AccScience Publishing / ARNM / Online First / DOI: 10.36922/ARNM025390049
Submit to ARNM
Cite this article
7
Download
53
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

CXCR6 expression as a predictive biomarker for immunotherapy responsiveness in nasopharyngeal carcinoma

Zhen-Chong Yang1,2* ,  Ying-He Li1,2 ,  Xi Zou1,2
Show Less
1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
2 Department of Nuclear Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
ARNM, 025390049 https://doi.org/10.36922/ARNM025390049
Received: 23 September 2025 | Revised: 12 November 2025 | Accepted: 18 November 2025 | Published online: 13 January 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
XML
Cite
Abstract

Immunotherapy breakthroughs have revolutionized the treatment of nasopharyngeal carcinoma (NPC). The addition of toripalimab to gemcitabine–cisplatin (GP) chemotherapy as a first-line treatment for patients with NPC resulted in a manageable safety profile and superior progression-free survival compared with GP alone. However, the treatment benefited only a subset of patients. Therefore, we evaluated response patterns in patients with NPC who were treated with programmed cell death protein 1 (PD-1) inhibitors to assess the influence of the tumor immune microenvironment on the efficacy of immunotherapies. Fifty NPC patients treated with PD-1 inhibitors at the Sun Yat-sen University Cancer Center were identified, and 50 and 28 samples were collected before and during treatment, respectively. mRNA expression levels of 289 tumor-immune-related genes were analyzed using the NanoString nCounter. Immune infiltration and correlations between clinical characteristics and the expression of immune-related genes were assessed. Tumors that responded to immunotherapy had significantly lower T helper 1 cell infiltration and higher chemokine signature scores compared with non-responding tumors. Notably, anti-PD-1 immunotherapy-responsive tumors had higher CXCR6 expression levels, suggesting that CXCR6 may be involved in the immune surveillance of NPC and in shaping the tumor microenvironment (TME). In addition, significant differences in the TME were observed between pre-treatment and treatment samples. Overall, CXCR6 expression was identified as a predictive biomarker for response to immunotherapy in NPC.

Keywords
CXCR6
Immunotherapy
Tumor immune microenvironment
Toripalimab
Nasopharyngeal carcinoma
Programmed cell death protein 1 inhibitors
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
References
  1. Zhang Y, Chen L, Hu GQ, et al. Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma. N Engl J Med. 2019;381:1124-1135. doi: 10.1056/nejmoa1905287

 

  1. Luo W. Nasopharyngeal carcinoma ecology theory: Cancer as multidimensional spatiotemporal “unity of ecology and evolution” pathological ecosystem. Theranostics. 2023;13(5):1607-1631. doi: 10.7150/thno.82690

 

  1. Chen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. Lancet. 2019;394:64-80. doi: 10.1016/S0140-6736(19)30956-0

 

  1. Zhang L, Huang Y, Hong S, et al. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: A multicentre, randomised, open-label, phase 3 trial. Lancet. 2016;388:1883-1892. doi: 10.1016/S0140-6736(16)31388-5

 

  1. Hsu C, Lee SH, Ejadi S, et al. Safety and antitumor activity of pembrolizumab in patients with programmed death-ligand 1-positive nasopharyngeal carcinoma: Results of the KEYNOTE-028 study. J Clin Oncol. 2017;35:4050-4056. doi: 10.1200/JCO.2017.73.3675

 

  1. Fang W, Zhang J, Hong S, et al. EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy. Oncotarget. 2014;5:12189-12202. doi: 10.18632/oncotarget.2608

 

  1. Hsu MC, Hsiao JR, Chang KC, et al. Increase of programmed death-1-expressing intratumoral CD8 T cells predicts a poor prognosis for nasopharyngeal carcinoma. Mod Pathol. 2010;23:1393-1403. doi: 10.1038/modpathol.2010.130

 

