Predictive Value of Peripheral Blood Follicular Helper T Cells for Short-term Prognosis in Patients with Hepatocellular Carcinoma Treated with Immune Checkpoint Inhibitors
Abstract
Peripheral blood follicular helper T cells (Tfh) are essential in humoral immunity; however, their prognostic significance in hepatocellular carcinoma (HCC) patients treated with immune checkpoint inhibitors (ICIs) is not well understood. This study aimed to evaluate the predictive value of Tfh cells for short-term prognosis in 200 HCC patients undergoing ICIs.
A retrospective analysis categorized patients based on their clinical outcomes at six months post-treatment: those demonstrating improvement were classified as having a favorable prognosis (n=86), while those with no remission, deterioration, or death were classified as having a poor prognosis (n=114). Key prognostic factors assessed included C-reactive protein (CRP), interleukin-6 (IL-6), Tfh cell counts, and combination therapy.
Significant associations were identified between prognosis and CRP, IL-6, Tfh cell counts, and combination therapy. Multivariate analysis revealed these factors as independent predictors of short-term prognosis, explaining 78.3% of the variance. The area under the curve (AUC) for Tfh cells was 0.902 (95% CI: 0.8567-0.9477), with 100% sensitivity and 80.70% specificity at a cut-off of 1.995. Patients with elevated Tfh levels (≥1.995, n=93) had a median overall survival (OS) of 5 months, significantly earlier than those with lower levels (<1.995, n=107), whose median OS was not reached.
Tfh cells are independent predictors of short-term prognosis in HCC patients receiving ICIs. Reduced Tfh levels correlate with improved outcomes, providing crucial insights for clinical decision-making.
1. Akbulut Z, Aru B, Aydın F, Yanıkkaya Demirel G. Immune checkpoint inhibitors in the treatment of hepatocellular carcinoma. Front Immunol. 2024;15:1379622.
2. Celsa C, Cabibbo G, Fulgenzi CAM, Scheiner B, D'Alessio A, Manfredi GF, et al. Characteristics and outcomes of immunotherapy-related liver injury in patients with hepatocellular carcinoma versus other advanced solid tumours. J Hepatol. 2024;80(3):431-42.
3. Chen CR, Qi WX, Liu T, Tong X. Efficacy of addition ICIs to chemotherapy as first-line treatment for small cell lung cancer patients with liver or brain metastases: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2022;26(16):5857-67.
4. Chen EX, Loree JM, Titmuss E, Jonker DJ, Kennecke HF, Berry S, et al. Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA network open. 2023;6(12):e2346094.
5. Cheng Z, Yang C, Zhao Q, Zhong J, Zhang J, Jin R, et al. Efficacy and predictors of ICIs in patients with gallbladder cancer. Cancer Sci. 2024;115(6):1979-88.
6. Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res. 2021;149:1-61.
7. El Hajj J, Reddy S, Verma N, Huang EH, Kazmi SM. ICIs in pMMR/MSS Colorectal Cancer. J gastrointestinal Cancer. 2023;54(4):1017-30.
8. Greten TF, Villanueva A, Korangy F, Ruf B, Yarchoan M, Ma L, et al. Biomarkers for immunotherapy of hepatocellular carcinoma. Nat Rev Clin Oncol. 2023;20(11):780-98.
9. Hewitt DB, Rahnemai-Azar AA, Pawlik TM. Potential experimental ICIs for the treatment of cancer of the liver. Exp Opin Investigational Drugs. 2021;30(8):827-35.
10. Hong C, Dong HZ, Li RN, Zhu HB, Li QM, Cui H, et al. Predictive Value of the Hepatic Immune Predictive Index for Patients with Primary HCC Treated with ICIs. Digestive Dis. 2023;41(3):422-30.
11. Lee PC, Wu CJ, Hung YW, Lee CJ, Chi CT, Lee IC, et al. Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma. J Immunotherapy Cancer. 2022;10(6).
