Evaluating Oral Probiotic Supplements as Complementary Treatment in Advanced Lung Cancer Patients Receiving ICIs: A Prospective Real-World Study

Abstract

Objective

To evaluate the effectiveness of oral probiotic supplements in patients undergoing immune checkpoint inhibitors (ICIs) for the treatment of advanced lung cancer.

Methods

This prospective real-world study enrolled patients with advanced lung cancer who were receiving ICIs as part of their treatment. The patients were divided into 2 groups: Group OPS received oral probiotic supplements along with ICIs, while Group C did not. The primary endpoint was progression-free survival (PFS). The secondary outcome measure was the objective response rate (ORR).

Results

A total of 253 patients were included in the study, with 71 patients in Group OPS and 182 patients in the control group (Group C). No significant differences were observed in the median PFS between the 2 groups for all patients. However, for small cell lung cancer (SCLC) patients, the median PFS was significantly better in the Group OPS compared to the Group C (11.1 months vs 7.0 months, P = .049). No significant differences were observed in median PFS for the non-small cell lung cancer (NSCLC) cohort between the 2 groups, but a trend towards better median PFS in Group OPS was noticed (16.5 months vs 12.3 months, P = .56). The ORR for the entire cohort was 58.0%.

Conclusion

Oral probiotics supplements in combination with ICIs included regimen may improve the outcome in patients with advanced SCLC. The above points should be proved by further study.

Plain language summary

This study examined whether the addition of oral probiotic supplements to ICIs could enhance the treatment of advanced lung cancer. A total of 253 patients with advanced lung cancer were involved in the study, with some receiving probiotics in combination with ICIs and others not. The findings revealed that patients with SCLC who took probiotics had significantly better PFS compared to those who did not. Additionally, there was a tendency towards enhanced PFS in NSCLC patients who received probiotics. In conclusion, the study indicates that incorporating oral probiotics with ICIs may lead to better outcomes for patients with advanced SCLC, although further research is necessary to validate these results.This real world study explores whether oral probiotic supplements along with immune checkpoint inhibitors (ICIs) can help treat advanced lung cancer. The study included 253 patients with advanced lung cancer receiving ICIs treatment, part of them taking probiotics along with ICIs. The results showed that patients with small cell lung cancer (SCLC) who took probiotics had better progression-free survival (PFS) compared to those who didn't. There was also a trend towards better PFS in non-small cell lung cancer (NSCLC) patients who took probiotics. Overall, the study suggests that taking oral probiotics along with ICIs may improve outcomes for patients with advanced SCLC, but more research is needed to confirm these findings.

Keywords

oral probiotics immune checkpoint inhibitors advanced lung cancer real-world study

Introduction

Lung cancer (LC) is commonly considered the most prevalent form of cancer affecting the respiratory system. It is a complex and diverse disease known for its aggressive behavior, rapid growth, and early tendency to metastasize to other parts of the body.¹ LC is typically categorized into 2 main groups: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), each exhibiting distinctive pathological characteristics.^1,2 Unfortunately, individuals diagnosed with this condition often face a grim prognosis due to the limited efficacy of current treatment modalities. Consequently, LC continues to present a significant challenge to global initiatives aimed at increasing life expectancy.³ Globally, LC is the leading cause of global cancer mortality, accounting for 18.4% of total cancer deaths, and resulting in significant societal burden and economic loss.^4,5 The use of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced lung cancer, offering improved overall survival (OS) rates and durable responses in a subset of patients, especially for patients without driver mutations.⁶ ICIs, such as pembrolizumab, nivolumab, and atezolizumab, work by blocking the inhibitory signals of immune checkpoint proteins, thereby restoring the immune system’s ability to recognize and eliminate cancer cells.⁷ However, while ICIs have demonstrated significant efficacy in a subset of patients, there are still several challenges that limit their overall effectiveness. These challenges include the unsatisfactory response rate, unclear predictors of treatment response, complex assessment of efficacy and resistance, and unpredictable side effects.^8,9 In order to optimize the effectiveness of immunotherapy, further research is necessary to explore potential factors that may enhance treatment outcomes. One area of interest is the relationship between the gut microbiota and immune response to therapy. Emerging evidence suggests that the composition of the gut microbiota may play a role in modulating the efficacy of immunotherapy.¹⁰

