A Combined Immune-Inflammatory Score for Predicting Treatment Response and Survival in Advanced Gastric Cancer Receiving Chemoimmunotherapy
-
Xiaoyan Huang
,
Chunhong Xiao
,
Weixuan Hong
,
Xi Chen
,
Junwei Fang
,
Zhirong Yang
,
Lifen Cai
,
Jiaqi Huang
Abstract
Effective biomarkers are urgently needed to guide chemoimmunotherapy in advanced gastric cancer (AGC) and improve clinical outcomes. This study aimed to explore a blood-based immune score for predicting outcomes in patients with AGC receiving chemoimmunotherapy.
In this retrospective analysis, patients with AGC receiving chemoimmunotherapy were included. Treatment response was assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Peripheral blood immune-inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and C-reactive protein-to-albumin ratio (CAR), and immune cell subsets, including CD4+, CD8+, and natural killer (NK) cells, were measured pre- and post-treatment. Receiver operating characteristic (ROC) analysis determined optimal cutoffs. Logistic regression identified independent predictors of objective response rate (ORR), and a combined immune-inflammatory score was constructed. Progression-free survival (PFS) was estimated using the Kaplan–Meier method, with risk stratification based on the score. Bootstrap resampling was used for internal validation.
Among 100 patients, the ORR was 46.0%. Multivariate analysis confirmed NLR ≤ 2.5 (adjusted odds ratio [aOR]=0.333), CD8+ T cells≥30% (aOR=3.439), and SII ≤ 600 (aOR=0.386) as independent predictors of ORR. The combined score (range 0–3) achieved an area under the curve (AUC) of 0.874 for ORR prediction. During a median follow-up of 15.3 months, patients with a score≥2 (favorable immune profile group) had significantly longer PFS than those with a score≤1 (unfavorable immune profile group) (median PFS: 15.6 vs 7.8 months). Bootstrap internal validation confirmed the stability of the score (concordance index [C-index]=0.814).
The NLR/SII/CD8+ T-cell score was associated with treatment response and survival among patients with AGC receiving chemoimmunotherapy, suggesting that it is a hypothesis-generating tool requiring external validation and is not ready for clinical use.
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8.Shoji H, Kudo-Saito C, Nagashima K, Imazeki H, Tsugaru K, Takahashi N, et al. Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study). J Immunother Cancer. 2024;12(11):e010174.
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10.Körfer J, Lordick F, Hacker UT. Molecular Targets for Gastric Cancer Treatment and Future Perspectives from a Clinical and Translational Point of View. Cancers (Basel). 2021;13(20): 5216.
11. Zamboni GA, Cappello G, Caruso D, Gourtsoyianni S, Cyran C, Schlemmer HP, et al. ESR Essentials: response assessment criteria in oncologic imaging-practice recommendations by the European Society of Oncologic Imaging. Eur Radiol. 2025;35(2):674-83.
12. Parums DV. Editorial: The 2024 Revision of the Declaration of Helsinki and its Continued Role as a Code of Ethics to Guide Medical Research. Med Sci Monit. 2024;30:e947428.
13. Ma Y, Wang Z, Qiu C, Xiao M, Wu S, Han K, et al. Nomogram based on CT imaging and clinical data to predict the efficacy of PD-1 inhibitors combined with chemotherapy in advanced gastric cancer. Front Immunol. 2025;16:1504387.
14. Kim HS, Kim JW, Kim JH, Choi DR, Han AR, Kim MJ, et al. Single-lesion measurement per organ for assessing tumor response in advanced gastric cancer. Oncology. 2015;88(2):69-75.
15. Lan T, Zhu Y, Zhong W, Tan Q, Lin T, Huang J, et al. Evaluating the efficacy and safety of bladder-sparing regimen with Disitamab Vedotin combined with Toripalimab and pelvic lymph node dissection in muscle-invasive bladder cancer patients: study protocol of a multicenter single-arm phase II trial. BMC Cancer. 2025;25:868.
16.Araki T, Kanda S, Komatsu M, Sonehara K, Tateishi k, Takada M, et al. Rechallenge of afatinib for EGFR-mutated non-small cell lung cancer previously treated with osimertinib: a multicenter phase II trial protocol (REAL study). Transl Lung Cancer Res. 2023;12(6): 1320-1327.
