Anti-PD-1 therapy achieves favorable outcome in gastric cancer combined with chronic hepatitis B

Abstract

Purpose

To investigate the efficacy and safety of immune checkpoint inhibitors in the treatment of gastric cancer patients with different hepatitis B virus (HBV) infection statuses.

Patients and methods

The clinical data of 89 gastric cancer patients treated at our centre were retrospectively analysed. The patients were divided into chronic hepatitis B (CHB)-infected patients (13 patients), resolved hepatitis B (RHB)-infected patients (49 patients), and HBV-uninfected (HBV-) patients (27 patients) according to their HBV infection status. The efficacy and safety of antitumour treatment in patients in the three groups were analysed.

Results

During anti-programmed death (ligand) 1 (PD-(L)1) therapy, no significant differences in the overall response rate (69.2% vs. 53.1% vs. 51.9%; P = 0.536) or disease control rate (92.3% vs. 79.6% vs. 81.5%; P = 0.567) were observed among the three groups. Progression-free survival benefited more from anti-PD-(L)1 antibody therapy in CHB patients than in HBV- patients (Not reached vs. 7 months; P = 0.024; hazard ratio (HR) = 0.38(95%CI 0.17–0.88)) and RHB patients (Not reached vs. 6 months; P = 0.001; HR = 0.34(95%CI 0.17–0.65)). Overall survival was also better in CHB patients than in HBV- patients (Not reached vs. 15 months; P = 0.014; HR = 0.31(95%CI 0.12–0.79)) and RHB patients (Not reached vs. 16 months; P = 0.005; HR = 0.32(95%CI 0.14–0.71)).

Conclusion

Anti-PD-(L)1 immunotherapy may be safe and effective in gastric cancer patients with HBV infection. CHB patients are more likely to have lasting benefits than are HBV- patients and RHB patients. This may be attributed to alterations in the immune microenvironment in patients, and future studies should further explore the relevant mechanisms involved. CHB patients may have a more inflamed immune microenvironment, leading to enhanced ICI efficacy.

Introduction

Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide. Over 1 million new cases of gastric cancer are estimated each year, and the disease is often diagnosed late due to its insidious onset, resulting in a high mortality rate. Previously, advanced gastric cancer was treated primarily with chemotherapy, resulting in a median survival time of less than one year [1]. The emergence of tumour immunotherapy has changed the landscape of cancer treatment and represents a milestone in the fight against tumours. To date, biological targets related to immunotherapy include several pathways, such as programmed death 1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA4), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and lymphocyte activation gene-3 (LAG-3). Among these pathways, the PD-1/programmed death ligand 1 (PD-L1) pathway is the most widely studied [2–4].

Tumour cells typically have high expression levels of PD-L1, while PD-L1 is expressed on the surface of T cells. The binding of PD-1 to PD-L1 can inhibit checkpoint signals and reduce the toxicity of T cells. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block the interaction between PD-1 and PD-L1 on tumour cells and enhance the immune response against tumour cells [5]. Multiple clinical trials have reported that immunotherapy combined with chemotherapy yields benefits in terms of overall survival (OS) in patients with advanced gastric cancer [6–9]. In recent years, multiple immunotherapeutic drugs, including nivolumab, pembrolizumab, sintilimab, and tislelizumab, have been approved for the treatment of advanced gastric cancer.

The PD-1/PD-L1 pathway regulates antiviral immune responses and plays an essential role in the process of antitumour treatment. In furthermore, the efficacy and safety of immunotherapy are also influenced by many viruses. During the acute phase of viral infection, the PD-1/PD-L1 axis regulates the intensity and quality of cytotoxic CD8 + T-cell attacks, thereby affecting viral elimination and tissue damage. PD-L1 is strongly upregulated in the late stages of acute viral infection, thereby downregulating the terminal differentiation of CD8 + T cells and preventing excessive tissue damage caused by uncontrolled cytotoxic attacks [10]. HBV infection has been reported to cause T cell depletion in patients, which is mediated by cytokine and inhibitory receptor regulation and varies among patients with different status of HBV infection [11–13]. It has been shown that blocking the PD-1/PD-L1 pathway increases HBV antibody production as well as T cell numbers and function [14–16]. This may account for the different responses to anti-PD-1 therapy in patients with different status of HBV infection or HBV uninfection.