12. Lee WS, Yang H, Chon HJ, Kim C. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med. 2020;52(9):1475-85.
13. Llovet JM, Pinyol R, Yarchoan M, Singal AG, Marron TU, Schwartz M, et al. Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma. Nat Rev Clin Oncol. 2024;21(4):294-311.
14. Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol. 2023;29(6):1054-75.
15. Muhammed A, D'Alessio A, Enica A, Talbot T, Fulgenzi CAM, Nteliopoulos G, et al. Predictive biomarkers of response to ICIs in hepatocellular carcinoma. Exp Rev Mol Diagnostics. 2022;22(3):253-64.
16. Peeraphatdit TB, Wang J, Odenwald MA, Hu S, Hart J, Charlton MR. Hepatotoxicity From ICIs: A Systematic Review and Management Recommendation. Hepatology. 2020;72(1):315-29.
17. Qu FJ, Zhou Y, Wu S. Progress of ICIs therapy for non-small cell lung cancer with liver metastases. British J Cancer. 2024;130(2):165-75.
18. Scheiner B, Pomej K, Kirstein MM, Hucke F, Finkelmeier F, Waidmann O, et al. Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. J Hepatol. 2022;76(2):353-63.
19. Sonbol MB, Riaz IB, Naqvi SAA, Almquist DR, Mina S, Almasri J, et al. Systemic Therapy and Sequencing Options in Advanced Hepatocellular Carcinoma: A Systematic Review and Network Meta-analysis. JAMA Oncol. 2020;6(12):e204930.
20. Suzuki K, Yasui Y, Tsuchiya K, Matsumoto H, Yamazaki Y, Uchihara N, et al. Impact of immune-related adverse events in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab. J Gastroenterol Hepatol. 2024;39(6):1183-9.
21. Tian BW, Han CL, Wang HC, Yan LJ, Ding ZN, Liu H, et al. Effect of liver metastasis on the efficacy of ICIs in cancer patients: a systemic review and meta-analysis. Clin Exp Metastasis. 2023;40(4):255-87.
22. Wang W, Lin G, Hao Y, Guan Y, Zhang Y, Xu C, et al. Treatment outcomes and prognosis of ICIs therapy in patients with advanced thymic carcinoma: A multicentre retrospective study. Europ J Cancer. 2022;174:21-30.
23. Wu M, Wang Y, Yang Q, Wang X, Yang X, Xing H, et al. Comparison of Baseline (68)Ga-FAPI and (18)F-FDG PET/CT for Prediction of Response and Clinical Outcome in Patients with Unresectable Hepatocellular Carcinoma Treated with PD-1 Inhibitor and Lenvatinib. J Nucl Med. 2023;64(10):1532-9.
24. Xiao L, Liao Y, Wang J, Li Q, Zhu H, Hong C, et al. Efficacy and safety of ICIs in elderly patients with primary HCC: a retrospective, multicenter, real-world cohort study. Cancer Immunol Immunotherapy. 2023;72(7):2299-308.
25. Xiao LS, Li RN, Cui H, Hong C, Huang CY, Li QM, et al. Use of computed tomography-derived body composition to determine the prognosis of patients with primary HCC treated with ICIs: a retrospective cohort study. BMC cancer. 2022;22(1):737.
26. Xu H, Cao D, Zheng Y, Zhou D, Chen X, Lei J, et al. Potential predictors for survival in hepatocellular carcinoma patients treated with ICIs: A meta-analysis. Int Immunopharmacol. 2021;100:108135.
27. Yibirin M, Mustafayev K, Hosry J, Pundhir P, Klingen J, Yepez Guevara E, et al. ICIs Suppress Hepatitis C Virus Replication in Infected Patients With Solid Tumors. Am j Gastroenterol. 2023;118(9):1609-17.
28. Zhang L, Chen C, Chai D, Li C, Guan Y, Liu L, et al. The association between antibiotic use and outcomes of HCC patients treated with ICIs. Front Immunol. 2022;13:956533.
