Clinic-Pathological Characteristics and Prognostic Value of PD-L1 and HER2 in Gastric Cancer

Abstract

The aim of this study is to study the relationship between programmed cell death-1 ligand (PD-L1) and human epidermal growth receptor 2 (HER2) and the clinical–pathological features of gastric cancer (GC) and its predictive effect on the prognosis of gastric cancer (GC) patients. A retrospective analysis was performed on 113 patients undergoing GC surgery. The expression of PD-L1 and HER2 in GC and paired adjacent nontumor tissues was detected by immunohistochemistry or fluorescence in situ hybridization, and the relationships between PD-L1 and HER2 expression and clinical–pathological features and survival were analyzed by chi-square analysis, Pearson analysis, logistic regression analysis, Kaplan–Meier analysis, and Cox regression model. PD-L1 and HER2 were expressed in tumor tissues, but not in adjacent nontumor tissues. There was no correlation between the expression of PD-L1 and HER2. The expression of PD-L1 in GC was closely related to gender (p = 0.019), regional lymph node (p = 0.006), metastasis (p = 0.033), and survival status (p = 0.033), while HER2 was closely related to tumor differentiation (p = 0.033), regional lymph node (p = 0.016), and tumor–node–metastasis (TNM) stage (p = 0.036). The survival time of PD-L1-positive patients was longer than that of PD-L1-negative patients (p = 0.020). The expression of HER2 showed no difference in overall survival (p = 0.125). Multivariate analysis suggested that the TNM stage (p = 0.001) and PD-L1 expression (p = 0.047) were independent prognostic factors for survival time of GC. The expression of PD-L1 has biological significance in GC, which is closely related to the clinical–pathological characteristics and prognosis of GC patients.

Introduction

Gastric cancer (GC) is among the most common cancer types worldwide and one of the most lethal gastrointestinal cancers. The incidence rate of GC was highest in East Asia. GC is the first leading cause of cancer-associated death in China, with the 5-year survival rate of only 35.9% (Chen et al., 2016). Surgical resection is adopted in the treatment of early GC as far as possible (Sumiyama, 2017). However, most patients with GC are found at an advanced stage. Even if patients with advanced GC receive comprehensive surgical treatment, the 5-year survival rate is still less than 30% (Katai et al., 2018). The ToGA study showed that trastuzumab combined with standard chemotherapy improved survival with human epidermal growth receptor 2 (HER2, also known as ERBB2) overexpression of metastatic GC and gastroesophageal junction cancer (Bang et al., 2010). However, the proportion of patients with HER2 overexpression in GC is low, which limits the use of trastuzumab.

Immune checkpoint inhibitors (ICIs) represent a breakthrough in oncology; the efficacy of ICIs has been demonstrated in numerous tumor types, including bladder cancer, nonsmall cell lung cancer, renal cell carcinoma, and melanoma (Sharma and Allison, 2015). With the rapid development of ICIs in other tumors, immunotherapy for GC has also been rapidly developed. The Keynote-059 study showed that the objective remission rate of GC patients receiving pembrolizumab as second-line or multiline treatment was 11.6%. The objective remission rate of patients with high expression of programmed cell death-1 ligand (PD-L1, also known as CD274) was 15.5% and that of patients with low expression of PD-L1 was 6.4% (Fuchs et al., 2018). We believe that ICIs may be more effective in patients expressing PD-L1. ICI immunotherapy has revolutionized the treatment of most advanced cancers, and a large number of clinical trials have been carried out with tumor neoadjuvant and adjuvant therapy, and some good results have been achieved (Weber et al., 2017; Vansteenkiste et al., 2019).

Nowadays, PD-L1 has become one of the most important negative regulatory factors in immune response. The development of therapeutic antibodies to inhibit the PD-1/PD-L1 pathway has great therapeutic potential in terms of clinical benefits and overall survival of patients. However, tumor cells evade an efficient tumor immune response, especially through the PD-1/PD-L1 axis (Guan et al., 2017; Wang and Wu, 2017), so only a small number of patients can benefit from PD-1/PD-L1 blockade therapy and fewer patients obtain a sustained response (Braun et al., 2016). In this study, we analyzed the expression of PD-L1 and HER2 in GC and evaluated their influence on tumor progression by analyzing their correlation with clinical–pathological characteristics so as to provide more evidence for the treatment strategy of GC.