  1. Xiao M, Qi F, Chen X, et al. Functional polymorphism of cytotoxic T-lymphocyte antigen 4 and nasopharyngeal carcinoma susceptibility in a Chinese population. Int J Immunogenet. 2010;37:27-32. doi: 10.1111/j.1744-313X.2009.00888.x

 

  1. Andrei G, Trompet E, Snoeck R. Novel therapeutics for Epstein-Barr virus. Molecules. 2019;24:997. doi: 10.3390/molecules24050997

 

  1. Yang Y, Qu S, Li J, et al. Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): A multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2021;22: 1162-1174. doi: 10.1016/S1470-2045(21)00302-8

 

  1. Xu R, Mai H, Chen Q, et al. JUPITER-02: Randomized, double-blind, phase III study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment forrecurrent or metastatic nasopharyngeal carcinoma (NPC). J Clin Oncol. 2021;39:LBA2. doi: 10.1200/jco.2021.39.15_suppl.lba2

 

  1. Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (Poplar): A multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387: 1837-1846. doi: 10.1016/S0140-6736(16)00587-0

 

  1. Ayers M, Lunceford J, Nebozhyn M, et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127:2930-2940. doi: 10.1172/jci91190

 

  1. Vitiello GA, Bowler TG, Liu M, et al. Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor. J Clin Invest. 2019;129: 1863-1877. doi: 10.1172/jci124108

 

  1. Danaher p, Warren s, Dennis L, et al. Gene expression markers of tumor infiltrating leukocytes. J Immunother Cancer. 2017;5:18. doi: 10.1186/s40425-017-0215-8

 

  1. Jiang P, Gu S, Pan D, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med. 2018;24:1550-1558. doi: 10.1038/s41591-018-0136-1

 

  1. Groblewska M, Litman-Zawadzka A, Mroczko B. The role of selected chemokines and their receptors in the development of gliomas. Int J Mol Sci. 2020;21:3704. doi: 10.3390/ijms21103704

 

  1. Ikeda T, Nishita M, Hoshi K, Honda T, Kakeji Y, Minami Y. Mesenchymal stem cell-derived CXCL16 promotes progression of gastric cancer cells by STAT3-mediated expression of Ror1. Cancer Sci. 2020;111:1254-1265. doi: 10.1111/cas.14339

 

  1. Mir H, Kaur G, Kapur N, et al. Higher CXCL16 exodomain is associated with aggressive ovarian cancer and promotes the disease by CXCR6 activation and MMP modulation. Sci Rep. 2019;9:1-12. doi: 10.1038/s41598-019-38766-6

 

  1. Hong L, Wang S, Li W, Wu D, Chen W. Tumor-associated macrophages promote the metastasis of ovarian carcinoma cells by enhancing CXCL16/CXCR6 expression. Pathol Res Pract. 2018;214:1345-1351. doi: 10.1016/j.prp.2018.07.009

 

  1. Adamski V, Mentlein R, Lucius R, Synowitz M, Held- Feindt J, Hattermann K. The chemokine receptor CXCR6 evokes reverse signaling via the transmembrane chemokine CXCL16. Int J Mol Sci. 2017;18:1468. doi: 10.3390/ijms18071468

 

  1. Gillard-Bocquet M, Caer C, Cagnard N, Crozet L, et al. Lung tumor microenvironment induces specific gene expression signature in intratumoral NK cells. Front Immunol. 2013;4:19. doi: 10.3389/fimmu.2013.00019

 

  1. Parsonage G, Machado LR, Hui JW, et al. CXCR6 and CCR5 localize T lymphocyte subsets in nasopharyngeal carcinoma. Am J Pathol. 2012;180:1215-1222. doi: 10.1016/j.ajpath.2011.11.032

 

  1. Borst O, Abed M, Alesutan I, et al. Dynamic adhesion of eryptotic erythrocytes to endothelial cells via CXCL16/ SR-PSOX. Am J Physiol Cell Physiol. 2012;302:C644-C651. doi: 10.1152/ajpcell.00340.2011