29. Zhang L, Feng J, Kuang T, Chai D, Qiu Z, Deng W, et al. Blood biomarkers predict outcomes in patients with hepatocellular carcinoma treated with ICIs: A pooled analysis of 44 retrospective sudies. Int Immunopharmacol. 2023;118:110019.
30. Zhu HF, Feng JK, Xiang YJ, Wang K, Zhou LP, Liu ZH, et al. Combination of alpha-fetoprotein and neutrophil-to-lymphocyte ratio to predict treatment response and survival outcomes of patients with unresectable hepatocellular carcinoma treated with ICIs. BMC cancer. 2023;23(1):547.
2. Celsa C, Cabibbo G, Fulgenzi CAM, Scheiner B, D'Alessio A, Manfredi GF, et al. Characteristics and outcomes of immunotherapy-related liver injury in patients with hepatocellular carcinoma versus other advanced solid tumours. J Hepatol. 2024;80(3):431-42.
3. Chen CR, Qi WX, Liu T, Tong X. Efficacy of addition ICIs to chemotherapy as first-line treatment for small cell lung cancer patients with liver or brain metastases: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2022;26(16):5857-67.
4. Chen EX, Loree JM, Titmuss E, Jonker DJ, Kennecke HF, Berry S, et al. Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA network open. 2023;6(12):e2346094.
5. Cheng Z, Yang C, Zhao Q, Zhong J, Zhang J, Jin R, et al. Efficacy and predictors of ICIs in patients with gallbladder cancer. Cancer Sci. 2024;115(6):1979-88.
6. Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res. 2021;149:1-61.
7. El Hajj J, Reddy S, Verma N, Huang EH, Kazmi SM. ICIs in pMMR/MSS Colorectal Cancer. J gastrointestinal Cancer. 2023;54(4):1017-30.
8. Greten TF, Villanueva A, Korangy F, Ruf B, Yarchoan M, Ma L, et al. Biomarkers for immunotherapy of hepatocellular carcinoma. Nat Rev Clin Oncol. 2023;20(11):780-98.
9. Hewitt DB, Rahnemai-Azar AA, Pawlik TM. Potential experimental ICIs for the treatment of cancer of the liver. Exp Opin Investigational Drugs. 2021;30(8):827-35.
10. Hong C, Dong HZ, Li RN, Zhu HB, Li QM, Cui H, et al. Predictive Value of the Hepatic Immune Predictive Index for Patients with Primary HCC Treated with ICIs. Digestive Dis. 2023;41(3):422-30.
11. Lee PC, Wu CJ, Hung YW, Lee CJ, Chi CT, Lee IC, et al. Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma. J Immunotherapy Cancer. 2022;10(6).
12. Lee WS, Yang H, Chon HJ, Kim C. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med. 2020;52(9):1475-85.
13. Llovet JM, Pinyol R, Yarchoan M, Singal AG, Marron TU, Schwartz M, et al. Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma. Nat Rev Clin Oncol. 2024;21(4):294-311.
14. Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol. 2023;29(6):1054-75.
15. Muhammed A, D'Alessio A, Enica A, Talbot T, Fulgenzi CAM, Nteliopoulos G, et al. Predictive biomarkers of response to ICIs in hepatocellular carcinoma. Exp Rev Mol Diagnostics. 2022;22(3):253-64.
16. Peeraphatdit TB, Wang J, Odenwald MA, Hu S, Hart J, Charlton MR. Hepatotoxicity From ICIs: A Systematic Review and Management Recommendation. Hepatology. 2020;72(1):315-29.
17. Qu FJ, Zhou Y, Wu S. Progress of ICIs therapy for non-small cell lung cancer with liver metastases. British J Cancer. 2024;130(2):165-75.
18. Scheiner B, Pomej K, Kirstein MM, Hucke F, Finkelmeier F, Waidmann O, et al. Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. J Hepatol. 2022;76(2):353-63.