Oral probiotic supplements have gained attention as a potential strategy to manipulate the gut microbiota and enhance the tumor response to ICIs. By improving gut microbial diversity and promoting a favorable immune environment, probiotics have the potential to enhance the efficacy of ICIs and overcome some of the challenges associated with immunotherapy.¹¹ Prior studies showed that gut microbiota composition and diversity are predictive of response to ICI immunotherapy.^12,13 Similar results were reported in patients with advanced melanoma and lung cancer.^14,15 A phase I study showed an impressive improvement in progression-free survival (PFS) in patients with metastasis renal cell carcinoma receiving CBM588 in combination with ICI immunotherapy.¹⁶ In addition, several studies have reported the beneficial role of the probiotics Bifidobacterium and Lactobacillus reuteri (Lr) in promoting ICI therapy.^17-19 Currently, patients can easily obtain a variety of marketed probiotics supplements from all over the world, and they may take the above preparations by themselves clinically. However, there is a lack of research data to explain the relationship between oral probiotic supplements and the outcome of ICIs including treatment.

Therefore, this real-world study aims to evaluate the effectiveness of oral probiotics supplements in patients undergoing ICIs including treatment for advanced lung cancer initially.

Materials and Methods

Patients

Patients with advanced lung cancer who were treated as in-patients in the oncology department of Shangjin Nanfu Hospital/West China Hospital during the period from June 2021 to December 2022 were screened for inclusion in this real-world study. Those who met all the inclusion criteria and were without any exclusion criteria had been enrolled in this real-world study. This study has received approval from the Biomedical Ethics Review Committee of West China Hospital, Sichuan University (2021 Audit (1671)). Written consent has been obtained from all subjects.

Inclusion and Exclusion Criteria

Participants who meet the following criteria will be included in the study. Inclusion criteria: ① Patients diagnosed with advanced non-small cell lung cancer or small cell lung cancer by pathology. ② Clinical or pathological stages diagnosed according to the AJCC eighth staging system of stage IV and/or locally advanced where radical resection is not possible. ③ Negative for driver gene mutation or failure of targeted therapy in mutation-positive patients. ④ Patients scheduled to receive ICIs such as PD1 inhibitors, PDL1 inhibitors, CTLA4 inhibitors, etc., as part of their treatment. ⑤ Patients aged 18 years or older. ⑥ Patients willing and able to provide written informed consent. Exclusion criteria: ① Patients with a history of allergic reactions to probiotics or any of its components. ② Patients with a history of gastrointestinal disorders that may affect the absorption or metabolism of oral probiotic supplements. ③ Patients with a history of immune-related adverse events or autoimmune diseases. ④ Patients receiving radical treatment (including radical concurrent radiotherapy and chemotherapy, etc.). ⑤ Patients participating in another clinical trial involving investigational drugs or therapies. ⑥ Patients who are unable to swallow oral liquid medications. ⑦ Patients with serious violations of the study protocol, irregular use of probiotic supplements during the study, and withdrawal of informed consent were excluded from study observation.

Study Design and Participants

This real-world study aimed to estimate the efficacy of oral probiotic supplements in combination with ICIs for the treatment of advanced lung cancer. We employed a prospective non-intervention cohort design and collected data from the electronic medical records of patients who underwent ICI treatment between June 2021 and December 2022 in the Department of Medical Oncology, Shangjin Nanfu Hospital, and the Department of Thoracic Oncology, West China Hospital, S.C.U.

All participants in the current study were scheduled to receive ICIs as part of their anti-cancer treatment. According to the situation of a daily oral probiotic supplement, patients would be assigned into Group OPS (those who received oral probiotic supplements along with ICIs) or Group C (control group). The study allowed the use of ICI agents approved for NSCLC or SCLC, including PD1 inhibitors, PDL1 inhibitors, and CTLA4 inhibitors. ICIs were administered as either first-line therapy or back-line therapy. The immunotherapy regimen included single-agent immunotherapy, combination with chemotherapy, combination with palliative radiotherapy, or combination with anti-vascular endothelial growth factor medications such as bevacizumab/anlotinib/apatinib, et al.