 

  1. Newman AM, Liu CL, Green MR, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453-457. doi: 10.1038/nmeth.3337

 

  1. Germano G, Frapolli R, Belgiovine C, et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell. 2013;23:249-262. doi: 10.1016/j.ccr.2013.01.008

 

  1. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2009;8:958-969. doi: 10.1038/nri2448

 

  1. Damotte D, Warren S, Arrondeau J, et al. The tumor inflammation signature (TIS) is associated with anti-PD-1 treatment benefit in the CERTIM pan-cancer cohort. J Transl Med. 2019;17:357. doi: 10.1186/s12967-019-2100-3

 

  1. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486-499. doi: 10.1038/nri3862

 

  1. Ritchie ME, Phipson B, Wu D, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47. doi: 10.1093/nar/gkv007

 

  1. Foong RE, Shaw NC, Berry LJ, Hart PH, Gorman S, Zosky GR. Vitamin D deficiency causes airway hyperresponsiveness, increases airway smooth muscle mass, and reduces TGF-β expression in the lungs of female BALB/c mice. Physiol Rep. 2014;2:e00276. doi: 10.1002/phy2.276

 

  1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. doi: 10.1016/j.ejca.2008.10.026

 

  1. Hou P, Kapoor A, Zhang Q, et al. Tumor microenvironment remodeling enables bypass of oncogenic KRAS dependency in pancreatic cancer TME. Cancer Discov. 2020;10: 1058-1077. doi: 10.1158/2159-8290.cd-19-0597

 

  1. Bi G, Chen Z, Yang X, et al. Identification and validation of tumor environment phenotypes in lung adenocarcinoma by integrative genome-scale analysis. Cancer Immunol Immunother. 2020;69:1293-1305. doi: 10.1007/s00262-020-02546-3

 

  1. Law AMK, Lim E, Ormandy CJ, Gallego-Ortega D. The innate and adaptive infiltrating immune systems as targets for breast cancer immunotherapy. Endocr Relat Cancer. 2017;24:R123-R144. doi: 10.1530/erc-16-0404

 

  1. Chen YP, Yin JH, Li WF, et al. Single-cell transcriptomics reveals regulators underlying immune cell diversity and immune subtypes associated with prognosis in nasopharyngeal carcinoma. Cell Res. 2020;30:1024-142. doi: 10.1038/s41422-020-0374-x

 

  1. Cabrita R, Lauss M, Sanna A, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 2020;577:561-565. doi: 10.1038/s41586-019-1914-8

 

  1. Derynck R, Turley SJ, Akhurst RJ. TGFβ biology in cancer progression and immunotherapy. Nat Rev Clin Oncol. 2021;18:9-34. doi: 10.1038/s41571-020-0403-1

 

  1. Su ZY, Siak PY, Leong CO, Cheah SC. Nasopharyngeal carcinoma and its microenvironment: Past, current, and future perspectives. Front Oncol. 2022;12:840467. doi: 10.3389/fonc.2022.840467

 

  1. Hamilton PT, Anholt BR, Nelson BH. Tumour immunotherapy: Lessons from predator-prey theory. Nat Rev Immunol. 2022;22(12):765-775. doi: 10.1038/s41577-022-00719-y

 

  1. Xu JY, Wei XL, Wang YQ, et al. Current status and advances of immunotherapy in nasopharyngeal carcinoma. Ther Adv Med Oncol. 2022;14. doi: 10.1177/17588359221096214

 

  1. Cui YY. Book review: Rethinking cancer: A new paradigm for the postgenomics era. Rethinking our path in the fight against cancer. Curr Cancer Rep. 2025;7:286-289. doi: 10.25082/ccr.2025.01.004
Next article in this issue
Share
Back to top
Advances in Radiotherapy & Nuclear Medicine, Electronic ISSN: 2972-4392 Print ISSN: 3060-8554, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept