TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models

doi:10.1038/s41467-023-36523-y

. 2023 Feb 16;14(1):865.

doi: 10.1038/s41467-023-36523-y.

TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models

Jun-Yan Li^#¹, Yin Zhao^#¹, Sha Gong^#¹, Miao-Miao Wang^#¹, Xu Liu^#¹, Qing-Mei He¹, Ying-Qin Li¹, Sheng-Yan Huang¹, Han Qiao¹, Xi-Rong Tan¹, Ming-Liang Ye¹, Xun-Hua Zhu¹, Shi-Wei He¹, Qian Li¹, Ye-Lin Liang¹, Kai-Lin Chen¹, Sai-Wei Huang¹, Qing-Jie Li¹, Jun Ma^{2

3}, Na Liu⁴

Affiliations

¹ State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P.R. China.
² State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P.R. China. majun2@mail.sysu.edu.cn.
³ Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. majun2@mail.sysu.edu.cn.
⁴ State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P.R. China. liun1@sysucc.org.cn.

^# Contributed equally.

PMID: 36797289
PMCID: PMC9935546
DOI: 10.1038/s41467-023-36523-y

TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models

Jun-Yan Li et al. Nat Commun. 2023.

. 2023 Feb 16;14(1):865.

doi: 10.1038/s41467-023-36523-y.

Authors

Affiliations

¹ State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P.R. China.
² State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P.R. China. majun2@mail.sysu.edu.cn.
³ Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. majun2@mail.sysu.edu.cn.
⁴ State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P.R. China. liun1@sysucc.org.cn.

^# Contributed equally.

PMID: 36797289
PMCID: PMC9935546
DOI: 10.1038/s41467-023-36523-y

Abstract

Although radiotherapy can promote antitumour immunity, the mechanisms underlying this phenomenon remain unclear. Here, we demonstrate that the expression of the E3 ubiquitin ligase, tumour cell-intrinsic tripartite motif-containing 21 (TRIM21) in tumours, is inversely associated with the response to radiation and CD8⁺ T cell-mediated antitumour immunity in nasopharyngeal carcinoma (NPC). Knockout of TRIM21 modulates the cGAS/STING cytosolic DNA sensing pathway, potentiates the antigen-presenting capacity of NPC cells, and activates cytotoxic T cell-mediated antitumour immunity in response to radiation. Mechanistically, TRIM21 promotes the degradation of the mitochondrial voltage-dependent anion-selective channel protein 2 (VDAC2) via K48-linked ubiquitination, which inhibits pore formation by VDAC2 oligomers for mitochondrial DNA (mtDNA) release, thereby inhibiting type-I interferon responses following radiation exposure. In patients with NPC, high TRIM21 expression was associated with poor prognosis and early tumour relapse after radiotherapy. Our findings reveal a critical role of TRIM21 in radiation-induced antitumour immunity, providing potential targets for improving the efficacy of radiotherapy in patients with NPC.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. TRIM21 expression in tumour cells impairs radiation-induced T-cell-mediated antitumour immunity.**
a Heatmap showing the clustering of NPC tumours with high or low CD8⁺ T-cell-mediated antitumour immunity scores. b Volcano plot showing that three E3 ligases, *RNF122*, *FBXO47* and *TRIM21*, were upregulated in NPC tumours with low CD8⁺ T-cell-mediated antitumour immunity scores. c CIBERSORTx analysis of CD8⁺ T cells and activated DCs that infiltrated into tumours with high or low *TRIM21* expression (two-tailed unpaired t test). d GSEA suggesting impaired type-I IFN responses in tumours with high *TRIM21* expression. e GO analysis of the scRNA-seq showing a negative association between *TRIM21* expression and the ‘activation of innate immune response’ and ‘antigen processing and presentation’ terms in NPC cells. f GSEA showed a poor radiation response in *TRIM21*-high tumours and cells (two-tailed unpaired t test). g–i WT and TRIM21-KO NPC cells were treated with or without IR. After 48 h, IFN-β1 concentration in the culture supernatant (g, ELISA), pSTAT1 levels (h, western blot analysis), and *CCL5* and *CXCL10* expression levels (i, qPCR) were measured (one-way ANOVA with the Tukey’s multiple comparisons test). j–n In total, 5 × 10⁵ WT or TRIM21^−/− MC38 cells were inoculated into C57BL/6 mice. Mice in the IR-treated groups were subjected to focal radiation with a single fraction of 15 Gy on day 10 after tumour cell inoculation (j). The tumour growth rate (k, two-way ANOVA), tumour eradication rate (l, log-rank test), weight of excised residual tumours (m, n = 7 in each control group, n = 15 in each IR group, Kruskal–Wallis test with Dunn’s multiple comparisons test), and proportions of tumour-infiltrating CD8⁺ T cells and CD11c⁺ DCs (n, n = 7 in each control group, n = 6 in each IR group, one-way ANOVA with Tukey’s test for multiple comparisons) are reported. o, Tumour growth of the unirradiated abscopal tumours (WT-MC38, left flank) and the irradiated (15 Gy) primary tumours (WT-MC38 or TRIM21^−/− MC38, right flank) in C57/BL6 mice (n = 9 in each group, two-way ANOVA). The data are shown as the mean ± SEM and are representative of three independent experiments (g–i).