According to data from the World Health Organization (WHO), over 350 million people are infected with chronic hepatitis B worldwide [17], and China accounts for approximately 10% of the global population of hepatitis B virus (HBV) carriers [18]. However, in the theoretical context of tumour immunotherapy, the association between HBV reactivation and immunotherapy represents a potential threat. The safety of immunotherapy in patients with HBV infection remains uncertain, as such patients were excluded from early PD-1 inhibitor clinical trials. However, retrospective studies have shown that immune checkpoint inhibitors are safe and effective for patients receiving antiviral treatment for HBV infection. In addition, patients with positive HBsAg (chronic HBV infection) may achieve better antitumour efficacy than patients with resolved hepatitis B virus (RHB) infection or HBV- uninfected. A phase 3 randomised study of first-line Atezolizumab plus Bevacizumab versus Sorafenib for the treatment of patients with unresectable hepatocellular carcinoma (HCC) who had not received prior systemic therapy (IMbrave150), showed in its corresponding subgroup analysis that patients infected with HBV may benefit more than non-virus HCC [19]. Zhang et al. showed that among non-small cell lung cancer patients, chronic HBV infection (CHB) patients gained more clinical benefit from anti-PD-(L)1 monotherapy than RHB patients, although the difference was not significant [20]. Another study indicated that HBV-positive non-liver cancer patients achieved better outcomes than HBV-negative patients in receiving anti-PD-1 therapy [21]. However, studies comparing the efficacy and safety of immunotherapy in gastric cancer patients with different HBV infection statuses are scarce, indicating a need for further investigation.

Considering the relatively high prevalence of HBV infection in China and the high incidence and mortality rates of gastric cancer, investigating the safety and efficacy of immunotherapy in these patients is important. Therefore, the clinical data of 89 gastric cancer patients treated at our centre were retrospectively analysed to determine the safety and efficacy of immune checkpoint inhibitor treatment in gastric cancer patients with different HBV infection statuses. This study provides insights into whether immunotherapy can be recommended for HBV-positive gastric cancer patients.

Materials and methods

This study was approved by the Ethics Committee of Taizhou Hospital, Zhejiang Province, China (ID: KL20240622). Retrospective data were collected from patients with advanced gastric cancer who were treated in the outpatient and inpatient departments of Taizhou Hospital from January 1, 2020, to June 30, 2024. The patients met the following inclusion criteria: 1. diagnosed with gastric cancer by pathological histology or cytology; 2. clinical Tumur Node Metastasis (TNM) staging in line with the IV stage of the seventh edition of the American Joint Committee on Cancer TNM staging system; 3. at least one measurable lesion was detected; 4. received at least two courses of immunotherapy; and 5. had available results for hepatitis B serology. The exclusion criteria were as follows: 1. more than two primary tumours; 2. without measurable tumour lesions; 3. lacking hepatitis B serology results; and 4. did not receive immunotherapy, received fewer than two courses of immunotherapy, or immunotherapy was interrupted.

All patients received immunotherapy, with or without chemotherapy. PD-L1 expression was measured using the combined positive score (CPS) at a central laboratory using the PD-L1 IHC 22C3 pharmDx assay to measure the combined expression of PD-L1 on tumour cells and immune cells. Tumour cell PD-L1 expression was defined as the percentage of viable tumour cells with partial or complete membrane staining in at least 100 viable tumour cells. CPSs were generated by rescoring PD-L1-stained slides using the CPS algorithm, which is defined as the number of PD-L1–positive tumour cells (partial or complete membrane staining), lymphocytes, and macrophages (membrane staining and/or intracellular staining) divided by the total number of viable tumour cells multiplied by 100 [7].

Efficacy was assessed every 2 cycles until disease progression or the occurrence of intolerable adverse reactions. All patients underwent computer tomography or magnetic resonance imaging examinations as imaging evaluations. HBV reactivation is defined as the abrupt reappearance or increase in HBV DNA in the serum of a patient with resolved or inactive chronic HBV infection [22]. Patients received tests of HBV serological markers every 2 to 4 cycles according to the decision of the treating physician to monitor for HBV reactivation. The last follow-up date was June 30, 2024. The target lesions were evaluated according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1), and the outcomes were classified into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) [23]. An objective response was defined as CR + PR, whereas disease control was defined as CR + PR + SD. Progression-free survival (PFS) was defined as the time from the start of drug use to disease progression or patient death. Overall survival (OS) was defined as the time from the start of drug use to patient death.

