Prognostic Significance of STING Immunoexpression in Relation to HPV16 Infection in Patients with Squamous Cell Carcinomas of Oral Cavity and Oropharynx
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Immunohistochemistry
2.3. Statistical Analysis
3. Results
3.1. Patients
3.2. Correlation between STING Immunoexpression and Epidemiological, Clinical and Histopathological Features
3.3. Survival Analysis
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Lechner, M.; Liu, J.; Masterson, L.; Fenton, T.R. HPV-associated oropharyngeal cancer: Epidemiology, molecular biology and clinical management. Nat. Rev. Clin. Oncol. 2022, 19, 306–327. [Google Scholar] [CrossRef] [PubMed]
- Dayyani, F.; Etzel, C.J.; Liu, M.; Ho, C.H.; Lippman, S.M.; Tsao, A.S. Meta-analysis of the impact of human papillomavirus (HPV) on cancer risk and overall survival in head and neck squamous cell carcinomas (HNSCC). Head Neck Oncol. 2010, 2, 15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, H.; Li, J.; Zhou, Y.; Hu, Q.; Zeng, Y.; Mohammadreza, M.M. Human papillomavirus as a favorable prognostic factor in a subset of head and neck squamous cell carcinomas: A meta-analysis. J. Med. Virol. 2017, 89, 710–725. [Google Scholar] [CrossRef] [PubMed]
- O’Rorke, M.A.; Ellison, M.V.; Murray, L.J.; Moran, M.; James, J.; Anderson, L.A. Human papillomavirus related head and neck cancer survival: A systematic review and meta-analysis. Oral. Oncol. 2012, 48, 1191–1201. [Google Scholar] [CrossRef]
- Ragin, C.C.; Taioli, E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: Review and meta-analysis. Int. J. Cancer 2007, 121, 1813–1820. [Google Scholar] [CrossRef]
- Silver, J.A.; Turkdogan, S.; Roy, C.F.; Subramaniam, T.; Henry, M.; Sadeghi, N. De-Escalation Strategies for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma-Where Are We Now? Curr. Oncol. 2022, 29, 3668–3697. [Google Scholar] [CrossRef]
- Jiang, M.; Chen, P.; Wang, L.; Li, W.; Chen, B.; Liu, Y.; Wang, H.; Zhao, S.; Ye, L.; He, Y.; et al. cGAS-STING, an important pathway in cancer immunotherapy. J. Hematol. Oncol. 2020, 13, 81. [Google Scholar] [CrossRef]
- Gan, Y.; Li, X.; Han, S.; Liang, Q.; Ma, X.; Rong, P.; Wang, W.; Li, W. The cGAS/STING Pathway: A Novel Target for Cancer Therapy. Front Immunol. 2021, 12, 795401. [Google Scholar] [CrossRef]
- Lau, L.; Gray, E.E.; Brunette, R.L.; Stetson, D.B. DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway. Science 2015, 350, 568–571. [Google Scholar] [CrossRef] [Green Version]
- Bortnik, V.; Wu, M.; Julcher, B.; Salinas, A.; Nikolic, I.; Simpson, K.J.; McMillan, N.A.; Idris, A. Loss of HPV type 16 E7 restores cGAS-STING responses in human papilloma virus-positive oropharyngeal squamous cell carcinomas cells. J. Microbiol. Immunol. Infect 2021, 54, 733–739. [Google Scholar] [CrossRef]
- Baird, J.R.; Feng, Z.; Xiao, H.D.; Friedman, D.; Cottam, B.; Fox, B.A.; Kramer, G.; Leidner, R.S.; Bell, R.B.; Young, K.H.; et al. STING expression and response to treatment with STING ligands in premalignant and malignant disease. PLoS ONE 2017, 12, e0187532. [Google Scholar] [CrossRef]