17. Dong S, Wei C, Wang X, Yang X, Shen W, Li S, et al. A retrospective multicenter study on the efficacy and safety of disitamab vedotin monotherapy versus combination with anti-PD-1 immunotherapy in advanced gastric cancer. Sci Rep. 2025;15(1):2232.
18. Wang FH, Zhang XT, Li YF, Tang L, Qu XJ, Ying JE, et al. The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2021. Cancer Commun (Lond). 2021;41(8):747-95.
19. Liu Z, Liu A, Li M, Xiang J, Yu G, Sun P. Efficacy and safety of sintilimab combined with trastuzumab and chemotherapy in HER2-positive advanced gastric or gastroesophageal junction cancer. Front Immunol. 2025;16:1545304.
20. Dong K, Zheng Y, Wang Y, Guo Q. Predictive role of neutrophil percentage-to-albumin ratio, neutrophil-to-lymphocyte ratio, and systemic immune-inflammation index for mortality in patients with MASLD. Sci Rep. 2024;14(1):30403.
21. Gu L, Wang M, Cui X, Mo J, Yuan L, Mao F, et al. Clinical significance of peripheral blood-derived inflammation markers in advanced gastric cancer after radical resection. BMC Surgery. 2020;20(1):219.
22. Zhang X, You Y, Zhang P, Wang Y, Shen F. Cytokine release syndrome caused by immune checkpoint inhibitors: a case report and literature review. Future Sci OA. 2024;10(1):2422786.
23.Xu R, Zhang W. Research Advances on the Role of Helicobacter pylori CagA Protein in the Pathogenesis of Gastric Cancer. Integrative Medicine and Nursing Advances. 2025;1(3):1-8.
24. Rugambwa TK, Abdihamid O, Zhang X, Peng Y, Cai C, Shen H, et al. Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as potential predictive markers of treatment response in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Front Oncol. 2023;13:1181248.
25. Chen G, Bao B, Ye Y, Hu A, Sun J, Liu W. Prognostic value of the systemic immune-inflammation index in non-small cell lung cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Front Oncol. 2025;15:1532343.
26.Casalegno Garduño R, Spitschak A, Pannek T, Pützer BM. CD8+ T Cell Subsets as Biomarkers for Predicting Checkpoint Therapy Outcomes in Cancer Immunotherapy. Biomedicines. 2025;13(4):930.
27.Kievit H, Muntinghe-Wagenaar MB, Abdulahad WH, Rutgers A, Hijmering-Kappelle LBM, Hiddinga BI, et al. Baseline Blood CD8(+) T Cell Activation Potency Discriminates Responders from Non-Responders to Immune Checkpoint Inhibition Combined with Stereotactic Radiotherapy in Non-Small-Cell Lung Cancer. Cancers (Basel). 2024;16(14): 2592.
28. Tietze JK, Angelova D, Heppt MV, Reinholz M, Murphy WJ, Spannagl M, et al. The proportion of circulating CD45RO(+)CD8(+) memory T cells is correlated with clinical response in melanoma patients treated with ipilimumab. Eur J Cancer. 2017;75:268-79.
29.Zhang Y, Zhang F, Liu Z, Li M, Wu G, Li H. P2RX1-blocked neutrophils induce CD8+ T cell dysfunction and affect the immune escape of gastric cancer cells. Cell Immunol. 2025;408:104901.
30. Ma X, Liu Y, Chen Y, Wang J, Zhang F, Liang W, et al. BFAR Promotes Neutrophil Infiltration and Immunosuppressive Reprogramming through the PRP19-YBX1 Axis to Induce Immune Evasion in Gastric Cancer. Cancer Immunol Res. 2025;13(12):2037-53.
31. Li J, Liu J, Yang S, Xia Y, Meng Q, Sun B, et al. PD-L1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancer. Cell Commun Signal. 2025;23(1):29.
32. Liu Y, Liu G, Wang X, Zhang X, Wu J, Li Y, et al. The m(1)A-SFRP2-NFAT/TOX axis governs T cell exhaustion in gastric cancer. Cell Oncol (Dordr). 2025;48(5):1553-69.