Materials and Methods

General information

A total of 113 GC tissues and paired adjacent nontumor tissues were collected retrospectively from patients who were diagnosed as having GC by both pathological and clinical methods. The distance between GC tissues and adjacent nontumor tissues was >3 cm. All patients did not receive any radiotherapy or chemotherapy before surgery. All pathological samples in this study were taken from GC tissue removed during surgery and made into tissue chips. The tissues and clinical information were obtained with the consent of patients and approved by the ethics committee of the First Affiliated Hospital of Naval Military Medical University (ID: CHEC2014-098). The influencing factors that may affect the survival time of patients were recorded, including age, gender, tumor size, tumor invasion depth, tumor location, differentiation, regional lymph node, metastasis, tumor thrombus, tumor–node–metastasis (TNM) stage, and preoperative carcinoembryonic antigen level.

Reagents

The PD-L1 antibody (clone 28–8) and HER-2 antibody for immunohistochemistry (IHC) were purchased from Abcam (Cambridge, United Kingdom). The kit for IHC was from Maixin Biotechnologies (Fuzhou, China). Fluorescence in situ hybridization (FISH) was conducted with the pharmDx™ test kit (Dako, Denmark). The sheep-derived serum, phosphate-buffered saline, and hydrogen peroxide were provided by ZSGB-BIO (Beijing, China).

Immunohistochemistry

The IHC assay was performed to detect the expression of PD-L1 and HER2 in GC tissues and paired adjacent nontumor tissues. The specific steps were carried out according to the instructions of the IHC kit. First, we put the tissue chip on a 63° baking sheet for 1 h. It is then dewaxed and hydrated in a fully automatic dyeing machine. Second, we used the high-pressure heat repair method for antigen retrieval, then added the primary antibody for 1 h at 37°C, and added goat anti-rabbit secondary antibody for 30 min at 37°C. Finally, DAB color development kit was developed for 1 min, counterstained with hematoxylin for 10 min, and the film was sealed.

Fluorescence in situ hybridization

HER2 FISH analysis was carried out by using the LSI HER2/CEP17 Dual Probe on the same automated Bond system (Leica Biosystems) according to the manufacturer's instructions. Slides were counterstained with 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI) in antifade solution and examined using an automated CytoVision platform (Leica Biosystems). The complete tissue section was scanned to detect any subpopulations of amplified cells. The HER2 gene amplification status was evaluated by counting signals in 20 nonoverlapping tumor cells with the highest gene counts.

Evaluation of PD-L1 and HER2 staining

The results were independently observed and evaluated by two senior pathologists who were double-blinded. When the PD-L1 protein was interpreted, the membrane staining of tumor cells and membrane staining of infiltrating monocytes in tumor stroma were included in the calculation of positive results. The combined positive score (CPS) was used to count the standard CPS = (total number of PD-L1-positive tumor cells, lymphocytes, and macrophages)/total number of viable tumor cells × 100%. When the CPS ≥1%, PD-L1 expression was determined to be positive (Kulangara et al., 2019).

HER2 IHC staining was evaluated according to the criteria suggested by Hofmann et al. (2008). No membranous staining or staining of <10% of tumor cells was defined as 0, weak staining or staining detected in only one part of the membrane in ≥10% of cells was defined as 1+, moderate/weak complete or basolateral membranous staining in ≥10% of cells was defined as 2+, and strong complete or basolateral membranous staining in ≥10% of neoplastic cells was defined as 3+. The HER2-positive status was defined as IHC3+ and IHC2+ was defined as equivocal, and IHC0 and 1+ belonged to the HER2-negative status. For tumors with IHC2+, FISH was performed to confirm the results. The threshold for HER2 amplification was a ratio of ≥2.0 between the HER2 gene copy number and chromosome 17 centromere, which is defined as HER2-positive status.

Statistical analyses

The correlation between PD-L1, HER2 expression, and clinical–pathological parameters of GC patients was analyzed by chi-square test, and multivariate logistic regression analysis was used to analyze the variables. The correlation between PD-L1 and HER2 was analyzed using the Pearson method. The Kaplan–Meier method was used for survival analysis to draw the survival curve, and the difference in survival was estimated using the log-rank test. Univariate and multivariate Cox regression analysis was performed to determine survival trends adjusted for clinical and demographic factors. The statistical software SPSS 19.0 (SPSS, 19.0, Chicago) was used for all data analyses; p < 0.05 was defined as statistically significant.