19. Sonbol MB, Riaz IB, Naqvi SAA, Almquist DR, Mina S, Almasri J, et al. Systemic Therapy and Sequencing Options in Advanced Hepatocellular Carcinoma: A Systematic Review and Network Meta-analysis. JAMA Oncol. 2020;6(12):e204930.
20. Suzuki K, Yasui Y, Tsuchiya K, Matsumoto H, Yamazaki Y, Uchihara N, et al. Impact of immune-related adverse events in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab. J Gastroenterol Hepatol. 2024;39(6):1183-9.
21. Tian BW, Han CL, Wang HC, Yan LJ, Ding ZN, Liu H, et al. Effect of liver metastasis on the efficacy of ICIs in cancer patients: a systemic review and meta-analysis. Clin Exp Metastasis. 2023;40(4):255-87.
22. Wang W, Lin G, Hao Y, Guan Y, Zhang Y, Xu C, et al. Treatment outcomes and prognosis of ICIs therapy in patients with advanced thymic carcinoma: A multicentre retrospective study. Europ J Cancer. 2022;174:21-30.
23. Wu M, Wang Y, Yang Q, Wang X, Yang X, Xing H, et al. Comparison of Baseline (68)Ga-FAPI and (18)F-FDG PET/CT for Prediction of Response and Clinical Outcome in Patients with Unresectable Hepatocellular Carcinoma Treated with PD-1 Inhibitor and Lenvatinib. J Nucl Med. 2023;64(10):1532-9.
24. Xiao L, Liao Y, Wang J, Li Q, Zhu H, Hong C, et al. Efficacy and safety of ICIs in elderly patients with primary HCC: a retrospective, multicenter, real-world cohort study. Cancer Immunol Immunotherapy. 2023;72(7):2299-308.
25. Xiao LS, Li RN, Cui H, Hong C, Huang CY, Li QM, et al. Use of computed tomography-derived body composition to determine the prognosis of patients with primary HCC treated with ICIs: a retrospective cohort study. BMC cancer. 2022;22(1):737.
26. Xu H, Cao D, Zheng Y, Zhou D, Chen X, Lei J, et al. Potential predictors for survival in hepatocellular carcinoma patients treated with ICIs: A meta-analysis. Int Immunopharmacol. 2021;100:108135.
27. Yibirin M, Mustafayev K, Hosry J, Pundhir P, Klingen J, Yepez Guevara E, et al. ICIs Suppress Hepatitis C Virus Replication in Infected Patients With Solid Tumors. Am j Gastroenterol. 2023;118(9):1609-17.
28. Zhang L, Chen C, Chai D, Li C, Guan Y, Liu L, et al. The association between antibiotic use and outcomes of HCC patients treated with ICIs. Front Immunol. 2022;13:956533.
29. Zhang L, Feng J, Kuang T, Chai D, Qiu Z, Deng W, et al. Blood biomarkers predict outcomes in patients with hepatocellular carcinoma treated with ICIs: A pooled analysis of 44 retrospective sudies. Int Immunopharmacol. 2023;118:110019.
30. Zhu HF, Feng JK, Xiang YJ, Wang K, Zhou LP, Liu ZH, et al. Combination of alpha-fetoprotein and neutrophil-to-lymphocyte ratio to predict treatment response and survival outcomes of patients with unresectable hepatocellular carcinoma treated with ICIs. BMC cancer. 2023;23(1):547.
| Files | ||
| Issue | Articles in Press | |
| Section | Original Article(s) | |
| Keywords | ||
| Hepatocellular carcinoma Immune checkpoint inhibitor Peripheral blood follicular helper T cells Predictive value Short-term prognosis | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Lin Y, Hu Y, Zheng Z, Chi M. Predictive Value of Peripheral Blood Follicular Helper T Cells for Short-term Prognosis in Patients with Hepatocellular Carcinoma Treated with Immune Checkpoint Inhibitors. Iran J Allergy Asthma Immunol. 2025;:1-11.