- Luo, X.; Donnelly, C.R.; Gong, W.; Heath, B.R.; Hao, Y.; Donnelly, L.A.; Moghbeli, T.; Tan, Y.S.; Lin, X.; Bellile, E.; et al. HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING. J. Clin. Investig. 2020, 130, 1635–1652. [Google Scholar] [CrossRef] [Green Version]
- Lu, S.; Concha-Benavente, F.; Shayan, G.; Srivastava, R.M.; Gibson, S.P.; Wang, L.; Gooding, W.E.; Ferris, R.L. STING activation enhances cetuximab-mediated NK cell activation and DC maturation and correlates with HPV(+) status in head and neck cancer. Oral. Oncol. 2018, 78, 186–193. [Google Scholar] [CrossRef]
- Janecka-Widla, A.; Mucha-Malecka, A.; Majchrzyk, K.; Halaszka, K.; Przewoznik, M.; Slonina, D.; Biesaga, B. Active HPV infection and its influence on survival in head and neck squamous-cell cancer. J. Cancer Res. Clin. Oncol. 2020, 146, 1677–1692. [Google Scholar] [CrossRef]
- Zhu, C.; Li, J.; Yao, M.; Fang, C. Potential for treatment benefit of STING agonists plus immune checkpoint inhibitors in oral squamous cell carcinoma. BMC Oral. Health 2021, 21, 506. [Google Scholar] [CrossRef]
- Hayman, T.J.; Baro, M.; MacNeil, T.; Phoomak, C.; Aung, T.N.; Cui, W.; Leach, K.; Iyer, R.; Challa, S.; Sandoval-Schaefer, T.; et al. STING enhances cell death through regulation of reactive oxygen species and DNA damage. Nat. Commun. 2021, 12, 2327. [Google Scholar] [CrossRef]
- Lohinai, Z.; Dora, D.; Caldwell, C.; Rivard, C.J.; Suda, K.; Yu, H.; Rivalland, G.; Ellison, K.; Rozeboom, L.; Dziadziuszko, R.; et al. Loss of STING expression is prognostic in non-small cell lung cancer. J. Surg. Oncol. 2022, 125, 1042–1052. [Google Scholar] [CrossRef]
- Song, S.; Peng, P.; Tang, Z.; Zhao, J.; Wu, W.; Li, H.; Shao, M.; Li, L.; Yang, C.; Duan, F.; et al. Decreased expression of STING predicts poor prognosis in patients with gastric cancer. Sci. Rep. 2017, 7, 39858. [Google Scholar] [CrossRef] [Green Version]
- Kol, A.; Lubbers, J.M.; Terwindt, A.L.J.; Workel, H.H.; Plat, A.; Wisman, G.B.A.; Bart, J.; Nijman, H.W.; De Bruyn, M. Combined STING levels and CD103+ T cell infiltration have significant prognostic implications for patients with cervical cancer. Oncoimmunology 2021, 10, 1936391. [Google Scholar] [CrossRef]
- Chon, H.J.; Kim, H.; Noh, J.H.; Yang, H.; Lee, W.S.; Kong, S.J.; Lee, S.J.; Lee, Y.S.; Kim, W.R.; Kim, J.H.; et al. STING signaling is a potential immunotherapeutic target in colorectal cancer. J. Cancer 2019, 10, 4932–4938. [Google Scholar] [CrossRef]
- Xia, T.; Konno, H.; Barber, G.N. Recurrent Loss of STING Signaling in Melanoma Correlates with Susceptibility to Viral Oncolysis. Cancer Res. 2016, 76, 6747–6759. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tan, Y.S.; Sansanaphongpricha, K.; Xie, Y.; Donnelly, C.R.; Luo, X.; Heath, B.R.; Zhao, X.; Bellile, E.; Hu, H.; Chen, H.; et al. Mitigating SOX2-potentiated Immune Escape of Head and Neck Squamous Cell Carcinoma with a STING-inducing Nanosatellite Vaccine. Clin. Cancer Res. 2018, 24, 4242–4255. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liang, H.; Deng, L.; Hou, Y.; Meng, X.; Huang, X.; Rao, E.; Zheng, W.; Mauceri, H.; Mack, M.; Xu, M.; et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat. Commun. 2017, 8, 1736. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Deng, L.; Liang, H.; Xu, M.; Yang, X.; Burnette, B.; Arina, A.; Li, X.D.; Mauceri, H.; Beckett, M.; Darga, T.; et al. STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. Immunity 2014, 41, 843–852. [Google Scholar] [CrossRef] [Green Version]