Results

Clinical–pathological characteristics of GC patients

This study enrolled 113 GC cases. Among the selected patients, there were 83 males and 30 females, aged 25 to 82 years, with an average 67.5 ± 13.6 years; 24 patients had tumors <3 cm in diameter, 65 patients had tumors 3–6 cm in diameter, and 24 patients had tumors with diameter >6 cm. The high, middle, and low differentiation rates of tumors were 11 (9.7%), 57 (50.5%), and 45 (39.8%). The number of patients with TNM stage I, II, III, and IV GC was 25 (22.1%), 22 (19.5%), 48 (42.5%), and 18 (15.9%), respectively. There were 5 cases of vascular cancer thrombus and 108 cases without vascular cancer thrombus.

Expression of PD-L1 and HER2 in GC patients

We detected the expression of PD-L1 and HER2 in 113 GC and paired adjacent nontumor tissues by IHC assay. As shown in Figure 1, PD-L1 and HER2 were located mainly at the cell membrane. PD-L1 and HER2 were not expressed in adjacent nontumor tissues. The positive expression levels of PD-L1 and HER2 in GC tissues were 45.1% (51/113) and 20.4% (23/113), respectively.

FIG. 1.

Expression of PD-L1 and HER2 in GC tissues and adjacent nontumor tissues. (a) Positive expression of PD-L1 in GC tissues. (b) Negative expression of PD-L1 in GC tissues. (c) Negative expression of PD-L1 in adjacent nontumor tissues. (d) Positive expression of HER2 in GC tissues. (e) Negative expression of HER2 in GC tissues. (f) Negative expression of HER2 in adjacent nontumor tissues detected by immunohistochemistry. GC, gastric cancer; HER2, human epidermal growth receptor 2; PD-L1, programmed cell death-1 ligand. Color images are available online.

Relationship between PD-L1 and HER2 expression and clinical–pathological features of GC patients

The 113 cases of GC patients were divided into two groups according to the expression of PD-L1 or HER2. As shown in Table 1, PD-L1 expression was significantly correlated with gender (p = 0.019), regional lymph node (p = 0.006), metastasis (p = 0.033), and survival status (p = 0.033). There was no relationship between PD-L1 expression and other clinical–pathological features of GC patients (p > 0.05). Multivariate logistic regression analysis showed that PD-L1 expression was related to gender (p = 0.026) and regional lymph node (p = 0.008) (Table 2). HER2 expression was significantly correlated with tumor differentiation (p = 0.033), regional lymph node (p = 0.016), and TNM stage (p = 0.036) (Table 3). As shown in Table 4, multivariate logistic regression analysis showed that HER2 expression was related to regional lymph node only (p = 0.019). Pearson analysis showed that there was no correlation between the expression of PD-L1 and HER2 in tumor tissues (r = 0.116, p = 0.222) (Table 5). We also analyzed the correlation between PDL1 and HER2 in the GEPIA database, and data of the GEPIA database came from TCGA and GTEx; according to the Pearson test, there was no correlation between the two expression levels in GC (r = −0.02, p = 0.64) (Fig. 2).

FIG. 2.

The correlation between PD-L1 and HER2. There was no correlation between PD-L1 and HER2 in gastric cancer by GEPIA database analysis (r = −0.02, p = 0.64). p-Value is based on the Pearson analysis. GEPIA, Gene Expression Profiling Interactive Analysis.

Table 1.

Relationship Between Programmed Cell Death-1 Ligand Expression and Clinical–Pathological Characteristics in Gastric Cancer

Variables	Total	Expression of PD-L1		p^a
Variables	Total	−	+	p^a
Gender
Male	83	51	32	0.019
Female	30	11	19
Age, years
<30	7	4	3	0.914
30–59	42	24	18
>60	64	34	30
Tumor site
Cardia	8	4	4	0.310
Gastric body	44	29	15
Gastric antrum	55	26	29
Whole stomach	6	3	3
Tumor size (cm)
<3	24	13	11	0.690
3–6	65	34	31
>6	24	15	9
Tumor differentiation
High	11	6	5	0.418
Middle	57	28	29
Low	45	28	17
Tumor invasion depth
T1+T2	29	14	15	0.408
T3+T4	84	48	36
Regional lymph node
No	44	17	27	0.006
Yes	69	45	24
Metastases
No	95	48	47	0.033
Yes	18	14	4
TNM stage
I+II	47	22	25	0.146
III+IV	66	40	26	0.146
Cancer embolus
No	108	60	48	0.494
Yes	5	2	3
Survival state
Alive	77	37	40	0.033
Death	36	25	11
CEA (ng/mL)
50<	89	46	43	0.191
≥50	24	16	8
HER2
Positive	23	10	13	0.219
Negative	90	52	38

Values in bold indicate statistically significant differences between groups at the p < 0.05 level.