Patients in Group OPS regularly took commercially available oral probiotic supplements during the course of their ICI treatment course by their own choice, while patients in Group C did not. Participants adhered to the instructions of the probiotic supplements recorded daily doses in journals, and continued taking probiotics from the start of immunotherapy until the study endpoint (ie, tumor progression). Commonly available oral probiotic supplements contain 1 or more of the following ingredients: Lactobacillus acidophilus, Bifidobacterium lactis, Streptococcus thermophilus, Bacillus subtilis, Enterococcus faecium, Lactobacillus rhamnosus, Bacillus Licheniformis, and Fructooligosaccharide, et al.

Sample Size Estimation

The sample size was calculated based on the primary endpoint of PFS. Participants were to receive treatment in a 1:2 ratio, with ICI immunotherapy combined with platinum-containing doublet chemotherapy as first-line treatment for NSCLC. The anticipated median PFS was 6.4 months, and participants were expected to be enrolled evenly over a period of 6 months. With an estimated dropout rate of approximately 2% per month, a total of 276 participants were needed to be enrolled (92 in the experimental group and 184 in the control group). This sample size would allow for the observation of 171 PFS events approximately 18 months after the randomization of the first participant, providing 80% power to detect a significant improvement in PFS between the experimental and control groups at a significance level of .05 (two-sided) (equivalent to a hazard ratio HR = .64).

Data Collection

Clinical medical data of the participants were collected using the electronic medical record system. The study extracted the following information from the medical records: demographic data (age, gender), cancer stage, histology, treatment regimen, ICIs received, duration of treatment, smoking status, Eastern Cooperative Oncology Group (ECOG) performance status, and any adverse events experienced. Data on the use of oral probiotic supplements during the course of ICI treatment were collected through a self-administered questionnaire.

The primary endpoint of the study was progression-free survival (PFS), which was defined as the time from initiation of ICI treatment to tumor progression from any cause. The secondary outcome measure was objective response rate (ORR), and the best objective tumor response of patients was evaluated by RECIST 1.1 criteria. The study stratified the participants based on tumor cell type, stage of lung cancer, and type of ICIs (anti-PD1 or anti-PDL1). These outcomes were assessed through regular follow-up visits and reviewed medical records.

Statistical Analysis

Statistical analysis was performed using SPSS version 26.0. Descriptive statistics were used to summarize the baseline characteristics of the study participants. Continuous variables were presented as mean ± standard deviation or median (interquartile range), while categorical variables were presented as frequencies and percentages. The primary outcome (progression-free survival) was analyzed using Kaplan-Meier survival analysis, and the log-rank test was used to compare survival curves between the study and control groups. Cox proportional hazard regression models were used to estimate hazard ratios and their corresponding 95% confidence intervals. Secondary outcomes (objective response rate) were analyzed using chi-square or Fisher’s exact tests. A P-value of less than .05 was considered statistically significant.

The reporting of this study conforms to STROBE guidelines.²⁰

Results

Patients’ Characteristics

A total of 278 patients were screened. 12 were lost to follow-up, 7 received neoadjuvant therapy, and 6 were unable to take liquid medications. Finally, 253 patients were enrolled in the current study. Among them, 71 patients received oral probiotic supplements during the ICI treatment period as a result of their own willingness and were assigned to Group OPS. The remaining 182 patients who did not receive any probiotics were assigned to the control group (Group C). The study flow chart is shown in Figure 1.

Figure 1.

Research flowchart. (Group C: control group; Group OPS: received oral probiotic supplements along with ICIs).

There were no significant differences observed in terms of gender (P = .851), age (P = .36), smoking status (P = .572), ECOG performance status (P = .643), and the number of treatment lines (P = .238). The median age in the OPS group was 60.0 (IQR: 54.5-68), compared to 62.5 (IQR: 57-69) in group C. However, there were significant differences observed in the distribution of pathological types and disease stages between the 2 groups (P < .001 for both). Group C had a higher prevalence of non-small cell lung cancer (NSCLC) (82%) compared to group OPS (62%), while group OPS had a higher prevalence of small cell lung cancer (SCLC) (38%) compared to group C (18%). Additionally, although there was a significant association between stage at diagnosis and treatment groups (P = .001), stage III plus IV disease were similar in both groups, with 100% in group OPS and 98% in group C. Finally, the expression of PD-1/PD-L1 was similar across the groups, with the majority of patients expressing PD-1 (83% of the overall cohort) (Table 1).