Adverse events (AEs) were evaluated using the grading criteria for antitumour drug toxicity (WHO standard) and were divided into 0-IV degrees. Immune-related adverse events (irAEs) referred to the CSCO guidelines for the management of immune checkpoint inhibitor toxicity and were divided into grades G1-G4.

Statistical analysis

All the statistical analyses were performed using SPSS version 25.0. Comparisons of count data were performed using the χ2 test or Fisher’s exact test. Survival analysis was conducted using the product‒limit method (the Kaplan‒Meier method), and survival curves were drawn. The survival curves were compared using the log-rank test. A two-tailed P value of ≤ 0.05 was considered to indicate statistical significance.

Results

Patients

A total of 89 eligible patients were screened from among 477 gastric cancer patients, and the baseline characteristics of the patients are summarized in Table 1. Patients were classified on the basis of their hepatitis B virus infection status according to the Guidelines for the Prevention and Treatment of Chronic Hepatitis B (version 2022) [24]. Thirteen patients were hepatitis B surface antigen (HBsAg)-positive, hepatitis B e antigen (HBeAg)-positive or negative, indicating CHB infection; 49 patients were HBsAg- and HBeAg-negative, hepatitis B core antibody (HBcAb)-positive, suggesting RHB infection; 27 patients were HBV-uninfected (HBV-).

Table 1.

Baseline characteristics of study patients (n = 89)

Characteristics	Different status of HBV infection			P Value
	CHB n(%)	RHB n(%)	HBV n(%)
Total	13	49	27
Age (years)				0.936
≤60	6(46.2)	20(40.8)	11(40.7)
＞60	7(53.8)	29(59.2)	16(59.3)
Sex				0.284
Male	11(84.6)	30(61.2)	18(66.7)
Female	2(15.4)	19(38.8)	9(33.3)
BMI（kg/m2）				0.082
BMI ≥ 24	2(15.4)	13(26.5)	5(18.5)
18.5 ≤ BMI < 24	8(61.5)	19(38.8)	19(70.4)
BMI < 18.5	3(23.1)	17(34.7)	3(11.1)
Smoking status				0.871
Current or former	2(15.4)	5(10.2)	3(11.1)
Never	11(84.6)	44(89.8)	24(88.9)
Comorbidity of Hepatitis C				/
Yes	0 (0.0)	0 (0.0)	0 (0.0)
No	13(100.0)	49(100.0)	27(100.0)
Pathological type				0.656
Adenocarcinoma	12(92.3)	41(83.7)	24(88.9)
Other	1(7.7)	8(16.3)	3(11.1)
Lines of immunotherapy				0.377
First-line	10(76.9)	37(75.6)	20(74.1)
Second-line	1(7.7)	5(10.2)	6(22.2)
Back-line	2(15.4)	7(14.2)	1(3.7)
Combined chemotherapy				0.854
Yes	12(92.3)	46(93.9)	26(96.3)
No	1(7.7)	3(6.1)	1(3.7)
Baseline HBV-DNA				0.106
Detectable	11(84.6)	28(57.1)	/
Unknown	2(15.4)	21(42.9)	/
PD-L1				0.096
Detectable	3(23.1)	27(55.1)	11(40.7)
Unknown	10(76.9)	22(44.9)	16(59.3)
PD-1 inhibitor type				0.577
Nivolumab	2(15.4)	8(16.3)	2(7.4)
Sintilimab	9(69.2)	38(77.6)	21(77.8)
Others	2(15.4)	3(6.1)	4(14.8)

HBV hepatitis B virus, CHB chronic hepatitis B virus infection, RHB resolved hepatitis B virus infection, HBV- HBV uninfected, HBV-DNA HBV deoxyribonucleic acid, BMI Body Mass Index, PD-(L)1 programmed death (ligand) 1