- Drzyzga, A.; Cichon, T.; Czapla, J.; Jarosz-Biej, M.; Pilny, E.; Matuszczak, S.; Wojcieszek, P.; Urbas, Z.; Smolarczyk, R. The Proper Administration Sequence of Radiotherapy and Anti-Vascular Agent-DMXAA Is Essential to Inhibit the Growth of Melanoma Tumors. Cancers 2021, 13, 3924. [Google Scholar] [CrossRef]
- Zheng, Z.; Jia, S.; Shao, C.; Shi, Y. Irradiation induces cancer lung metastasis through activation of the cGAS-STING-CCL5 pathway in mesenchymal stromal cells. Cell Death Dis. 2020, 11, 326. [Google Scholar] [CrossRef]
- Shamseddine, A.A.; Burman, B.; Lee, N.Y.; Zamarin, D.; Riaz, N. Tumor Immunity and Immunotherapy for HPV-Related Cancers. Cancer Discov. 2021, 11, 1896–1912. [Google Scholar] [CrossRef]
- Shaikh, M.H.; Bortnik, V.; McMillan, N.A.; Idris, A. cGAS-STING responses are dampened in high-risk HPV type 16 positive head and neck squamous cell carcinoma cells. Microb. Pathog. 2019, 132, 162–165. [Google Scholar] [CrossRef]
Characteristics | All n (%) a | Tumor STING Expression | Stromal STING Expression | ||||
---|---|---|---|---|---|---|---|
Yes n (%) b | No n (%) | p Level (χ2 Pearson) | Yes n (%) b | No n (%) | p Level (χ2 Pearson) | ||
All | 77 (100.0) | 55 (71.4) | 22 (28.6) | 55 (71.4) | 22 (28.6) | ||
Age | |||||||
≤59 years | 39 (50.6) | 29 (74.4) | 10 (25.6) | 31 (79.5) | 8 (20.5) | ||
>59 years | 38 (49.4) | 26 (68.4) | 12 (31.6) | 0.564 | 24 (63.2) | 14 (36.8) | 0.113 |
Gender | |||||||
Male | 57 (74.0) | 39 (68.4) | 18 (31.6) | 38 (66.7) | 19 (33.3) | ||
Female | 20 (26.0) | 16 (80.0) | 4 (20.0) | 0.324 | 17 (85.0) | 3 (15.0) | 0.118 |
Status in the Karnofsky scale | |||||||
<80% | 42 (54.6) | 31 (73.8) | 11 (26.2) | 30 (71.4) | 12 (28.6) | ||
≥80% | 5 (45.4) | 24 (68.6) | 11 (31.4) | 0.612 | 25 (71.4) | 10 (28.6) | 1.000 |
Localization | |||||||
Oral cavity | 22 (28.6) | 17 (23.7) | 5 (77.3) | 22 (1000.0) | 0 (0.0) | ||
Oropharynx | 55 (71.4) | 38 (69.1) | 17 (30.9) | 0.473 | 33 (60.0) | 22 (40.0) | 0.000 |
The level of smoking—Brinkman index | |||||||
≤520 | 37 (48.1) | 29 (78.4) | 8 (21.6) | 27 (73.0) | 10 (27.0) | ||
>520 | 40 (51.9) | 26 (65.0) | 14 (35.0) | 0.194 | 28 (70.0) | 12 (30.0) | 0.773 |
The level of drinking | |||||||
Low | 34 (44.2) | 25 (73.5) | 9 (26.5) | 26 (76.5) | 8 (23.5) | ||
High | 43 (55.8) | 30 (69.8) | 13 (30.2) | 0.717 | 29 (67.4) | 14 (32.6) | 0.384 |
T stage | |||||||
2 | 15 (17.8) | 11 (73.3) | 4 (26.7) | 11 (73.3) | 4 (26.7) | ||
3 | 42 (49.2) | 31 (73.8) | 11 (26.2) | 30 (71.4) | 12 (28.6) | ||
4 | 20 (31.6) | 13 (65.0) | 7 (35.0) | 0.760 | 14 (70.0) | 6 (30.0) | 0.977 |
N stage | |||||||
0 | 11 (14.3) | 7 (63.6) | 4 (36.4) | 9 (81.8) | 2 (18.2) | ||
1 | 16 (20.8) | 11 (68.7) | 5 (31.3) | 10 (62.5) | 6 (37.6) | ||
2 | 43 (55.8) | 34 (79.1) | 9 (20.9) | 33 (76.7) | 10 (23.3) | ||
3 | 7 (9.1) | 3 (42.9) | 4 (57.1) | 0.220 | 3 (42.9) | 4 (57.1) | 0.203 |
Grade | |||||||
1 | 29 (37.7) | 19 (65.5) | 10 (34.5) | 19 (65.5) | 10 (34.5) | ||
2 | 41 (53.2) | 32 (78.1) | 9 (21.9) | 30 (73.2) | 11 (26.8) | ||
3 | 7 (9.1) | 4 (57.1) | 3 (42.9) | 0.354 | 6 (85.7) | 1 (14.3) | 0.533 |