Table 1.

Patient Demographics and Baseline Characteristics.

Characteristic	Group			P-value
Characteristic	Overall, N = 253	OPS, N = 71	C, N = 182	P-value
Age				.360
Median (IQR)	61 (56, 69)	60 (55, 68)	63 (57, 69)
Gender				.851
Male	212 (84%)	59 (83%)	153 (84%)
Female	41 (16%)	12 (17%)	29 (16%)
Smoke				.572
Yes	115 (62%)	34 (65%)	81 (61%)
No	70 (38%)	18 (35%)	52 (39%)
ECOG				.643
0	105 (57%)	27 (53%)	78 (59%)
1	78 (42%)	24 (47%)	54 (41%)
2	1 (1%)	0 (0%)	1 (1%)
Pathological type				<.001
NSCLC	194 (77%)	44 (62%)	150 (82%)
SCLC	59 (23%)	27 (38%)	32 (18%)
Stage				.001
II	1 (0%)	0 (0%)	1 (1%)
III	35 (14%)	2 (3%)	33 (18%)
IV	216 (86%)	68 (97%)	148 (81%)
Number of treatment lines				.238
1	164 (65%)	43 (61%)	121 (66%)
2	54 (21%)	14 (20%)	40 (22%)
≥3	35 (14%)	14 (20%)	21 (12%)
Combination				.001
CT	154 (68%)	46 (87%)	108 (62%)
RT	18 (8%)	0 (0%)	18 (10%)
CRT	38 (17%)	4 (8%)	34 (20%)
anti-VEGF	1 (0%)	1 (2%)	0 (0%)
CT + anti-VEGF	7 (3%)	1 (2%)	6 (3%)
RT + anti-VEGF	1 (0%)	0 (0%)	1 (1%)
CRT + anti-VEGF	1 (0%)	0 (0%)	1 (1%)
Cells therapy	1 (0%)	1 (2%)	0 (0%)
Single-agent	5 (2%)	0 (0%)	5 (3%)
Anti-PD-1/PD-L1				.900
PD-1	210 (83%)	58 (83%)	152 (84%)
PD-L1	42 (17%)	12 (17%)	30 (16%)

CT: chemotherapy; RT: radiotherapy; CRT: chemoradiotherapy; VEGF: vascular endothelial growth factor.

(Group C: Control Group; Group OPS: Received Oral Probiotic Supplements Along With ICIs).

Furthermore, among the patients with SCLC (n = 59), there were 27 in Group OPS and 32 in Group C. No significant differences were observed in terms of gender (P > .999), age (P = .903), smoking status (P = .859), ECOG performance status (P = .054), and clinical stage (P = .056) between the 2 groups (Table 2).

Table 2.

Demographics and Baseline Characteristics for Patients With SCLC.

Characteristic	Group			P-value
Characteristic	Overall, N = 59	Group OPS, N = 27	Group C, N = 32	P-value
Age (yr)				.939
Median (IQR)	60 (54, 71)	60 (54, 70)	60 (54, 70)
Gender				>.999
Male	49 (83%)	22 (81%)	27 (84%)
Female	10 (17%)	5 (19%)	5 (16%)
Smoke				.859
Yes	24 (63%)	11 (65%)	13 (62%)
No	14 (37%)	6 (35%)	8 (38%)
ECOG				.054
0	20 (53%)	6 (35%)	14 (67%)
1	18 (47%)	11 (65%)	7 (33%)
Stage				.056
ES	54 (92%)	27 (100%)	27 (84%)
LS	5 (8%)	0 (0%)	5 (16%)
Combination				.567
CT	37 (80%)	15 (88%)	22 (76%)
RT	3 (7%)	0 (0%)	3 (10%)
CRT	3 (7%)	1 (6%)	2 (7%)
anti-VEGF	1 (2%)	1 (6%)	0 (0%)
CT + anti-VEGF	1 (2%)	0 (0%)	1 (3%)
CRT + anti-VEGF	1 (2%)	0 (0%)	1 (3%)
Anti-PD-1/PD-L1				.912
PD-1	33 (57%)	15 (58%)	18 (56%)
PD-L1	25 (43%)	11 (42%)	14 (44%)

ES: extensive stage; LS: limited stage; CT: chemotherapy; RT: radiotherapy; CRT: chemoradiotherapy; VEGF: vascular endothelial growth factor.

