Immunological Landscape and Chemokine Networks in Nasopharyngeal Carcinoma: Mechanisms of Treg-Mediated Suppression and Therapeutic Implications

Abstract

Background: Nasopharyngeal carcinoma (NPC) is distinct among head and neck malignancies due to its strong association with Epstein-Barr virus (EBV) infection and a unique tumor microenvironment (TME) characterized by heavy lymphocytic infiltration. Despite advances in intensity-modulated radiotherapy, recurrence remains a significant challenge, largely attributed to immune evasion mechanisms.

Methods: We conducted a comprehensive review and synthesis of recent genomic, proteomic, and single-cell transcriptomic studies regarding NPC. This analysis focuses on the interplay between tumor cells, the viral component (EBNA1), and the immune infiltrate, specifically Regulatory T cells (Tregs) and chemokine signaling networks.

Results: Analysis reveals that the NPC microenvironment is highly immunosuppressive despite being "immune hot." EBV nuclear antigen 1 (EBNA1) actively recruits Tregs, while tumor cells upregulate CD70 to enhance Treg suppressive capacity via the CD70-CD27 axis. Furthermore, the chemokine landscape is dysregulated; elevated KIF18B expression correlates with immune evasion, and the LIF-CXCL9 axis in tumor-associated macrophages impairs CD8+ T cell infiltration. Conversely, NK cells play a crucial role in recruiting type 1 conventional dendritic cells (cDC1) to prime anti-tumor immunity.

Conclusion: The efficacy of immunotherapy in NPC is contingent upon overcoming specific chemokine barriers and Treg-mediated suppression. Targeting the CD70-CD27 interaction and restoring CXCL9 expression represent promising strategies to sensitize recurrent NPC to checkpoint blockade.

Keywords:

Nasopharyngeal carcinoma, Tumor microenvironment, Regulatory T cells, Chemokines

References

Chen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. Lancet Lond Engl. 2019 Jul 6;394(10192):64–80.

Chang ET, Ye W, Zeng YX, Adami HO. The Evolving Epidemiology of Nasopharyngeal Carcinoma. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2021 Jun;30(6):1035–47.

Guo R, Mao YP, Tang LL, Chen L, Sun Y, Ma J. The evolution of nasopharyngeal carcinoma staging. Br J Radiol. 2019 Oct;92(1102):20190244.

Peng Z, Wang Y, Fan R, Gao K, Xie S, Wang F, et al. Treatment of Recurrent Nasopharyngeal Carcinoma: A Sequential Challenge. Cancers. 2022 Aug 25;14(17):4111.

Su ZY, Siak PY, Leong CO, Cheah SC. Nasopharyngeal Carcinoma and Its Microenvironment: Past, Current, and Future Perspectives. Front Oncol. 2022;12:840467.

Tang S, Wu Z, Chen L, She L, Zuo W, Luo W, et al. Multi-omics analysis reveals the association between elevated KIF18B expression and unfavorable prognosis, immune evasion, and regulatory T cell activation in nasopharyngeal carcinoma. Front Immunol. 2023;14:1258344.

Gong L, Luo J, Zhang Y, Yang Y, Li S, Fang X, et al. Nasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70-CD27 interaction. Nat Commun. 2023 Apr 6;14(1):1912.

Wang J, Luo Y, Bi P, Lu J, Wang F, Liu X, et al. Mechanisms of Epstein-Barr virus nuclear antigen 1 favor Tregs accumulation in nasopharyngeal carcinoma. Cancer Med. 2020 Aug;9(15):5598–608.

Yang Y, Chen X, Pan J, Ning H, Zhang Y, Bo Y, et al. Pan-cancer single-cell dissection reveals phenotypically distinct B cell subtypes. Cell. 2024 Aug 22;187(17):4790-4811.e22.

Liu Y, He S, Wang XL, Peng W, Chen QY, Chi DM, et al. Tumour heterogeneity and intercellular networks of nasopharyngeal carcinoma at single cell resolution. Nat Commun. 2021 Feb 2;12(1):741.

Jin S, Li R, Chen MY, Yu C, Tang LQ, Liu YM, et al. Single-cell transcriptomic analysis defines the interplay between tumor cells, viral infection, and the microenvironment in nasopharyngeal carcinoma. Cell Res. 2020 Nov;30(11):950–65.

van der Vorst EPC, Döring Y, Weber C. Chemokines. Arterioscler Thromb Vasc Biol. 2015 Nov;35(11):e52-56.

Mughees M, Kaushal JB, Sharma G, Wajid S, Batra SK, Siddiqui JA. Chemokines and cytokines: Axis and allies in prostate cancer pathogenesis. Semin Cancer Biol. 2022 Nov;86(Pt 3):497–512.

Goenka A, Khan F, Verma B, Sinha P, Dmello CC, Jogalekar MP, et al. Tumor microenvironment signaling and therapeutics in cancer progression. Cancer Commun Lond Engl. 2023 May;43(5):525–61.

Korbecki J, Grochans S, Gutowska I, Barczak K, Baranowska-Bosiacka I. CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands. Int J Mol Sci. 2020 Oct 15;21(20):7619.

Pascual-García M, Bonfill-Teixidor E, Planas-Rigol E, Rubio-Perez C, Iurlaro R, Arias A, et al. LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy. Nat Commun. 2019 Jun 11;10(1):2416.

Böttcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M, Sammicheli S, et al. NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control. Cell. 2018 Feb 22;172(5):1022-1037.e14.