33.Kim H, Shin K, Park SJ, Lee MA, Park J, Kim O, et al. Dynamic Integrative Immune Profiling Reveals Early Biomarkers of Response and Prognosis in Advanced Gastric Cancer Treated with Nivolumab Plus Chemotherapy. Cancers (Basel). 2025;17(19):3131.
34.Tashireva LA, Kalinchuk AY, Shmakova EO, Tsarenkova EA, Loos DM, Iamschikov P, et al. PD-1-Positive CD8+ T Cells and PD-1-Positive FoxP3+ Cells in Tumor Microenvironment Predict Response to Neoadjuvant Chemoimmunotherapy in Gastric Cancer Patients. Cancers (Basel). 2025;17(14):2407.
35.Trontzas IP, Syrigos KN. Immune Biomarkers for Checkpoint Blockade in Solid Tumors: Transitioning from Tissue to Peripheral Blood Monitoring and Future Integrated Strategies. Cancers (Basel). 2025;17(16):2639.
36. Kuang X, Xu R, Li J. Association of PD-L1 expression with survival benefit from PD-1/PD-L1 inhibitors in advanced cancer: Systematic review and meta-analysis of phase III randomized clinical trials. Crit Rev Oncol Hematol. 2024;198:104357.
37. Ahn S, Kwak Y, Kwon GY, Kim KM, Kim M, Kim H, et al. Interpretation of PD-L1 expression in gastric cancer: summary of a consensus meeting of Korean gastrointestinal pathologists. J Pathol Transl Med. 2024;58(3):103-16.
38. Zhang L, Lin L, Ni J, Ling T, Huang L. Prognostic value of the pretreatment Glasgow prognostic score or modified Glasgow prognostic score in patients with advanced cancer receiving immune checkpoint inhibitors: A systematic review and meta‑analysis. Oncol Lett. 2025;30(1):323.
39.Xia J, Chen Y, Wen S, Du X, Shen B. [Peripheral Blood Inflammation Indicators as Predictive Indicators in Immunotherapy of Advanced non-small cell Lung Cancer]. Zhongguo Fei Ai Za Zhi. 2021;24(9):632-45.
2. Chen Y, Jia K, Xie Y, Yuan J, Liu D, Jiang L, et al. The current landscape of gastric cancer and gastroesophageal junction cancer diagnosis and treatment in China: a comprehensive nationwide cohort analysis. J Hematol Oncol. 2025;18(1):42.
3. Wei J, Zhang P, Hu Q, Cheng X, Shen C, Chen Z, et al. Nab-paclitaxel combined with cadonilimab (AK104) as second-line treatment for advanced gastric cancer: protocol for a phase II prospective, multicenter, single-arm clinical trial. Front Immunol. 2025;16:1519545.
4. Zhang W, Guo K, Zheng S. Immunotherapy Combined with Chemotherapy in the First-Line Treatment of Advanced Gastric Cancer: Systematic Review and Bayesian Network Meta-Analysis Based on Specific PD-L1 CPS. Curr Oncol. 2025;32(2): 112.
5. Shen L, Zhang Y, Li Z, Zhang X, Gao X, Liu B, et al. First-line cadonilimab plus chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: a randomized, double-blind, phase 3 trial. Nat Med. 2025;31(4):1163-70.
6. Ren J. Advances in Combination Therapy for Gastric Cancer: Integrating Targeted Agents and Immunotherapy. Advances in Clinical Pharmacology and Therapeutics. 2024;1(1):1-15.
7. Sasagawa S, Honma Y, Peng X, Maejima K, Nagaoka K, Kobayashi Y, et al. Predicting chemotherapy responsiveness in gastric cancer through machine learning analysis of genome, immune, and neutrophil signatures. Gastric Cancer. 2025;28(2):228-44.
8.Shoji H, Kudo-Saito C, Nagashima K, Imazeki H, Tsugaru K, Takahashi N, et al. Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study). J Immunother Cancer. 2024;12(11):e010174.
9. Gu Y, Sun M, Fang H, Shao F, Lin C, Liu H, et al. Impact of clonal TP53 mutations with loss of heterozygosity on adjuvant chemotherapy and immunotherapy in gastric cancer. Br J Cancer. 2024;131(8):1320-7.
10.Körfer J, Lordick F, Hacker UT. Molecular Targets for Gastric Cancer Treatment and Future Perspectives from a Clinical and Translational Point of View. Cancers (Basel). 2021;13(20): 5216.
11. Zamboni GA, Cappello G, Caruso D, Gourtsoyianni S, Cyran C, Schlemmer HP, et al. ESR Essentials: response assessment criteria in oncologic imaging-practice recommendations by the European Society of Oncologic Imaging. Eur Radiol. 2025;35(2):674-83.
12. Parums DV. Editorial: The 2024 Revision of the Declaration of Helsinki and its Continued Role as a Code of Ethics to Guide Medical Research. Med Sci Monit. 2024;30:e947428.
13. Ma Y, Wang Z, Qiu C, Xiao M, Wu S, Han K, et al. Nomogram based on CT imaging and clinical data to predict the efficacy of PD-1 inhibitors combined with chemotherapy in advanced gastric cancer. Front Immunol. 2025;16:1504387.
14. Kim HS, Kim JW, Kim JH, Choi DR, Han AR, Kim MJ, et al. Single-lesion measurement per organ for assessing tumor response in advanced gastric cancer. Oncology. 2015;88(2):69-75.
15. Lan T, Zhu Y, Zhong W, Tan Q, Lin T, Huang J, et al. Evaluating the efficacy and safety of bladder-sparing regimen with Disitamab Vedotin combined with Toripalimab and pelvic lymph node dissection in muscle-invasive bladder cancer patients: study protocol of a multicenter single-arm phase II trial. BMC Cancer. 2025;25:868.
16.Araki T, Kanda S, Komatsu M, Sonehara K, Tateishi k, Takada M, et al. Rechallenge of afatinib for EGFR-mutated non-small cell lung cancer previously treated with osimertinib: a multicenter phase II trial protocol (REAL study). Transl Lung Cancer Res. 2023;12(6): 1320-1327.
17. Dong S, Wei C, Wang X, Yang X, Shen W, Li S, et al. A retrospective multicenter study on the efficacy and safety of disitamab vedotin monotherapy versus combination with anti-PD-1 immunotherapy in advanced gastric cancer. Sci Rep. 2025;15(1):2232.
18. Wang FH, Zhang XT, Li YF, Tang L, Qu XJ, Ying JE, et al. The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2021. Cancer Commun (Lond). 2021;41(8):747-95.
19. Liu Z, Liu A, Li M, Xiang J, Yu G, Sun P. Efficacy and safety of sintilimab combined with trastuzumab and chemotherapy in HER2-positive advanced gastric or gastroesophageal junction cancer. Front Immunol. 2025;16:1545304.
20. Dong K, Zheng Y, Wang Y, Guo Q. Predictive role of neutrophil percentage-to-albumin ratio, neutrophil-to-lymphocyte ratio, and systemic immune-inflammation index for mortality in patients with MASLD. Sci Rep. 2024;14(1):30403.
21. Gu L, Wang M, Cui X, Mo J, Yuan L, Mao F, et al. Clinical significance of peripheral blood-derived inflammation markers in advanced gastric cancer after radical resection. BMC Surgery. 2020;20(1):219.
22. Zhang X, You Y, Zhang P, Wang Y, Shen F. Cytokine release syndrome caused by immune checkpoint inhibitors: a case report and literature review. Future Sci OA. 2024;10(1):2422786.
23.Xu R, Zhang W. Research Advances on the Role of Helicobacter pylori CagA Protein in the Pathogenesis of Gastric Cancer. Integrative Medicine and Nursing Advances. 2025;1(3):1-8.
24. Rugambwa TK, Abdihamid O, Zhang X, Peng Y, Cai C, Shen H, et al. Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as potential predictive markers of treatment response in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Front Oncol. 2023;13:1181248.
25. Chen G, Bao B, Ye Y, Hu A, Sun J, Liu W. Prognostic value of the systemic immune-inflammation index in non-small cell lung cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Front Oncol. 2025;15:1532343.
26.Casalegno Garduño R, Spitschak A, Pannek T, Pützer BM. CD8+ T Cell Subsets as Biomarkers for Predicting Checkpoint Therapy Outcomes in Cancer Immunotherapy. Biomedicines. 2025;13(4):930.