Clinical Outcomes

In the overall population, the media PFS for the entire cohort was 12.0 months (95% confidence interval [CI]: 10.4-13.6 months). Among the probiotic supplement users (group OPS), the median PFS was 13.3 months (95% CI: 8.5-18.40), while non-users (group C) had a median PFS of 12.0 months (95% CI: 9.9-14.1 months) (P = .24).

Among patients with small cell lung cancer (SCLC), the median PFS for the entire cohort was 9.3 months (95% CI: 6.1-12.5 months). SCLC patients in group OPS achieved a significantly better median PFS (11.1 months, 95% CI: 5.9-16.3) compared to group C (7.0 months, 95% CI: 5.0-9.0) (P = .049). There was a trend towards better mPFS in the patients with NSCLC in Group OPS (16.5 months vs 12.3 months), but the difference was unable to be statistically significant (P = .56) (Figure 2).

Figure 2.

(A)-(C) Kaplan-Meier curve for Progression-free survival (PFS) for SCLC patients, NSCLC patients, and all patients. (Group C: control group; Group OPS: received oral probiotic supplements along with ICIs).

A radiographic efficacy assessment was obtained from a total of 250 patients. There was no statistically significant difference in the ORR between the 2 groups (57.7% vs 58.1%, P > .26). In patients with small cell lung cancer, the ORR in Group OPS was higher than that in Group C, with 66.7% and 53.1% respectively. However, this difference was not statistically significant (P = .39) (Figure 3).

Figure 3.

Best objective Tumor Response of patients evaluated by RECIST 1.1 criteria. CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease. (A) The response rate for SCLC patients; (B) The response rate for all patients.

Discussion

In the past decade, ICI immunotherapy has significantly advanced traditional cancer treatment and has led to breakthroughs in the management of metastatic malignancies.^21-24 This is particularly true for lung cancer, including both NSCLC and SCLC, where immunotherapy has shown substantial benefits. As the use of ICIs in cancer treatment has become more widespread, researchers have been working tirelessly to identify factors that may influence their effectiveness.²⁵ One such factor that has gained increasing recognition is the human gut microbiota. Mounting evidence supports the role of the gut microbiota in the ICI response in preclinical and clinical studies.^17,26-30 Probiotics, which are live microorganisms that provide health benefits when administered in sufficient quantities, have emerged as a potential adjunct therapy to enhance the efficacy of ICIs and mitigate treatment-related adverse effects.¹¹ Given the potential role of oral probiotic supplements in enhancing immune responses and improving the outcomes of ICI treatments by modulating the composition of the gut microbiota, it is worthwhile to explore this topic further.

To the best of our knowledge, this is the first study to report on the impact of oral probiotic supplements on the efficacy of PFS in the treatment of SCLC. Currently, the combination of ICIs (such as pembrolizumab, durvalumab, or atezolizumab) with platinum-based chemotherapy has been shown to improve OS and PFS in extensive-stage SCLC and is recommended as the preferred first-line therapy (Rudin et al., 2020; Paz-Ares et al., 2019; Horn et al., 2018).^31-33 Our results demonstrate that the addition of oral probiotic supplements to ICIs significantly prolongs PFS in patients with advanced SCLC, and may also improve the response rate. These findings suggest a synergistic effect between oral probiotic supplements and ICIs, enhancing the immune response against cancer cells clinically. The mechanisms underlying the beneficial effects of oral probiotic supplements in combination with ICIs remain to be elucidated. It is possible that probiotic supplements enhance the composition of the gut microbiota, leading to a more favorable immune microenvironment and increased efficacy of ICIs. Previous studies have shown that the gut microbiome can interact with innate and adaptive immune cells, enhancing the anti-tumor effects of innate immune cells, promoting the anti-tumor effects of adaptive immune cells, and increasing the immunogenicity of tumor cells, which in turn modify the tumor microenvironment and improve ICI responses (Lu et al., 2022).³⁴ Further research is needed to explore the specific mechanisms involved.