**Fig. 2. TRIM21 deficiency promotes cytosolic mtDNA release to activate STING signalling.**
a–c WT and TRIM21-KO NPC cells were treated with or without IR. a After 48 h, the levels of total and phosphorylated STING, TBK1 and IRF3 were measured by western blot analysis. b Cytosolic DNA accumulation was assessed by IF staining with a dsDNA-specific antibody 24 h after IR. Representative images (scale bar, 10 μm) and quantitative results are shown (n = 30 cells per group). c The abundance of *MTATP8* DNA sequence in the cytosolic fraction was measured by qPCR 24 h after IR. d Representative images showing cytosolic mtDNA accumulation in irradiated WT and TRIM21-KO NPC cells 24 h after IR treatment (scale bar, 10 μm). TFAM (mitochondrial transcription factor A, green) not associated with mitochondria (MitoTracker Red CMXRos) was considered as cytosolic mtDNA (as indicated by the white arrows). Quantitative results from 30 cells per group are reported. e The amounts of gDNA (*GAPDH*) and mtDNA *(MTATP8*) in control and rho⁰ NPC cells were estimated by qPCR. Rho⁰/control ratios are reported. f *MTATP8* abundance in the cytosolic fraction of control and rho⁰ NPC cells 24 h after IR treatment. g, h Control and rho⁰ NPC cells were treated with IR. After 48 h, the levels of phosphorylated STING, TBK1, IRF3, and STAT1 (g) and the relative expression levels of *IFNB1*, *CCL5* and *CXCL10* were measured. The results are representative of three independent experiments (a–h). The data are presented as the mean ± SEM; one-way ANOVA with Tukey’s test for multiple comparisons (b–d, f, and h).

**Fig. 3. TRIM21 promotes the degradation of VDAC2 by increasing its K48-linked ubiquitination.**
a Silver staining of SDS–PAGE gels showed that the FLAG immunoprecipitates were pulled down from HONE1 cells overexpressing FLAG-TRIM21. The proteins of interest are indicated. b Left: Co-IP with an anti-FLAG (top) or an anti-HA (bottom) antibody revealed the interaction of exogenous TRIM21 and VDAC2 in HEK293T cells. Right: Co-IP with an anti-TRIM21 antibody in NPC cells revealed the interaction of endogenous TRIM21 and VDAC2. c FRET assay in HEK293T cells transfected with TRIM21-CFP and VDAC2-YFP. Representative cells with TRIM21-CFP and VDAC-YFP, and region of FRET analysis was indicated. The exponential decrease in VDAC2-YFP (acceptor) fluorescence and the concomitant increase in TRIM21-CFP (donor) fluorescence during YFP-photobleaching were analysed in 20 cells. The FRET efficacy (E_FRET) was reported. Scale bar, 5 μm. d VDAC2 protein level in HONE1 cells transfected with gradient concentrations of FLAG-tagged *TRIM21*. e Immunoblots (left) and corresponding greyscale analysis (right) of VDAC2 in WT and *TRIM21*-KO HONE1 cells treated with CHX for the indicated times. f *VDAC2* mRNA expression in TRIM21-KO NPC cells. g VDAC2 protein level in WT and TRIM21-KO HONE1 cells after 6 h of treatment with MG132 (top) or CQ (bottom). h Ubiquitination level of exogenous MYC-VDAC2 in WT and TRIM21-KO HONE1 cells. i VDAC2 protein level in TRIM21-KO NPC cells transfected with vector, FLAG-tagged WT *TRIM21* or three FLAG-tagged *TRIM21* mutants. j The ubiquitination of MYC-tagged VDAC2 in *TRIM21*-KO HONE1 cells transfected with vector, FLAG-tagged WT *TRIM21* or three FLAG-tagged *TRIM21* mutants. k MS analysis of VDAC2 ubiquitination sites. l Protein levels of FLAG-tagged WT and K135R VDAC2 in NPC cells transfected with gradient concentrations of MYC-tagged *TRIM21*. m Ubiquitination of FLAG-tagged WT and K135R VDAC2 by MYC-tagged TRIM21. The results are representative of three independent experiments (a–j, l, m). The data are presented as the mean ± SEM (c, e). Comparisons were performed using two-way ANOVA (e) and one-way ANOVA with Tukey’s test for multiple comparisons (f).