CEA, carcinoembryonic antigen; HER2, human epidermal growth receptor 2; PD-L1, programmed cell death-1 ligand; TNM, tumor–node–metastasis.

Table 2.

Multivariate Logistic Regression Analysis of the Relationship Between the Clinical-Related Risk Factors and Programmed Cell Death-1 Ligand Expression in Gastric Cancer Patients

Variables	OR (95% CI)	p^a
Gender	2.764 (1.130–6.759)	0.026
Regional lymph node	0.335 (0.150–0.747)	0.008

p-Values were examined by the multivariate logistic regression analysis.

CI, confidence interval; OR, odds ratio.

Table 3.

Relationship Between Human Epidermal Growth Receptor 2 Expression and Clinical–Pathological Characteristics in Gastric Cancer

Variables	Total	Expression of HER2		p^a
Variables	Total	−	+	p^a
Gender
Male	83	66	17	0.955
Female	30	24	6	0.955
Age, years
<30	7	5	2	0.845
30–59	42	34	8
>60	64	51	13
Tumor site
Cardia	8	5	3
Gastric body	44	39	5	0.201
Gastric antrum	55	42	13
Whole stomach	6	4	2
Tumor size (cm)
<3	24	18	6	0.769
3–6	65	52	13
>6	24	20	4
Tumor differentiation
High	11	9	2	0.033
Middle	57	40	17
Low	45	41	4
Tumor invasion depth
T1+T2	29	21	8	0.262
T3+T4	84	69	15	0.262
Regional lymph node
No	44	30	14	0.016
Yes	69	60	9	0.016
Metastases
No	95	76	19	0.830
Yes	18	14	4	0.830
TNM stage
I+II	47	33	14	0.036
III+IV	66	57	9	0.036
Cancer embolus
No	108	86	22	0.984
Yes	5	4	1	0.984
Survival state
Alive	77	58	19	0.095
Death	36	32	4	0.095
CEA (ng/mL)
50<	89	72	17	0.524
≥50	24	18	6	0.524
PD-L1
Positive	51	38	13	0.219
Negative	62	52	10	0.219

Values in bold indicate statistically significant differences between groups at the p < 0.05 level.

Table 4.

Multivariate Logistic Regression Analysis of the Relationship Between the Clinical-Related Risk Factors and Human Epidermal Growth Receptor 2 Expression in Gastric Cancer Patients

Variables	HR (95% CI)	p^a
Regional lymph node	0.321 (0.125–0.827)	0.019

p-Values were examined by the multivariate logistic regression analysis.

Table 5.

Correlation Between Programmed Cell Death-1 Ligand and Human Epidermal Growth Receptor 2

PD-L1	HER2		r	p^a
PD-L1	+	−	r	p^a
+	13	38	0.116	0.222
−	10	52	0.116	0.222

p-Values were examined by Pearson analysis.

Relationship between PD-L1 and HER2 expression and prognosis of GC patients

The mean survival time of GC patients with negative PD-L1 expression and positive PD-L1 expression was 53.48 ± 3.66 months (95% confidence interval [CI]: 46.31–60.65) and 82.39 ± 4.34 months (95% CI: 73.89–90.89), respectively, as determined by the Kaplan–Meier method. After the log-rank test, the survival time of GC patients with PD-L1-positive expression was significantly longer than that of patients with PD-L1-negative expression (p < 0.05), and the GEPIA database analysis showed that the high expression of PD-L1 was closely related to longer overall survival and disease-free survival, indicating that positive expression of PD-L1 was associated with better prognosis of GC patients (Fig. 3). The Kaplan–Meier analysis showed that the mean survival time of HER2-positive GC patients was 64.95 ± 4.54 months, while that of negative GC patients was 71.35 ± 3.95 months. No difference in the overall survival between the two groups was observed using the log-rank test, and the GEPIA database analysis also showed that there was no difference in overall survival and disease-free survival between patients with high expression and low expression of HER2 (Fig. 3). The Cox regression model was introduced with the clinical–pathological features as variables, and the univariate analysis suggested that the tumor invasion depth (p = 0.023), regional lymph node (p = 0.001), TNM stage (p = 0.001), and PD-L1 expression (p = 0.024) were closely related to overall survival of GC (Table 6). Tumor invasion depth, regional lymph node, metastases, TNM stage, and HER2 and PD-L1 expression were included in the multivariate Cox regression analysis. We found that TNM stage and PD-L1 expression were independent prognostic factors for GC patients (Table 7).

