Abstract
Purpose
Immune checkpoint inhibitors (ICIs) have improved the prognosis of cancer patients significantly with few predictive makers for treatment efficiency. Since interferon-gamma (IFN-γ) displayed its association with immunotherapy, we explored the correlation between IFN-γ and the efficacy of ICIs in tumor treatment.
Methods
We retrospectively examined cancer patients who received immune checkpoint inhibitors as first-line therapy at the Fourth Hospital of Hebei Medical University. The patients were divided into a low concentration group of IFN-γ (≤ 1.2 pg/mL) and a high concentration group (≥ 1.3 pg/mL) to evaluate the efficacy, which was indicated by the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS).
Results
Thirty-five patients with low IFN-γ and 56 patients with high IFN-γ were involved in the evaluation, and the DCR was significantly different between these two groups (p = 0.009) with a high group of 81.4% (95% CI 69–94%) and a low group of 51.9% (95% CI 32–72%). The subsequent Kaplan–Meier survival analysis showed that the high IFN-γ patients displayed longer median OS than that of the low IFN-γ patients (p = 0.049), while no statistical difference existed for PFS (p = 0.971). The multivariate analysis also confirmed that the high IFN-γ level was independently associated with a better prognosis (HR: 0.318 95% CI 0.113–0.894, p = 0.030).
Conclusions
Basal serum IFN-γ levels were associated with the DCR and OS of cancer patients with higher IFN-γ exhibiting beneficial efficiency for ICIs treatment.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
References
Borghaei H, Paz-Ares L, Horn L, Spigel D, Steins M, Ready N, Chow L, Vokes E, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio M, Fayette J, Lena H, Poddubskaya E, Gerber D, Gettinger S, Rudin C, Rizvi N, Crinò L, Blumenschein G, Antonia S, Dorange C, Harbison C, Graf FF, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627–1639. https://doi.org/10.1056/NEJMoa1507643
Brahmer J, Lacchetti C, Schneider B, Atkins M, Brassil K, Caterino J, Chau I, Ernstoff M, Gardner J, Ginex P, Hallmeyer S, Holter CJ, Leighl N, Mammen J, McDermott D, Naing A, Nastoupil L, Phillips T, Porter L, Puzanov I, Reichner C, Santomasso B, Seigel C, Spira A, Suarez-Almazor M, Wang Y, Weber J, Wolchok J, Thompson J (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline. J Clin Oncol 36:1714–1768. https://doi.org/10.1200/jco.2017.77.6385
Briesemeister D, Sommermeyer D, Loddenkemper C, Loew R, Uckert W, Blankenstein T, Kammertoens T (2011) Tumor rejection by local interferon gamma induction in established tumors is associated with blood vessel destruction and necrosis. Int J Cancer 128(371):378. https://doi.org/10.1002/ijc.25350
Bromberg J, Horvath C, Wen Z, Schreiber R, Darnell JE (1996) Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma. Proc Nat Acad Sci USA 93:7673–7678. https://doi.org/10.1073/pnas.93.15.7673
Chin Y, Kitagawa M, Su W, You Z, Iwamoto Y, Fu XJS (1996) Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Science 272:719–722. https://doi.org/10.1126/science.272.5262.719
Dai S, Jia R, Zhang X, Fang Q, Huang L (2014) The PD-1/PD-Ls pathway and autoimmune diseases. Cell Immunol 290:72–79. https://doi.org/10.1016/j.cellimm.2014.05.006
Dangaj D, Bruand M, Grimm AJ, Ronet C, Barras D, Duttagupta PA, Lanitis E, Duraiswamy J, Tanyi JL, Benencia F, Conejo-Garcia J, Ramay HR, Montone KT, Powell DJ, Gimotty PA, Facciabene A, Jackson DG, Weber JS, Rodig SJ, Hodi SF, Kandalaft LE, Irving M, Zhang L, Foukas P, Rusakiewicz S, Delorenzi M, Coukos G (2019) Cooperation between constitutive and inducible chemokines enables T cell engraftment and immune attack in solid tumors. Cancer Cell 35:885-900.e10. https://doi.org/10.1016/j.ccell.2019.05.004
Dubin K, Callahan M, Ren B, Khanin R, Viale A, Ling L, No D, Gobourne A, Littmann E, Huttenhower C, Pamer E, Wolchok JD (2016) Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun 7:10391. https://doi.org/10.1038/ncomms10391
Duncan T, Rolland P, Deen S, Scott I, Liu D, Spendlove I, Durrant LG (2007) Loss of IFN gamma receptor is an independent prognostic factor in ovarian cancer. Clin Cancer Res 13:4139–4145. https://doi.org/10.1158/1078-0432.Ccr-06-2833
Fay A, Signoretti S, Callea M, Telό G, McKay R, Song J, Carvo I, Lampron M, Kaymakcalan M, Poli-de-Figueiredo C, Bellmunt J, Hodi F, Freeman G, Elfiky A, Choueiri TK (2015) Programmed death ligand-1 expression in adrenocortical carcinoma: an exploratory biomarker study. J Immunother Cancer 3:3. https://doi.org/10.1186/s40425-015-0047-3