**Fig. 4. TRIM21 depletion facilitates VDAC2 oligomerization-mediated mtDNA release.**
a–d The indicated NPC cells were treated with IR. The relative *MTATP8* abundance in the cytosolic fractions was assessed by qPCR (a). Cytosolic mtDNA accumulation was evaluated by quantification of cytoplasmic TFAM (indicated by the white arrows) 24 h after IR treatment. Representative images (scale bar, 10 μm) and quantitative results are shown (n = 30 cells per group) (b). The levels of total and phosphorylated STING, TBK1, IRF3 and STAT1 (c) and the IFN-β1 level in culture supernatants (d) were measured 48 h after IR treatment. e Co-IP with an anti-FLAG antibody revealed the enhanced interaction of two exogenous VDAC2 monomers in lysates of irradiated NPC cells. f Immunoblot analysis showed an increased level of VDAC2 oligomers in NPC cells 24 h after IR treatment. g VDAC2 oligomers in WT and TRIM21-KO NPC cells 24 h after IR treatment. h–j NPC cells were pre-treated with the VDAC2 oligomerization inhibitor DIDS (100 μM) or DMSO for 24 h and were then treated with IR. The relative cytosolic *MTATP8* abundance was assessed by qPCR 24 h after IR treatment (h). The levels of phosphorylated STING, TBK1, IRF3 and STAT1 (i), as well as the expression levels of *IFNB1*, *CCL5*, and *CXCL10* (j), were measured 48 h after IR treatment. n = 3 independent experiments. The data are presented as the mean ± SEM (a, b, d, h and j). Comparisons were performed using one-way ANOVA with the Tukey’s test for multiple comparisons.

**Fig. 5. TRIM21 deficiency potentiates radiation-induced antigen presentation.**
a, b WT and TRIM21-KO NPC cells were treated with or without IR. After 48 h, the mRNA expression of antigen presentation molecules, including *HLA-A*, *B2M*, *TAP1* and *TAP2*, was measured by qPCR (a), and the surface MHC-I molecules HLA-A/B/C and β2m were analysed by flow cytometry (b). The results are representative of three independent experiments. c A total of 1 × 10⁶ WT or TRIM21-KO SUNE1 cells were subcutaneously injected into the flanks of BALB/c nude mice, and 1 × 10⁶ WT or TRIM21^−/− MC38 cells were subcutaneously injected into the flanks of C57BL/6 mice. Tumour formation was confirmed 10 days later, and the SUNE1 and MC38 tumours in mice in the IR-treated groups were then subjected to focal radiation with a single fraction of 6 Gy or 15 Gy, respectively. Tumours were dissected 3 or 5 days after IR. The expression of antigen presentation molecules, including *HLA-A*, *B2M*, *TAP1* and *TAP2* in SUNE1 tumours (d, n = 4) and *B2m*, *Erap1*, *Tapbp*, *Tap1* and *Tap2* in MC38 tumours (e, n = 4), was measured by RT–qPCR, and surface MHC-I molecules on murine CD45^– cells in SUNE1 tumours (f, n = 5) and MC38 tumours (g, n = 3) were analysed by flow cytometry. h, i qPCR analysis of *IFNB1*, *CCL5* and *CXCL10* mRNA expression in SUNE1 tumours (h, n = 4) and MC38 tumours (i, n = 4) as indicated in (c). All data are presented as the mean ± SEM. Statistical analysis was performed by one-way ANOVA with Tukey’s test for multiple comparisons (a, b and d–i).

**Fig. 6. TRIM21 depletion enhances radiation-induced antitumour immunity.**
a, b WT and TRIM21-KO NPC cells were treated with or without IR. After 24 h, (a) NPC cells were cocultured with Mo-DCs for another 48 h. Then, the expression of maturation markers, including HLA-DR, CD80, CD83, and CD86, on Mo-DCs was measured by flow cytometry. b WT and TRIM21-KO NPC cells were cocultured with PBMCs for 24 h. The proportion of CD69⁺ cells among CD8⁺ T cells was determined by flow cytometry (the data are presented as the mean ± SEM of three independent experiments; one-way ANOVA with Tukey’s test for multiple comparisons). c–e Established WT or TRIM21^−/− MC38 tumours (from inoculation with 1 × 10⁶ cells) in C57BL/6 mice were subjected to focal radiation with a single fraction of 15 Gy. Tumours were harvested 5 days after IR. The surface expression level of CD40 on CD11c⁺ DCs (d, n = 5), the expression level of the activation marker CD69 on CD8⁺ T cells (e, n = 3), and the expression levels of IFN-γ and TNF-α in CD8⁺ T cells after stimulation with PMA and ionomycin (f, n = 4) were determined by flow cytometry (one-way ANOVA with the Tukey’s test for multiple comparisons). g–i WT and TRIM21-KO SUNE1 tumours were established in humanised NSG mice. Tumours were treated twice (on days 10 and 13 after tumour cell inoculation) with focal radiation (6 Gy). The tumour volume (g, two-way ANOVA), tumour weight (h, n = 10 and n = 13 in WT and TRIM21-KO1 groups respectively, two-tailed unpaired t test), and proportions of tumour-infiltrating CD45⁺ immune cells, CD3⁺ T cells, and CD8⁺ T cells (i, n = 8, two-tailed unpaired t test) are shown. The data are presented as the mean ± SEM.

