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Review
. 2024 Mar 28;16(7):1312.
doi: 10.3390/cancers16071312.

The Role of Natural Killer Cells in the Tumor Immune Microenvironment of EBV-Associated Nasopharyngeal Carcinoma

Shuzhan Li  1   2   3 , Wei Dai  4 , Ngar-Woon Kam  4   5 , Jiali Zhang  1   2   3 , Victor H F Lee  4   6 , Xiubao Ren  1   2   3 , Dora Lai-Wan Kwong  4   6
Affiliations
Review

The Role of Natural Killer Cells in the Tumor Immune Microenvironment of EBV-Associated Nasopharyngeal Carcinoma

Shuzhan Li et al. Cancers (Basel). .

Abstract

Endemic nasopharyngeal carcinoma (NPC) is closely associated with the Epstein-Barr virus (EBV), which contributes to tumor development and influences the tumor immune microenvironment (TIME) in NPC. Natural killer (NK) cells, as part of the innate immune system, play a crucial role in responding to viral infections and malignant cell transformations. Notably, NK cells possess a unique ability to target tumor cells independent of major histocompatibility complex class I (MHC I) expression. This means that MHC I-deficient tumor cells, which can escape from effective T cell attack, are susceptible to NK-cell-mediated killing. The activation of NK cells is determined by the signals generated through inhibitory and activating receptors expressed on their surface. Understanding the role of NK cells in the complex TIME of EBV+ NPC is of utmost importance. In this review, we provide a comprehensive summary of the current understanding of NK cells in NPC, focusing on their subpopulations, interactions, and cytotoxicity within the TIME. Moreover, we discuss the potential translational therapeutic applications of NK cells in NPC. This review aims to enhance our knowledge of the role of NK cells in NPC and provide valuable insights for future investigations.

Keywords: Epstein–Barr virus; anti-cancer therapy; nasopharyngeal carcinoma; natural killer cells; tumor immune microenvironment.

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Conflict of interest statement

The author declares no conflicts of interest.

Figures

Figure 1
Figure 1
Tumor immune microenvironment of EBV+ NPC. EBV-associated LMP1/2 and EBERs activate NF-κB, PI3K/AKT, and Wnt/β-catenin pathways to induce the proliferation and immune evasion of NPC cells. TGF-β released by EBV+ NPC recruits immune-suppressive Tregs and LAMP3+ DCs. LAMP3+ DCs release IDO to promote Treg proliferation. TGF-β induces the M2 polarization of TAMs. MDSC promotes M2 proliferation. The effective T cell is inhibited by Treg and MDSC. T cell cytotoxicity is negatively regulated by the binding immune checkpoint receptors and their ligands. The NPC cell escapes the CD8+ T cell’s killing effect by diminishing MHC I expression. IL-2 activates the CD8+ T cell and NK cell, which are the major immune effectors. The B cell is a component within the TIME of EBV+ NPC. How NK cells interact with cytokines and other components and whether immune checkpoint molecules impact NK cell function need further discussion. Abbreviations: TIME, tumor immune microenvironment; EBV, Epstein–Barr virus; NPC, nasopharyngeal carcinoma; LMP1/2, latent membrane protein 1/2; EBERs, EBV-encoded small RNAs; TGF-β, transforming growth factor-β; Treg, regulatory T cell; LAMP3, lysosome-associated membrane glycoprotein 3; DC, dendritic cell; IDO, indoleamine-pyrrole 2,3-dioxygenase; TAM, tumor-associated macrophage; M2, M2-polarized TAM; MDSC, myeloid-derived suppressor cell; MHC I, major histocompatibility complex class I; IL-2, interleukin-2; NK, natural killer; NKG2, members of C-type lectin-like receptor superfamily, receptors of NK cells; MICA/B, major histocompatibility complex class-I-related chain A/B; IFN-γ, interferon-γ; Gal-9, galectin-9; TIM-3, T cell immunoglobulin domain and mucin domain-3; PD-1, programmed death-1; PD-L1, programmed death ligand-1; CTLA-4, cytotoxic T-lymphocyte antigen 4.
Figure 2
Figure 2
Profile of NK cells within the TIME of EBV+ NPC. (A) EBV+ NPC impairs NK cell activation; (B) EBV+ NPC promotes NK cell inhibition; (C) exhausted markers on NK cell; (D) cytotoxic function of NK cell is suboptimal. Abbreviations: EBV, Epstein–Barr virus; NPC, nasopharyngeal carcinoma; NK, natural killer; LMP2, latent membrane protein 2; miR, microRNA, a small non-coding RNA molecule; MACC1, metastasis-associated colon cancer 1; B7-H6, B7 homolog 6; HLA, human leukocyte antigen; ULBP, UL16 binding protein; MICA/B, major histocompatibility complex class-I-related chain A/B; CD94, killer cell lectin-like receptor subfamily D, member 1 (KLRD1), pairs with the NKG2 molecule as a heterodimer; NKp30, natural cytotoxicity triggering receptor 3; NKG2, members of C-type lectin-like receptor superfamily, receptors of NK cells; TFs, transcription factors; KIR, killer immunoglobulin-like receptor; MHC, major histocompatibility complex; TRAIL, TNF-related apoptosis-inducing ligand; TRAILR, receptor of TRAIL; FASL, Fas ligand; FAS, Fas receptor, apoptosis antigen 1; CD16, Fc receptors FcγRIII; ADCC, antibody-dependent cell-mediated cytotoxicity; PD-1, programmed death-1; PD-L1, programmed death ligand-1; TIGIT, T cell immunoreceptor with Ig and ITIM domains; PVR, polio virus receptor; CD96, T cell activation, increased late expression (TACTILE); LAG3, lymphocyte-activation gene 3; GAL3, galectin 3; B7-H3, B7 homolog 3, CD276; B7-H3R, receptor of B7-H3, not identified yet.
Figure 3
Figure 3
Interaction between NK cells and cytokines, chemokines, and other immune cells. NK-cell-derived CCL5 and XCL1/2 play a vital role in recruiting DCs; IFN-γ released by NK cells induces the apoptosis of NPC cells. IL-12, IL-15, and IL-18 cocktail cytokines convert NK cells into “memory-like” NK cells. IL-2 and IL-21 promote strong NK cell expansion and cytotoxicity. “×” The cytotoxicity of CD8+ T cells is inhibited through MHC I downregulation in EBV+ NPC. “√” The NK cell is activated via “missing self” recognition of downregulated MHC I expression on EBV+ NPC. Effective T cells release pro-inflammatory cytokine IFN-β to enhance NK cell cytotoxicity. Abbreviations: NPC, nasopharyngeal carcinoma; TGF-β, transforming growth factor-β; MDSC, myeloid-derived suppressor cell; Treg, regulatory T cell; NK, natural killer; IFN, interferon; TCR, T-cell receptor; MHC I, major histocompatibility complex class I; NKG2, members of C-type lectin-like receptor superfamily, receptors of NK cells; KIR, killer immunoglobulin-like receptor; CCL5, chemokine (C–C motif) ligand 5; XCL1/2, chemokine C motif ligand 1/2; DC, dendritic cell; TAM, tumor-associated macrophage.
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