Previous prospective clinical studies have demonstrated that the combination of ICIs and platinum-based chemotherapy has resulted in a median progression-free survival (mPFS) of up to 5.4 months (95% CI 4·8-6·2) for SCLC.³² In our study, SCLC in Group C showed an mPFS of approximately 7.0 months (95% CI: 5.0-9.0), which is slightly higher than the previously reported data. The reason for this difference may be attributed to the fact that our study did not solely focus on the combination of chemotherapy and immunotherapy. Instead, it also included patients who received chemoradiotherapy in conjunction with immunotherapy, as well as chemoradiotherapy combined with immunotherapy and anti-vascular endothelial growth factor medications. In our study, the ORR in group C was similar to the previous study,³¹ while the ORR and mPFS of the OPS group were significantly prolonged. These findings suggest that probiotic combination therapy may be more suitable for SCLC.

Previous retrospective studies have suggested that probiotics could enhance the efficacy of ICIs in patients with non-small cell lung cancer. Tomita et al. conducted a retrospective evaluation of 118 patients with advanced NSCLC who underwent ICI treatment and found that probiotic CBT (clostridium butyricum therapy) significantly prolonged PFS (median, 250 vs 111 days; HR, .37; P = .001, 95% CI: .21-.65) and OS (median, not reported vs 361 days; HR, .2; P < .001; 95% CI: .07-.44) compared to those not receiving probiotic CBT.³⁵ A meta-analysis was conducted to assess the association between probiotic use and PFS using data from 5 studies. The results indicated that NSCLC patients treated with ICIs in combination with probiotics achieved significantly longer PFS (HR: .532, 95% CI: .354-.798, P = .002) and OS (HR: .528, 95% CI: .306-.912, P = .022).^35-38 In the current study, we observed a trend towards a higher median PFS in patients with NSCLC who received oral probiotic supplements (16.5 months vs 12.3 months). However, this difference was not statistically significant. Several factors may have contributed to these findings. Firstly, the variety of commercially available probiotic supplements and their varying compositions make it difficult to observe the specific effects of individual microbial strains. Secondly, the sample size in this real-world study might have been inadequate to detect subtle differences in treatment outcomes. Thirdly, there may have been inherent differences in the concurrent treatments received by the probiotic and control groups, which could have influenced the outcomes. Additionally, as a real-world study and to maintain the study sample size as much as possible, we did not perform propensity score matching (PSM), which may introduce confounding bias. Interestingly, another study by Takada et al. found no significant differences in PFS and OS between patients who did and did not receive probiotics before applying inverse probability of treatment weighting (IPTW). However, after IPTW, they observed a significant difference in PFS between the groups in a multicenter and retrospective study (Takada et al., 2021).³⁸ In order to obtain more robust evidence, future prospective randomized controlled trials should be conducted. These studies should aim to address the limitations identified in this real-world study, including the use of specific probiotic strains, larger sample sizes, and standardized treatment protocols. Conducting such studies will provide more powerful evidence regarding the efficacy of oral probiotics in the context of ICIs for the treatment of advanced LC.

In addition, limitations should be considered. Firstly, the study was designed as real-world observational research, which could not strictly limit the intervening measure, confounding factors might interfere with the analysis. Secondly, the sample size was not as large as expected when the study was designed. The insufficient case may make the significance to be a trend. Besides, the study relied on self-reporting of probiotics supplement usage, which may introduce recall bias and inaccuracies in the reporting. Additionally, the specific strains and dosages of the probiotic supplements were not assessed because of the complex kinds and different components. A further prospective randomized control study is warranted.

Conclusion

This prospective real-world study reveals that oral probiotic supplements in combination with ICIs included regimen may improve the outcome in patients with advanced SCLC. The above points should be proved by further study.

Footnotes

Acknowledgements

The authors would like to thank the Cancer Psychology and Health Management Committee of Sichuan Cancer Society & Cancer Recovery and Palliative Care Committee of Sichuan Anti-cancer Association for their valuable guidance. We extend our special thanks to researcher Jian Wang from Kangzhe Biotechnology Co., Ltd., for serving as our statistical research consultant and providing support on statistical issues.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Innovative Scientific Research Project program for medical youth in Sichuan province (No.Q20074), and the Project of Medical Research in Chengdu (NO.2021321).

Ethical Statement

ORCID iD

Liping Tong

Jiang Zhu

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.*

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