FIG. 3.

The effect of PD-L1 and HER2 expression on survival of gastric cancer patients. (a) Overall survival of 113 gastric cancer patients according to PD-L1 expression. (b) Overall survival of gastric cancer patients in the GEPIA database according to PD-L1 expression. (c) Disease-free survival of gastric cancer patients in the GEPIA database according to PD-L1 expression. (d) Overall survival of 113 gastric cancer patients according to HER2 expression. (e) Overall survival of gastric cancer patients in the GEPIA database according to HER2 expression. (f) Disease-free survival of gastric cancer patients in the GEPIA database according to HER2 expression. The survival rates were determined by Kaplan–Meier analysis. Color images are available online.

Table 6.

Univariate Cox Proportional Hazard Regression Analyses of the Relationship Between the Clinical-Related Factors and Survival in Gastric Cancer Patients

Variables	Overall survival (month)
Variables	HR	95% CI	p^a
Tumor invasion depth	3.335	1.179–9.437	0.023
Regional lymph node	4.971	1.930–12.799	0.001
TNM stage	4.569	1.899–10.994	0.001
PD-L1	2.266	1.114–4.607	0.024

p-Values were examined by the Cox proportional hazard model for multivariate survival analysis.

HR, hazard ratio.

Table 7.

Multivariate Cox Proportional Hazard Regression Analyses of the Relationship Between Clinical-Related Factors and Survival in Gastric Cancer Patients

Variables	Overall survival (month)
Variables	HR	95% CI	p^a
TNM stage	4.326	1.795–10.425	0.001
PD-L1	0.486	0.239–0.989	0.047

p-Values were examined by the Cox proportional hazard model for multivariate survival analysis.

Discussion

HER2 is a ligand-less member of the human epidermal growth factor receptor or the ErbB family of tyrosine kinases, which can activate downstream pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway and the Ras/mitogen-activated protein kinase (MAPK) pathways (Sliwkowski et al., 1999; Zhao et al., 2018). A study has shown that HER2 overexpression was associated with poor prognosis in GC patients (Lei et al., 2017), but another study has found no significant correlation between HER2 expression and prognosis in GC patients (He et al., 2013).

Trastuzumab combined with chemotherapy has been approved for the first-line treatment of HER2-overexpressing metastatic GC (Bang et al., 2010). These results confirm the value of HER2 in the treatment of advanced GC. However, the role of HER2 needs to be further evaluated in perioperative GC. Our study showed that HER2-positive GC patients have better differentiation, less local lymph node metastasis, and earlier clinical stage disease, suggesting that HER2-positive patients may have lower malignancy, but there was no significant difference in overall survival between the two groups. In this study, most of the patients had earlier clinical stage disease, so we speculated that the effect of HER2 may be different at different stages of tumor development, which partly explains why trastuzumab is not recommended for patients with early GC and also suggests that there are other influencing factors in the process of tumor development.

PD-L1, also known as CD274, is a member of the B7 superfamily, whose gene is located in human chromosome 9q24 and encodes a transmembrane protein of 290 amino acids (Keir et al., 2017), which is widely expressed in a variety of tumor cells and some immune cells such as T lymphocytes, B lymphocytes, dendritic cells, and macrophages. PD-1 is a programmed death receptor that is widely expressed on the surface of T lymphocytes, B lymphocytes, and NK cells. PD-L1 transmits immunosuppressive signals to T cells by binding with the IGV domain of PD-1 extracellular domain, which makes T cells lose their immune activity, thus blocking the antitumor immune response process of the body and causing immune escape of tumor cells. This suggests that the immune microenvironment of the tumor plays an important role in tumor development and prognosis. Xing et al. (2017) have found that GC patients with higher T cell infiltration also showed elevated PD-L1, PD-L2, and PD-1 expression, which predicts a favorable outcome, indicating that an adaptive immune resistance mechanism may exist. The group of patients infiltrated with lower density CD3+ T cells and also without PD-L1 expression in tumor cells predict the worst outcome in the subgroup of different TNM stages, which may suggest an inactive immune status.

