD15/CD8 ratio Low (< 2.25) High ( ≧ 2.25)		P-value	NLR Low (< 3.07) High ( ≧ 3.07)		P-value
All cases 82	66	16		63	19
Age ༜69	31	6	0.495	31	6	0.176
(median; 69, 3189) ≧69	35	10	0.495	32	13	0.176
Gender male	49	14	0.259	47	16	0.539
female	17	2	0.259	16	3	0.539
Depth of invasion T1a	23	3	0.214	24	2	0.024*
T1b–T4	43	13	0.214	39	17	0.024*
LN metastasis N0	49	7	0.019*	51	5	< 0.001*
N1–N3	17	9	0.019*	12	14	< 0.001*
Staging Ⅰ	45	9	0.367	46	8	0.013*
Ⅱ–Ⅲ	21	7	0.367	17	11	0.013*
Histological grade differentiated	31	8	0.828	32	7	0.286
undifferentiated	35	8	0.828	31	12	0.286
lymphatic invasion ly0, ly1	49	6	0.005*	50	5	< 0.001*
ly2, ly3	17	10	0.005*	13	14	< 0.001*
venous invasion v0, v1	47	9	0.249	45	11	0.266
v2, v3	19	7	0.249	18	8	0.266
CEA (ng/ml) < 5.0	55	12	1.000	54	13	0.356
≧5.0	7	1	1.000	5	3	0.356
CA19-9 (U/ml) < 37.0	55	13	0.583	55	13	0.111
≧37.0	6	0	0.583	3	3	0.111
ALB (g/dl) < 3.8	23	9	0.115	21	11	0.054
≧3.8	43	7	0.115	42	8	0.054

P-values were estimated using chi-squared test or Fisher’s exact test * P < 0.05.

CD, cluster of differentiation; LN, lymph node; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19 − 9; ALB, albumin.

Nlr And Cd15/cd8 Ratios Are Independent Of Each Other

NLR was determined using preoperative peripheral blood data. NLR had a median value of 2.29 (range: 0.83–9.67). According to the ROC curve, based on the 5-year RFS, the optimal NLR cut-off value was 3.07. Patients with a high NLR had a worse RFS (Fig. 2b). There was no relationship between the intratumoral CD15/CD8 ratio and NLR (Fig. 2c).

Relapses occurred in 9 of the 29 patients with a high NLR or CD15/CD8 ratio, at a relapse rate of 31.0%. In contrast, recurrence occurred in 2 of 53 patients with low NLR or CD15/CD8 ratio, at a recurrence rate of 3.8%.

A High Intratumoral Cd15/cd8 Ratio Is An Independent Prognostic Factor Of Gastric Cancer

The RFS-related factors were evaluated using univariate and multivariate analyses. These analyses also included albumin (ALB), a component of prognostic scores, such as the Prognostic Nutritional Index and Glasgow Prognostic Score. Univariate analysis revealed a significant difference in intratumoral CD15/CD8 ratio, NLR, and venous invasion. Multivariate analysis, which included the intratumoral CD15/CD8 ratio, NLR, lymph node metastasis, lymphatic invasion, venous invasion, and ALB, revealed that the intratumoral CD15/CD8 ratio was independently associated with RFS (Table 3).

Table 3

Univariate and Multivariate Cox proportional hazards regression analysis of clinicopathological factors for relapse-free survival.
Clinicopathological factors	Univariate analysis		Multivariate analysis
	Hazard ratio	P	Hazard ratio	P
Depth of invasion (T1a or T1b–T4)	37.6 (0.2, > 1000)	0.179
Lymph node metastasis (N0 or N1–N3)	284.3 (0.5, > 1000)	0.077**	8.0E + 3 (< 0.001, > 1000)	0.919
Histological grade (differentiated or undifferentiated)	2.4 (0.6, 8.9)	0.204
lymphatic invasion (ly0,ly1 or ly2,ly3)	273.0 (0.6, > 1000)	0.076**	2.1E + 4 (< 0.001, > 1000)	0.914
venous invasion (v0,v1 or v2,v3)	4.1 (1.2, 14.0)	0.025*	2.0 (0.4, 8.6)	0.377
Intratumoral CD15/CD8 ratio (< 2.25 or ≧ 2.25)	10.8 (3.2, 37.2)	< 0.001*	7.8 (1.8, 33.5)	0.005*
NLR (< 3.07 or ≧ 3.07)	4.7 (1.4, 15.3)	0.011*	2.1 (0.4, 9.5)	0.354
CEA (< 5.0 or ≧ 5.0) (ng/ml)	0.04 (< 0.001, 297.2)	0.481
CA19-9 (< 37 or ≧ 37) (U/ml)	1.3 (0.2, 10.6)	0.794
ALB (< 3.8 or ≧ 3.8) (g/dl)	0.3 (0.1, 1.1)	0.066**	1.2 (0.3, 4.8)	0.798
* P < 0.05, ** P < 0.1