All three groups of patients were matched for clinical characteristics. The median age of the three groups was 69 years (range: 40–89 years). The majority of patients in all three groups were male, with 11 (84.6%), 30 (61.2%), and 18 (66.7%) male patients, respectively, in each group. According to National Clinical Practice Guideline on Obesity Management (2024 Edition) [25], the majority of the patients in the three groups with Body mass index (BMI) greater than or equal to 18.5 kg/m2 and less than 24 kg/m2 were of normal weight, which were 8 (61.5%), 19 (38.3%) and 19 (70.4%) in each group, respectively. None of the patients included in the study had comorbid hepatitis C. Histologically, adenocarcinoma accounted for the vast majority of cases, with 12 (92.3%), 41 (83.7%), and 24 (88.9%) patients, respectively, in the three groups. In the present study, patients were treated with different PD-1 inhibitors, with sintilimab and nivolumab being the most common, in 68 patients (76.4%) and 12 patients (13.5%), respectively, and the remaining PD-1 inhibitors were used in 9 patients (10.1%). The numbers of patients in the three groups who received anti-PD-1 treatment as first-line therapy were 10 (76.9%), 37 (75.6%), and 20 (74.1%). Among them, 26 patients (96.3%), 46 patients (94.9%), and 12 patients (92.3%) received combined chemotherapy.

Efficacy

All 89 patients included in our study received treatment with PD-(L)1 inhibitors. During the treatment period, none of the three groups of patients achieved complete remission, but the efficacy in CHB patients was better than that in the other two groups, although the difference was not significant. Only one of the 13 CHB patients exhibited PD, while the other nine achieved PR, and three achieved SD, resulting in an overall response rate (ORR) of 69.2%. Moreover, the disease control rate (DCR) was as high as 92.3% (Table 2). In contrast, 5 of the HBV- patients had PD, 8 had SD, and 14 achieved PR, with an ORR of 51.9% and a DCR of 81.5% (Table 2). The efficacy in RHB patients was similar to that in HBV- patients, with 10 out of 49 patients showing PD, 13 showing SD, and 26 showing PR. The ORR was 53.1%, and the DCR was 79.6% (Table 2).

Table 2.

The comparison of treatment efficacy among different status of HBV infection (n=89)

	Different status of HBV infection			χ2	P Value
	CHB n(%)	RHB n(%)	HBV- n(%)
Total	13	49	27
CR	0(0.0)	0(0.0)	0(0.0)
PR	9(69.2)	26(53.1)	14(51.9)
SD	3(23.1)	13(26.5)	8(29.6)
PD	1(7.7)	10(20.4)	5(18.5)
ORR	9(69.2)	26(53.1)	14(51.9)	1.246	0.536
DCR	12(92.3)	39(79.6)	22(81.5)	1.134	0.567

CR complete response, PR partial response, SD stable disease, PD progressive disease, ORR overall response rate, DCR disease control rate, HBV hepatitis B virus, CHB chronic hepatitis B virus infection, RHB resolved hepatitis B virus infection, HBV- HBV uninfected

Additionally, PFS benefited more from anti-PD-(L)1 antibody therapy in CHB patients than in HBV- patients (Not reached vs. 7 months; P = 0.024; hazard ratio (HR) = 0.38(95%CI 0.17–0.88)) and RHB patients (Not reached vs. 6 months; P = 0.001; HR = 0.34(95%CI 0.17–0.65)) (Fig. 1). OS was also better in CHB patients than in HBV- patients (Not reached vs. 15 months; P = 0.014; HR = 0.31(95%CI 0.12–0.79)) and RHB patients (Not reached vs. 16 months; P = 0.005; HR = 0.32(95%CI 0.14–0.71)) (Fig. 2). But there was no significant difference in OS and PFS between HBV- patients and RHB patients. In addition, we analysed the data and reported that age, sex, BMI, and whether immunotherapy was the patient’s first option did not significantly affect patient outcomes (Fig. 3). Although these patients received different PD-1 antibody treatments, there was no significant difference in the outcome of different PD-1 antibodies (Fig. 4a). The outcomes of combined chemotherapy were better than those of monotherapy in terms of PFS and OS (Fig. 4b), although the differences were not significant. However, there were no significant differences between the different chemotherapy regimens (Fig. 4c).

Fig. 1.