In this study, we collected the detailed medical information of patients with GC and investigated the clinical significance of PD-L1 in these patients. Our results showed that PD-L1 expression was significantly correlated with gender, regional lymph node, metastasis, and survival status. Patients with negative expression of PD-L1 had poorer clinical outcomes than those with PD-L1 positive expression. Moreover, negative expression of PD-L1 is an independent and significant prognostic factor for poor survival outcomes in patients with GC. The expression of PD-L1 decreased the relative risk of death in these patients analyzed by the multivariate Cox proportional hazards model. Similar to our results, a study of a GC cohort of Caucasian patients showed that the high PD-L1/PD-1 expression was associated with a significantly better patient outcome, and PD-L1 turned out to be an independent survival prognosticator (Böger et al., 2016). Recent studies also conducted survival analyses of tissue samples from 1014 patients with GC in combination with TCGA database samples, which also proved that patients with GC with a high level of PD-L1 expression had a longer survival period (Xing et al., 2017). Evaluation of PD-L1 expression in GC by the CPS showed that PD-L1 was an independent, favorable prognostic factor for overall survival. Yan et al. (2019) have found that the combined positive status of PD-L1 and CD8 tumor-infiltrating leukocytes in GC patients was strongly associated with better overall survival rates. For the above results, we believe that in the tumor immune microenvironment, due to the interaction between tumor cells and immune cells, the expression of PD-L1 not only promotes infiltration of immune cells but also promotes tumor cell death, which can also be understood as early changes of tumor immune escape.

However, the relationship between the expression of PD-L1 in GC and the prognosis of patients has also been reported to the contrary. Some studies have shown that the positive expression of PD-L1 in GC patients has a negative effect on their survival (Zhang et al., 2015; Eto et al., 2016; Ma et al., 2018; Saito et al., 2018). The possible causes of these opposite results are as follows: the antibodies used for detection of PD-L1 are different in different studies, so the sensitivity of the test is different; in different studies, PD-L1 interpretation and the cutoff value are also different; and PD-L1 expression in tumors is not uniform, and sampling time and location may affect the results of PD-L1 staining (Jin and Yoon, 2016; Wang et al., 2016). The latest study found that the objective response rate of pembrolizumab alone or in combination with chemotherapy for advanced GC was significantly related to the CPS of PD-L1 protein in GC, but not to the tumor proportion score (TPS). Some TPS-negative cases could still benefit from immunotherapy, while CPS-negative cases rarely benefited (Fuchs et al., 2018). Currently, the CPS is recommended in National Comprehensive Cancer Network GC clinical practice guidelines to determine the expression of PD-L1 protein. In addition, different ICIs also have corresponding PD-L1 interpretation antibodies. These measures can interpret the expression of PD-L1 in GC more normatively so as to better guide prognosis prediction and clinical medication.

In this study, our results showed that there was no correlation between HER2 overexpression and PD-L1-positive expression. However, some studies have shown that there is a correlation between the overexpression of HER2 and the expression of PD-L1 in GC, and inhibition of HER2 expression could downregulate PD-L1 expression (Oki et al., 2017; Suh et al., 2017), suggesting that anti-HER2 therapy may create a more favorable environment for tumor immunotherapy. At present, preclinical studies have shown that anti-HER2 combined with anti-PD-L1 therapy can significantly improve the therapeutic effect of tumor therapy (Zhang et al., 2018). The application of PD-1/PD-L1 pathway inhibitors to restore the body's antitumor immune activity is a hot topic in tumor treatment; a number of clinical studies on HER2-targeting drugs combined with anti-PD-L1 in the treatment of GC have been carried out (NCT02689284, NCT02901301, NCT02954536, NCT03615326, and NCT03409848). We also expect exciting results from these studies.

Perspectives and Conclusions

Immunotherapy has been approved in the field of GC treatment. The blocking of immune checkpoint regulators mainly focuses on the PD-1/PD-L1 pathway, which can restore the activity of T cells and enhance the host's immunity to the tumor, thus improving the clinical therapeutic effect in patients with GC. In addition, the combination of HER2-targeted therapy may further improve the therapeutic effect. Therefore, how to select an effective treatment for patients is a problem that needs to be solved. PD-L1 may be an effective biomarker for prognosis and efficacy prediction, but the selection of its antibody and evaluation of IHC results need standardization. Clinical information is available as Supplementary Data.

Footnotes

Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by the Budget internal medicine research project of the Shanghai Municipal Education Commission (2019LK003); Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Dragon Medical Scholars (Nursery Program) of National Clinical Research Base of Traditional Chinese Medicine (LYTD-82); Research project of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine (2019YYQ25); and Youth Program of the National Natural Science Foundation of China (81803888).

Supplementary Material

Supplementary Data

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