CD, cluster of differentiation; NLR, neutrophil-to-lymphocyte ratio; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19 − 9; ALB, albumin

The intratumoral CD15/CD8 ratio predicts the recurrence of gastric cancer in patients with stage II and III tumors

Only Stage II and III cancer patients who were candidates for postoperative adjuvant chemotherapy were included in the analysis. The RFS of patients with a high intratumoral CD15/CD8 ratio was significantly worse than that of patients with a low CD15/CD8 ratio (Fig. 3). The five-year RFS in the low and high CD15/CD8 groups were 81.0% and 14.3%, respectively (P < 0.0001). The HR for RFS was 9.3 (HR: 2.5–34.8, P = 0.001). The five-year RFS in the low and high NLR groups were 70.6% and 54.5%, respectively (P = 0.241). HR for OS was 2.1 (HR: 0.6–7.2, P = 0.255).

In this study, we investigated the relationship between recurrence and prognosis in patients who underwent gastrectomy for radical resection and the ratio of CD15-positive neutrophils to CD8-positive lymphocytes in cancer tissue (CD15/CD8 ratio), which may reflect the immunologic landscape within the gastric cancer tissue. Furthermore, the correlation between this value and clinicopathological factors was investigated, and the mechanism by which this value influences prognosis was determined.

An elevated CD15/CD8 ratio in gastric cancer tissues is associated with poor overall survival and recurrence-free survival. Immunohistological investigations validate the results of comprehensive gene expression analysis in TCGA, and these findings may be applied to clinical practice as a simple, rapid, and cost-effective prognostic factor. Similar results were found in a previous investigation evaluating the fraction of tissue-infiltrating lymphocytes in gastric cancer by immunostaining for CD3, CD8, CD45RO, and CD66b, with the lymphocyte-to-neutrophil ratio being a prognostic factor, although the mechanism was not elucidated [4].

In this study, we analyzed the correlation between the CD15/CD8 ratio and clinicopathological factors and found that lymph node metastasis was significantly more frequent in tumor tissues with a high ratio. Recent studies have demonstrated that cancer cells restructure their immune landscape by secreting cytokines and chemokines. This phenotype, termed cancer cell-intrinsic inflammation, triggers a metastatic cascade. Animal studies have reported that cancer cell-intrinsic inflammation is amplified with cancer progression and triggers neutrophil-dependent metastasis [5–7]. Our findings suggest that a higher CD15/CD8 ratio in cancer tissues may indicate an immunological milieu susceptible to lymphatic invasion and lymph node metastasis. Another possible mechanism is decreased immune surveillance of cancer cells by lymphocytes due to the suppression of CD8 cells by infiltrating neutrophils.

The polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC), a potent immunosuppressive cell type derived from neutrophils, is a well-known cancer-associated neutrophil [8]. PMN-MDSCs are known to inhibit lymphocytes, decreasing their quantity and function. The mechanism by which PMN-MDSCs release arginase 1 and reduce the arginine concentration required for lymphocyte proliferation in the surrounding tissues [9] and the function of lymphocytes in response to reactive oxygen species (ROS), peroxynitrite, and prostaglandin E2 (PGE2) has been elucidated [10]. Due to the lack of an immunostaining marker that can differentiate PMN-MDSCs from neutrophils, we cannot identify whether the CD15-positive neutrophils observed in this investigation were PMN-MDSCs. However, tumor-infiltrating neutrophils represent a potential novel target for cancer therapy [10].