Ferris R, Blumenschein G, Fayette J, Guigay J, Colevas A, Licitra L, Harrington K, Kasper S, Vokes E, Even C, Worden F, Saba N, Iglesias DL, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese W, Kopit J, Shaw J, Gillison ML (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375:1856–1867. https://doi.org/10.1056/NEJMoa1602252
Harvat B, Seth P, Jetten AM (1997) The role of p27Kip1 in gamma interferon-mediated growth arrest of mammary epithelial cells and related defects in mammary carcinoma cells. Oncogene 14:2111–2122. https://doi.org/10.1038/sj.onc.1201055
Hodi F, Chesney J, Pavlick A, Robert C, Grossmann K, McDermott D, Linette G, Meyer N, Giguere J, Agarwala S, Shaheen M, Ernstoff M, Minor D, Salama A, Taylor M, Ott P, Horak C, Gagnier P, Jiang J, Wolchok J, Postow MA (2016) Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 17:1558–1568. https://doi.org/10.1016/s1470-2045(16)30366-7
Horn L, Spigel D, Vokes E, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp K, Burgio M, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann M, Geese W, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt W (2017) Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase iii trials (checkmate 017 and checkmate 057). J Clin Oncol 35:3924–3933. https://doi.org/10.1200/jco.2017.74.3062
Hu JR, Florido R, Lipson EJ, Naidoo J, Ardehali R, Tocchetti CG, Lyon AR, Padera RF, Johnson DB, Moslehi J (2019) Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res 115:854–868. https://doi.org/10.1093/cvr/cvz026
Ivashkiv LB (2018) IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol 18:545–558. https://doi.org/10.1038/s41577-018-0029-z
Jacobs J, Idema A, Bol K, Nierkens S, Grauer O, Wesseling P, Grotenhuis J, Hoogerbrugge P, de Vries I, Adema GJ (2009) Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors. Neuro-Oncol 11:394–402. https://doi.org/10.1215/15228517-2008-104
Jorgovanovic D, Song M, Wang L, Zhang Y (2020) Roles of IFN-gamma in tumor progression and regression: a review. Biomark Res 8:49. https://doi.org/10.1186/s40364-020-00228-x
Kamali-Sarvestani E, Merat A, Talei A (2005) Polymorphism in the genes of alpha and beta tumor necrosis factors (TNF-alpha and TNF-beta) and gamma interferon (IFN-gamma) among Iranian women with breast cancer. Cancer Lett 223:113–119. https://doi.org/10.1016/j.canlet.2004.09.025
Katsuya Y, Fujita Y, Horinouchi H, Ohe Y, Watanabe S, Tsuta K (2015) Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma. Lung Cancer 88:154–159. https://doi.org/10.1016/j.lungcan.2015.03.003
Kursunel M, Esendagli G (2016) The untold story of IFN-γ in cancer biology. Cytokine Growth Factor Rev 31:73–81. https://doi.org/10.1016/j.cytogfr.2016.07.005
Lu Y, Yang W, Qin C, Zhang L, Deng J, Liu S, Qin Z (2009) Responsiveness of stromal fibroblasts to IFN-gamma blocks tumor growth via angiostasis. J Immunol 183:6413–6421. https://doi.org/10.4049/jimmunol.0901073
Luo X, Xiong X, Shao Q, Xiang T, Li L, Yin X, Li X, Tao Q, Ren G (2017) The tumor suppressor interferon regulatory factor 8 inhibits β-catenin signaling in breast cancers, but is frequently silenced by promoter methylation. Oncotarget 8:48875–48888. https://doi.org/10.18632/oncotarget.16511
McLaren J, Ramji D (2009) Interferon gamma: a master regulator of atherosclerosis. Cytokine Growth Factor Rev 20:125–135. https://doi.org/10.1016/j.cytogfr.2008.11.003
Meng X, Liu Y, Zhang J, Teng F, Xing L, Yu J (2017) PD-1/PD-L1 checkpoint blockades in non-small cell lung cancer: new development and challenges. Cancer Lett 405:29–37. https://doi.org/10.1016/j.canlet.2017.06.033
Mojic M, Takeda K, Hayakawa Y (2017) The dark side of IFN-gamma: its role in promoting cancer immunoevasion. Int J Mol Sci. https://doi.org/10.3390/ijms19010089
Motzer R, Escudier B, McDermott D, George S, Hammers H, Srinivas S, Tykodi S, Sosman J, Procopio G, Plimack E, Castellano D, Choueiri T, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler T, Ueda T, Tomita Y, Schutz F, Kollmannsberger C, Larkin J, Ravaud A, Simon J, Xu L, Waxman I, Sharma P (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803–1813. https://doi.org/10.1056/NEJMoa1510665
Ortiz BA, Sibaud V, Herbault-Barrés B, Betrian S, Korakis I, De Bataille C, Gomez-Roca C, Epstein J, Vigarios E (2020) Sicca syndrome induced by immune checkpoint inhibitor therapy: optimal management still pending. Oncologist 25:e391–e395. https://doi.org/10.1634/theoncologist.2019-0467