27.Kievit H, Muntinghe-Wagenaar MB, Abdulahad WH, Rutgers A, Hijmering-Kappelle LBM, Hiddinga BI, et al. Baseline Blood CD8(+) T Cell Activation Potency Discriminates Responders from Non-Responders to Immune Checkpoint Inhibition Combined with Stereotactic Radiotherapy in Non-Small-Cell Lung Cancer. Cancers (Basel). 2024;16(14): 2592.
28. Tietze JK, Angelova D, Heppt MV, Reinholz M, Murphy WJ, Spannagl M, et al. The proportion of circulating CD45RO(+)CD8(+) memory T cells is correlated with clinical response in melanoma patients treated with ipilimumab. Eur J Cancer. 2017;75:268-79.
29.Zhang Y, Zhang F, Liu Z, Li M, Wu G, Li H. P2RX1-blocked neutrophils induce CD8+ T cell dysfunction and affect the immune escape of gastric cancer cells. Cell Immunol. 2025;408:104901.
30. Ma X, Liu Y, Chen Y, Wang J, Zhang F, Liang W, et al. BFAR Promotes Neutrophil Infiltration and Immunosuppressive Reprogramming through the PRP19-YBX1 Axis to Induce Immune Evasion in Gastric Cancer. Cancer Immunol Res. 2025;13(12):2037-53.
31. Li J, Liu J, Yang S, Xia Y, Meng Q, Sun B, et al. PD-L1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancer. Cell Commun Signal. 2025;23(1):29.
32. Liu Y, Liu G, Wang X, Zhang X, Wu J, Li Y, et al. The m(1)A-SFRP2-NFAT/TOX axis governs T cell exhaustion in gastric cancer. Cell Oncol (Dordr). 2025;48(5):1553-69.
33.Kim H, Shin K, Park SJ, Lee MA, Park J, Kim O, et al. Dynamic Integrative Immune Profiling Reveals Early Biomarkers of Response and Prognosis in Advanced Gastric Cancer Treated with Nivolumab Plus Chemotherapy. Cancers (Basel). 2025;17(19):3131.
34.Tashireva LA, Kalinchuk AY, Shmakova EO, Tsarenkova EA, Loos DM, Iamschikov P, et al. PD-1-Positive CD8+ T Cells and PD-1-Positive FoxP3+ Cells in Tumor Microenvironment Predict Response to Neoadjuvant Chemoimmunotherapy in Gastric Cancer Patients. Cancers (Basel). 2025;17(14):2407.
35.Trontzas IP, Syrigos KN. Immune Biomarkers for Checkpoint Blockade in Solid Tumors: Transitioning from Tissue to Peripheral Blood Monitoring and Future Integrated Strategies. Cancers (Basel). 2025;17(16):2639.
36. Kuang X, Xu R, Li J. Association of PD-L1 expression with survival benefit from PD-1/PD-L1 inhibitors in advanced cancer: Systematic review and meta-analysis of phase III randomized clinical trials. Crit Rev Oncol Hematol. 2024;198:104357.
37. Ahn S, Kwak Y, Kwon GY, Kim KM, Kim M, Kim H, et al. Interpretation of PD-L1 expression in gastric cancer: summary of a consensus meeting of Korean gastrointestinal pathologists. J Pathol Transl Med. 2024;58(3):103-16.
38. Zhang L, Lin L, Ni J, Ling T, Huang L. Prognostic value of the pretreatment Glasgow prognostic score or modified Glasgow prognostic score in patients with advanced cancer receiving immune checkpoint inhibitors: A systematic review and meta‑analysis. Oncol Lett. 2025;30(1):323.
39.Xia J, Chen Y, Wen S, Du X, Shen B. [Peripheral Blood Inflammation Indicators as Predictive Indicators in Immunotherapy of Advanced non-small cell Lung Cancer]. Zhongguo Fei Ai Za Zhi. 2021;24(9):632-45.
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How to Cite
1.
Huang X, Xiao C, Hong W, Chen X, Fang J, Yang Z, Cai L, Huang J. A Combined Immune-Inflammatory Score for Predicting Treatment Response and Survival in Advanced Gastric Cancer Receiving Chemoimmunotherapy. Iran J Allergy Asthma Immunol. 2026;:1-18.