Kaplan-Meier analysis of progression-free survival (PFS) according to hepatitis B virus infection status The median progression-free survival was not reached yet for chronic hepatitis B virus infection (CHB) patients, 7months for hepatitis B virus uninfected (HBV-) patients and 6months for resolved hepatitis B virus infection (RHB) patients. The median progression-free survival was significantly better in CHB patients than in HBV- (P = 0.024) and RHB patients(P = 0.001)

Fig. 2.

Kaplan-Meier analysis of overall survival (OS) according to hepatitis B virus infection status The median overall survival was not reached yet for chronic hepatitis B virus infection (CHB) patients, 15months for hepatitis B virus uninfected (HBV-) patients and 16months for resolved hepatitis B virus infection (RHB) patients. The median overall survival was significantly better in CHB patients than in HBV- (P = 0.014) and RHB patients (P = 0.005)

Fig. 3.

Kaplan-Meier analysis of progression-free survival (PFS) and overall survival (OS). a PFS and OS of patients with different age. b PFS and OS of patients with different gender. c PFS and OS of patients with different Body Mass Index (BMI)‌. d PFS and OS of patients whether immunotherapy was the patient’s first option

Fig. 4.

Kaplan-Meier analysis of progression-free survival (PFS) and overall survival (OS). a PFS and OS of patients treated with different PD-1 antibodies. b PFS and OS of patients with or without chemotherapy. c PFS and OS of patients treated with different chemotherapy regimens

Safety

Treatment-related AEs are listed in Table 3. No grade IV adverse reactions were observed in any of the three groups. Among the 89 patients included in the study, 75 (84.3%) developed at least one treatment-related AE during the treatment period. The more common AEs included neutropenia, thrombocytopenia, anaemia, hypothyroidism, and hypocortisolism, with a total of 14 AEs of grade III and above. In addition, 4 patients developed immune-mediated hepatitis.

Table 3.

The comparison of adverse events among different status of HBV infection

Adverse reactions	Different status of HBV infection												P*	P※	P#
Classification (Grade）	CHB (n=13)				RHB (n=49)				HBV- (n=27)
	None	I	II	III	None	I	II	III	None	I	II	III
Neutropenia	9	2	1	1	43	1	3	2	22	2	2	1	0.211	0.799	0.706
Thrombocytopenia	10	1	1	1	44	1	2	2	22	2	2	1	0.622	0.959	0.619
Anemia	10	1	2	0	44	1	3	1	23	1	3	0	0.463	0.787	0.723
Hypothyroidism	9	3	1	0	42	5	2	0	24	2	1	0	0.380	0.299	0.917
Hypocortisolism	10	2	1	0	43	5	1	0	25	1	1	0	0.496	0.346	0.560
Immune hepatitis	13	0	0	0	41	4	1	3	26	0	0	1	0.487	1.000	0.385
Immune pneumonia	12	1	0	0	46	2	1	0	26	0	1	0	0.762	0.276	0.523
Multiple myositis	12	0	0	1	49	0	0	0	27	0	0	0	0.210	0.325

HBV hepatitis B virus, CHB chronic hepatitis B virus infection, RHB resolved hepatitis B virus infection, HBV- HBV uninfected

*CHB vs HBV-

※CHB vs RHB

#RHB vs HBV-

CHB patients were retested for HBV serological markers every 2 to 4 cycles according to the decision of the treating physician, whereas RHB patients were irregular. We found that no events of HBV reactivation were observed throughout the follow-up process.

Further analysis revealed that among the HBV- patients, 31 cases of AEs were registered during treatment, with 3 cases being Grade III or higher, including only 1 case of immune-mediated hepatitis. RHB patients had 40 AEs, with 8 AEs of grade III and above, 3 of which were immune-mediated hepatitis. In contrast, 19 cases of AEs were recorded among the CHB patients, including 3 cases of grade III AEs and above, and no patients were found to have immune-mediated hepatitis. The incidence of each adverse reaction was not significantly different among the three groups of patients.