Ossina N, Cannas A, Powers V, Fitzpatrick P, Knight J, Gilbert J, Shekhtman E, Tomei L, Umansky S, Kiefer MC (1997) Interferon-gamma modulates a p53-independent apoptotic pathway and apoptosis-related gene expression. J Biol Chem 272:16351–16357. https://doi.org/10.1074/jbc.272.26.16351
Ricci AD, Rizzo A, Rojas Llimpe FL, Di Fabio F, De Biase D, Rihawi K (2021) Novel HER2-directed treatments in advanced gastric carcinoma: AnotHER paradigm shift? Cancers (basel) 13(7):1664. https://doi.org/10.3390/cancers13071664
Rizzo A, Ricci AD (2022) PD-L1, TMB, and other potential predictors of response to immunotherapy for hepatocellular carcinoma: how can they assist drug clinical trials? Expert Opin Investig Drugs 31:415–423. https://doi.org/10.1080/13543784.2021.1972969
Rizzo A, Mollica V, Santoni M, Ricci AD, Rosellini M, Marchetti A, Montironi R, Ardizzoni A, Massari F (2022) Impact of clinicopathological features on survival in patients treated with first-line immune checkpoint inhibitors plus tyrosine kinase inhibitors for renal cell carcinoma: a meta-analysis of randomized clinical trials. Eur Urol Focus 8:514–521. https://doi.org/10.1016/j.euf.2021.03.001
Tanaka R, Okiyama N, Okune M, Ishitsuka Y, Watanabe R, Furuta J, Ohtsuka M, Otsuka A, Maruyama H, Fujisawa Y, Fujimoto M (2017) Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tumor necrosis factor-α is a biomarker of nivolumab recativity. J Dermatol Sci 86:71–73. https://doi.org/10.1016/j.jdermsci.2016.12.019
Taube J, Klein A, Brahmer J, Xu H, Pan X, Kim J, Chen L, Pardoll D, Topalian S, Anders RA (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20:5064–5074. https://doi.org/10.1158/1078-0432.Ccr-13-3271
Topalian S, Hodi F, Brahmer J, Gettinger S, Smith D, McDermott D, Powderly J, Carvajal R, Sosman J, Atkins M, Leming P, Spigel D, Antonia S, Horn L, Drake C, Pardoll D, Chen L, Sharfman W, Anders R, Taube J, McMiller T, Xu H, Korman A, Jure-Kunkel M, Agrawal S, McDonald D, Kollia G, Gupta A, Wigginton J, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. https://doi.org/10.1056/NEJMoa1200690
Twyman-Saint VC, Rech A, Maity A, Rengan R, Pauken K, Stelekati E, Benci J, Xu B, Dada H, Odorizzi P, Herati R, Mansfield K, Patsch D, Amaravadi R, Schuchter L, Ishwaran H, Mick R, Pryma D, Xu X, Feldman M, Gangadhar T, Hahn S, Wherry E, Vonderheide R, Minn AJN (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520:373–377. https://doi.org/10.1038/nature14292
Xu X, Fu X, Plate J, Chong A (1998) IFN-gamma induces cell growth inhibition by Fas-mediated apoptosis: requirement of STAT1 protein for up-regulation of Fas and FasL expression. Cancer Res 58:2832–2837
Xu S, Lai R, Zhao Q, Zhao P, Zhao R, Guo Z (2021) Correlation between immune-related adverse events and prognosis in hepatocellular carcinoma patients treated with immune checkpoint inhibitors. Front Immunol 12:794099. https://doi.org/10.3389/fimmu.2021.794099
Zhang X, Zeng Y, Qu Q, Zhu J, Liu Z, Ning W, Zeng H, Zhang N, Du W, Chen C, Huang J (2017) PD-L1 induced by IFN-γ from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer. Int J Clin Oncol 22:1026–1033. https://doi.org/10.1007/s10147-017-1161-7
Acknowledgements
We thank Iren Guo (Emma Willard School, New York) for editing the English of our manuscripts.
Funding
This work was supported by the Foundation of Hebei Provincial Department of Science and Technology & Hebei Medical University (Grant No. 2020TXZH03).
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JL contributed to study concepts, study design, data acquisition, quality control of data and algorithms, data analysis and interpretation, manuscript preparation, manuscript editing, and manuscript review. JM and NX contributed to study concepts, study design, manuscript editing, and manuscript review. ZJ, JL, and SZ contributed to data analysis and interpretation, and statistical analysis. ZG contributed to study concepts, study design, data acquisition, quality control of data and algorithms, data analysis and interpretation, manuscript editing, and manuscript review.
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Liu, J., Ma, J., Xing, N. et al. Interferon-γ predicts the treatment efficiency of immune checkpoint inhibitors in cancer patients. J Cancer Res Clin Oncol 149, 3043–3050 (2023). https://doi.org/10.1007/s00432-022-04201-z
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DOI: https://doi.org/10.1007/s00432-022-04201-z