Adjuvant chemotherapy is currently the gold standard of treatment for Stage II and III gastric cancer, with a good prognosis in the treatment group [11, 12]. However, identifying patients at high risk of recurrence and stratifying treatment is necessary for patient safety and cost-effective use of healthcare resources. When patients in our study were stratified by stage, the CD15/CD8 ratio accurately predicted the chance of tumor recurrence, even in stage II and III subgroups. The CD15/CD8 ratio may be a biomarker for predicting cancer recurrence and stratifying candidates for adjuvant therapy, although additional studies with larger patient populations are required.

The neutrophil-to-lymphocyte ratio (NLR), a measure of systemic immunological balance, has been identified as a prognostic predictor in several carcinomas [13, 14]. In the present study, an elevated NLR also affected recurrence and prognosis. The concern of whether an increased NLR reflects the immune environment within a tumor has attracted the attention of researchers. Reports suggest elevated NLR correlates with decreased tumor-infiltrating CD8-positive T lymphocytes (TILs) [15, 16]. However, this study is the first to explore the link between the CD15/CD8 ratio and NLR in gastric cancer tissue. Although the combination of NLR and TIL has been established as a good predictor of prognosis [15], the combination of NLR and CD15/CD8 ratio may be a more accurate predictor of cancer recurrence.

This study has several limitations. Anti-CD15 antibodies stain eosinophils, monocytes, histiocytes, and neutrophils. This study identified tumor-infiltrating neutrophils as CD15-positive cells, and excluded non-neutrophils based on their morphological characteristics. Neutrophil identification methods must be simplified for future clinical applications. Our CD15-based approach should be compared to previously reported CD66b-based methods. Moreover, CD8-positive cells comprise only a small fraction of the lymphocytes and are not always included in the total lymphocyte count. Thus, the intratumoral CD15/CD8 ratio measured in this study and the total neutrophil-to-lymphocyte ratio (NLR) were not identical. Infiltration of small fractions of lymphocytes, such as γδ lymphocytes, has been demonstrated to be a prognostic factor in studies using TCGA samples [2]. Further research is required to identify better prognostic indicators using a more finely fractionated subset of lymphocytes and neutrophils.

In conclusion, the CD15/CD8 ratio in the tumor is a predictor of cancer recurrence in gastric cancer patients, and combining the NLR with the CD15/CD8 ratio could more accurately predict cancer recurrence. However, a quick evaluation of the immunological landscape using immunostaining in tumor tissue can provide prognostic information in addition to TNM staging and may assist in establishing an appropriate test schedule for recurrence confirmation and identifying the need for adjuvant therapy. However, these findings should be validated in larger independent populations.

Acknowledgments

We express our gratitude to Professor Takashi Kimura and Dr. Zenichiro Saze for their assistance and guidance in conducting this research. We also thank Professor Shigeru Marubashi, Professor Koji Kono, Professor Tatsuo Shimura, Professor Akira Kenjo, Dr. Ryo Okada, Dr. Teruhide Ishigame, Dr. Yasuhide Kofunato, Dr. Naoya Sato, Dr. Hiroyuki Hanayama, Dr. Takeshi Tada, and Dr. Makoto Muto for their participation in multiple discussions that led to the development of various ideas. We want to thank Ms. Eiko Otomo, Ms. Yukiko Kikuta, Ms. Hidemi Sasaki, Ms. Yukari Yuda, Ms. Mie Otsuki, and Ms. Taeko Saito for their extensive support and guidance during this research.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Takashi Kimura, Zenichiro Saze and Junichiro Watanabe. The first draft of the manuscript was written by Takashi Kimura and Junichiro Watanabe and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

The authors did not receive support from any organization for the submitted work.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

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No competing interests reported.

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The ratio of intratumoral CD15⁺ neutrophils to CD8⁺ lymphocytes predicts recurrence in gastric cancer patients after resection

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Abstract

Figures

Introduction

Methods

Patient samples

Immunohistochemistry

Nlr Of Peripheral Blood

Statistical analysis

Results

Patient background

Gastric Cancer Tissue With High Intratumoral Cd15-positive Cells Has A Worse Prognosis

High Intratumoral Cd15/cd8 Ratio Worsen Prognosis

Nlr And Cd15/cd8 Ratios Are Independent Of Each Other

A High Intratumoral Cd15/cd8 Ratio Is An Independent Prognostic Factor Of Gastric Cancer

Discussion

Declarations

References

Additional Declarations

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