Discussion

Few studies have separately investigated the impact of the HBV infection status on the safety and efficacy of immunotherapy in patients with gastric cancer. Our results indicate that, compared with HBV- patients and RHB patients, CHB patients do not have an increased risk of irAEs, including grade 3–4 irAEs and liver-related irAEs, during anti-PD-(L)1 treatment. Moreover, CHB and RHB patients showed no HBV reactivation during immunotherapy. Previous studies have shown that HBV reactivation is lower in patients receiving antiviral treatment than in those not receiving antiviral treatment and that a lack of antiviral prophylaxis is the most significant risk factor for HBV reactivation [26, 27]. However, in the present study, we were unable to determine the antiviral treatment status of each patient. Interestingly, compared with patients in the other two groups, patients in the CHB group responded significantly better to anti-PD-1 therapy. A similar phenomenon has been reported in patients with other viral infections and tumours. For example, patients with concomitant Epstein–Barr virus infection and gastric cancer or non-Hodgkin’s lymphoma all respond better to anti-PD-1 therapy than Epstein–Barr virus-negative patients do [28, 29]. Therefore, anti-PD-(L)1 therapy may be considered for CHB patients with controlled HBV, as evidenced by the favourable safety profile and superior efficacy of this therapy during immunotherapy.

With the rapid development of medicine, PD-1/PD-L1 pathway inhibitors have emerged as cornerstones in the treatment of gastric cancer. The most representative clinical study is CheckMate-649 [6], a phase III trial comparing nivolumab plus chemotherapy to chemotherapy alone in the treatment of advanced gastric cancer, gastroesophageal junction adenocarcinoma, and oesophageal adenocarcinoma. The results revealed that patients treated with nivolumab plus chemotherapy achieved significantly better outcomes than did those treated with chemotherapy alone, with an ORR of 60%, a median OS of 14.3 months, and a median PFS of 8.3 months. However, this study excluded CHB patients. Additionally, the ORIENT-16 study, which included only Chinese gastric cancer patients, also indicated that sintilimab plus chemotherapy exhibited greater clinical benefit than chemotherapy alone in the first-line treatment of advanced gastric cancer patients [7]. The ORR was 58.2%, the median OS was 15.2 months, and the median PFS was 7.1 months. Although this study did not exclude HBV-positive patients, no relevant subgroup analysis was performed; hence, whether the differences in the efficacy and safety of immunotherapy for gastric cancer patients with chronic HBV compared with other patients remain uncertain. Moreover, some case reports have indicated that PD-(L)1 inhibitors are safe and effective in solid tumour patients with chronic HBV or HCV infection [30–33]. Nonetheless, few data have been published on gastric cancer patients. Our study revealed that CHB patients have a DCR of 92.3% and an ORR of 69.2%; the median OS and median PFS have not yet been reached. These findings are significantly better than those in RHB patients and HBV- patients, with comparable safety profiles across all three groups. However, this study is retrospective and has a small sample size, so conclusions should be drawn with caution.

HBV-positive gastric cancer patients may respond better to anti-PD-1 treatment because of changes in the immune microenvironment, which are primarily mediated by changes in T-cell function. A study showed that in solid tumours, including gastric cancer, the ligands PD-L1 and PD-L2 expressed by tumour cells are upregulated and bind to PD-1 expressed on activated T cells, leading to T-cell exhaustion [34]. Chronic HBV infection also causes T-cell dysfunction and exhaustion, which is influenced by cytokines and inhibitory receptors, including inhibition of cytokine production (IL-10, TGF-β) and an increase in the number of Tregs and co-inhibitory receptors (e.g., PD-1, TIM-3, CTLA-4, TIGIT, and CD244) [11, 35].