**Fig. 7. TRIM21 overexpression indicates poor survival and is associated with tumour relapse.**
a TRIM21 and VDAC2 protein expression was evaluated by IHC staining in 46 NPC tumour tissues (scale bar, 50 μm). b VDAC2 IHC scores in NPC tissues with high and low TRIM21 expression. The data are presented as the mean ± SD; two-tailed Mann–Whitney test). c, d Representative images (scale bar, 100 μm) and quantitative results of multiplex immunohistochemistry for CD3⁺, CD8⁺, CD3⁺CD8⁺ and CD11c⁺ cells in 46 NPC tissues with high and low TRIM21 expression (the data are presented as the mean ± SEM; two-tailed unpaired t test). e Association between TRIM21 expression and locoregional recurrence status after radical chemoradiotherapy in a cohort of 355 NPC samples (two-sided χ² test). f–h Kaplan–Meier analysis of locoregional recurrence-free (f), disease-free (g) and overall (h) survival based on the TRIM21 expression level (log-rank test). i Proposed working model of TRIM21. Bulk and scRNA-seq revealed that TRIM21 acts as a negative regulator of IFN signalling and the radiation response in NPC cells. Mechanistically, TRIM21 facilitates the ubiquitination and degradation of VDAC2 and inhibits pore formation by VDAC2 oligomers for mtDNA release, thus suppressing radiation-induced STING–type-I IFN signalling and antitumour immune responses. High TRIM21 expression is associated with impaired antitumour immunity and poor survival in NPC patients.

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References

1. Delaney G, Jacob S, Featherstone C, Barton M. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer. 2005;104:1129–1137. doi: 10.1002/cncr.21324. - DOI - PubMed
1. McLaughlin M, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat. Rev. Cancer. 2020;20:203–217. doi: 10.1038/s41568-020-0246-1. - DOI - PubMed
1. Dovedi SJ, et al. Fractionated radiation therapy stimulates antitumour immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade. Clin. Cancer Res. 2017;23:5514–5526. doi: 10.1158/1078-0432.CCR-16-1673. - DOI - PubMed
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1. Deng L, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type i interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41:843–852. doi: 10.1016/j.immuni.2014.10.019. - DOI - PMC - PubMed

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[1] Delaney G, Jacob S, Featherstone C, Barton M. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer. 2005;104:1129–1137. doi: 10.1002/cncr.21324. - DOI - PubMed

[2] Delaney G, Jacob S, Featherstone C, Barton M. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer. 2005;104:1129–1137. doi: 10.1002/cncr.21324. - DOI - PubMed

[3] McLaughlin M, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat. Rev. Cancer. 2020;20:203–217. doi: 10.1038/s41568-020-0246-1. - DOI - PubMed

[4] McLaughlin M, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat. Rev. Cancer. 2020;20:203–217. doi: 10.1038/s41568-020-0246-1. - DOI - PubMed

[5] Dovedi SJ, et al. Fractionated radiation therapy stimulates antitumour immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade. Clin. Cancer Res. 2017;23:5514–5526. doi: 10.1158/1078-0432.CCR-16-1673. - DOI - PubMed

[6] Dovedi SJ, et al. Fractionated radiation therapy stimulates antitumour immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade. Clin. Cancer Res. 2017;23:5514–5526. doi: 10.1158/1078-0432.CCR-16-1673. - DOI - PubMed

[7] Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10. doi: 10.1016/j.immuni.2013.07.012. - DOI - PubMed

[8] Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10. doi: 10.1016/j.immuni.2013.07.012. - DOI - PubMed

[9] Deng L, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type i interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41:843–852. doi: 10.1016/j.immuni.2014.10.019. - DOI - PMC - PubMed

[10] Deng L, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type i interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41:843–852. doi: 10.1016/j.immuni.2014.10.019. - DOI - PMC - PubMed

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TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models

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TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models

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