Several studies have shown that inhibition of the production of the cytokines and expression of the receptors restores both the number and function of T-cells, thereby recovering normal immune function. Fisicaro et al. found that T cells in HBV patients expressed higher levels of PD-1 and that blocking the PD-1/PD-L1 interaction increased CD8 cell proliferation as well as circulating intrahepatic lymphocyte-produced IFN-γ and IL-2, which restored antiviral T-cell function in peripheral lymphocytes and intrahepatic lymphocytes [15]. Another study showed that high expression of CTLA-4 in HBV-specific CD8 + T cells was positively correlated with HBV viral load in patients with chronic HBV infection, and that blocking CTLA-4 increased the proliferation of IFN-γ-secreting HBV-specific CD8 + T cells [36]. Wu et al. investigated the effects of Tim-3 expression on lymphocyte proliferation and cytokine secretary capacity. Interference of the Tim-3 pathway by either anti-Tim-3 antibodies or Tim-3 short hairpin RNAs rescues CD8 + T cell activity, improving their proliferation and enhancing their cytokine secretary capacity [37]. CD244 is highly expressed on virus-specific CD8 + T-cells in chronic HBV infection and blocking CD244 or its ligand CD48 may restore T-cell function [38]. Additionally, HBV induces T cell exhaustion by up-regulating the expression of TIGIT. Blocking the TIGIT/PVR pathway can reverse T cell exhaustion [39]. These studies indicate that patients with tumours and chronic HBV infection have a stronger immunosuppressive microenvironment. The systemic immune response mediated by chronic HBV infection may upregulate PD-L1 expression on tumour cells, such as in non-small cell lung cancer [40]. In addition, Jie Zhou et al. [21] analysed public data and reported that, compared with HBV- patients, HBV + Esophageal Squamous Cell Carcinoma patients have a greater proportion of functionally exhausted T cells. Anti-PD-1 treatment effectively reversed the dual inhibition of the body’s immune system by tumours and chronic viral infection. Therefore, compared with that in HBV- patients or RHB patients, the greater proportion of T-cell function recovery in CHB patients after PD-1 inhibitor administration may contribute to enhanced immune efficacy.

Nevertheless, the limitations of the present study should be acknowledged. First, as a retrospective study, we were not able to completely exclude confounders from the study, such as differences in treatment choices among the three groups. This difference was related to whether immunotherapy was the patient’s first option and whether it was combined with chemotherapy at the same time. Second, in this study, the interval for HBV DNA monitoring before and during anti-PD-(L)1 immunotherapy varied within patients and among patients, which may have led to insufficient monitoring of HBV reactivation events in these patients. Third, PD-L1 expression levels were not measured in most patients, so the association between HBV infection and PD-L1 expression in gastric cancer patients could not be assessed. Lack of PD-L1 data weakens the ability to stratify efficacy predictors. Fourth, this study was an observational study, not a cohort study, and tumour samples were unavailable, preventing further investigation of whether the enhanced immune response in CHB patients was related to changes in the immune microenvironment, whether due to increased initial infiltration of lymphocytes, increased neoantigen levels, or decreased end-point exhaustion. However, future studies should further explore the relevant mechanisms involved. Finally, the sample size was not large enough; hence, further studies with larger sample sizes are needed to verify the findings.

Conclusion

Our study indicates that anti-PD-(L)1 immunotherapy may be safe and effective for gastric cancer patients with HBV infection. Compared with HBV- patients and RHB patients, CHB patients are more likely to achieve long-term benefits. Moreover, the three groups presented similar safety profiles. Further research is needed to better describe the response patterns of immunotherapy in this special patient population. HBV + gastric cancer patients should be proactively enrolled and stratified in future ICI studies.

Authors’ contributions

All authors contributed to the study conception and design. LY. W.wrote the main manuscript text. F.Y.,TH.T and YP.Y conducted data collection and analysis. KL.C. prepared Figs. 1, 2, 3 and 4. QH.D. and JY.Y. prepared Tables 1, 2 and 3. All authors reviewed the manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Taizhou Hospital, Zhejiang Province, China (No. KL20240622).

This study is retrospective and the Ethics Committee has granted exemptions for informed consent forms for studies involving human participants or patient material.

The Ethics Committee exempts the informed consent of this retrospective study not arbitrarily, but based on certain ethical principles and laws and regulations. The Declaration of Helsinki, as an international code of medical ethics, clearly states, “In medical research, doctors have the responsibility to protect the life, health, dignity, integrity, self-determination, privacy and confidentiality of personal information of research subjects.” The Measures for the Ethical Review of Biomedical Research Involving Humans also provide that, in certain circumstances, research projects can be conducted without the informed consent of subjects. These provisions provide a basis for the Ethics Committee to exempt informed consent under certain conditions.

This retrospective study only collected part of the patients’ previous clinical data without causing any damage to the patients, and the research risk was extremely low. Moreover, the relevant data was anonymized, and the personal information of the study subjects could not be identified to protect their privacy. In addition, if this paper can be published successfully, it will have certain reference significance for the immunotherapy of gastric cancer patients complicated with chronic viral hepatitis B, and the research value is significant. At the same time, the Ethics Committee has perfect alternative measures and set up a supervision mechanism to ensure that the research is carried out legally and in compliance.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.