Keratinization | |||||||
Yes | 44 (57.1) | 32 (72.7) | 12 (27.3) | 34 (77.3) | 10 (22.7) | ||
No | 33 (42.9) | 23 (69.7) | 10 (30.3) | 0.771 | 21 (63.6) | 12 (36.4) | 0.120 |
P16 immunoexpression | |||||||
Yes | 24 (31.2) | 19 (79.2) | 5 (20.8) | 12 (50.0) | 12 (50.0) | ||
No | 53 (68.8) | 36 (67.9) | 17 (32.1) | 0.312 | 43 (81.1) | 10 (18.9) | 0.005 |
active HPV16 infection | |||||||
Yes | 24 (32.9) | 18 (75.0) | 6 (25.0) | 12 (50.0) | 12 (50.0) | ||
No | 49 (67.1) | 34 (69.4) | 15 (30.6) | 0.619 | 41 (83.7) | 8 (16.3) | 0.002 |
Tumor STING expression | |||||||
Yes | 55 (71.4) | 46 (83.6) | 9 (16.4) | ||||
No | 22 (28.6) | 9 (40.9) | 13 (59.1) | ||||
Treatment | |||||||
Definitive CisPt-CRT or surgery + CisPt-CRT | 28 (36.4) | 20 (71.4) | 8 (28.6) | 18 (64.3) | 10 (35.7) | ||
Definitive RT or surgery + RT | 30 (39.0) | 23 (76.7) | 7 (23.3) | 26 (86.7) | 4 (13.3) | ||
Induction CT + definitive RT | 19 (24.6) | 12 (63.2) | 7 (36.8) | 0.594 | 11 (57.9) | 8 (42.1) | 0.074 |
Treatment outcome | |||||||
Regression of cancer disease | 51 (66.2) | 41 (80.4) | 10 (19.6) | 37 (72.5) | 14 (27.5) | ||
Treatment failure | 15 19.5) | 7 (46.7) | 8 (53.3) | 11 (73.3) | 4 (26.7) | ||
Local recurrence | 6 (7.8) | 2 (33.3) | 4 (66.7) | 3 (50.0) | 3 (50.0) | ||
Distant metastases | 5 (6.5) | 5 (100.0) | 0 (0.0) | 0.005 | 4 (80.0) | 1 (20.0) | 0.662 |
Survival | |||||||
Alive at the last follow-up | 37 (48.0) | 27 (73.0) | 10 (27.0) | 25 (67.6) | 12 (32.4) | ||
Death from cancer disease | 22 (28.6) | 12 (54.6) | 10 (45.4) | 15 (68.2) | 7 (31.8) | ||
Death from other reasons | 18 (23.6) | 16 (88.9) | 2 (11.1) | 0.055 | 15 (83.3) | 3 (16.7) | 0.442 |
Characteristics | Overall Survival | Disease-Free Survival | ||||||
---|---|---|---|---|---|---|---|---|
Response n (%) * | HR | 95% CI | Log-Rank p | Response n (%) * | HR | 95% CI | Log-Rank p | |
Age: | ||||||||
≤58 years a | 16/39 (41.0) | 1.459 | 25/39 (64.1) | 1.354 | ||||
>58 years | 21/38 (55.3) | 1.000 | 0.784–2.714 | 0.313 | 27/38 (71.0) | 1.112 | 0.352–3.507 | 0.511 |
Gender | ||||||||
Female | 17/20 (85.0) | 1.000 | 17/20 (85.0) | 1.000 | ||||
Male | 20/57 (35.1) | 5.564 | 1.712–18.081 | 0.001 | 35/57 (61.4) | 3.866 | 0.496–10.107 | 0.023 |
Status in the Karnofsky scale | ||||||||
≤80% | 18/42 (42.9) | 1.682 | 27/42 (64.3) | 1.205 | ||||
>80% | 19/35 (54.3) | 1.000 | 0.924–3.059 | 0.212 | 25/35 (71.4) | 1.000 | 0.381–3.809 | 0.294 |
Localization | ||||||||
Oral cavity | 9/22 (40.9) | 1.368 | 13/22 (59.1) | 1.445 | ||||
Oropharynx | 28/55 (50.9) | 1.000 | 0.706–2.653 | 0.360 | 39/55 (70.9) | 1.000 | 0.390–5.359 | 0.221 |
T stage | ||||||||
1 + 2 | 34/57 (59.6) | 1.000 | 44/57 (77.2) | 1.000 | ||||
3 + 4 | 3/20 (15.0) | 3.129 | 1.657–5.910 | 0.000 | 8/20 (40.0) | 3.005 | 0.962–9.386 | 0.001 |
N stage | ||||||||
0 + 1 | 18/27 (66.7) | 1.000 | 19/27 (70.4) | 1.000 | ||||
2 + 3 | 19/50 (30.0) | 2.252 | 1.071–4.737 | 0.023 | 33/50 (66.0) | 2.341 | 0.630–8.695 | 0.428 |
Grade | ||||||||
1 | 16/29 (55.2) | 1.000 | 21/29 (72.4) | 1.000 | ||||
2 | 18/41 (43.9) | 1.363 | 0.990–2.694 | 28/41 (68.3) | 1.216 | 0,504–2.936 | ||
3 | 3/7 (42.8) | 1.428 | 1.311–3.609 | 0.648 | 3/7 (42.8) | 1.455 | 0.796–2.659 | 0.556 |
Keratinization | ||||||||
Yes | 17/44 (38.6) | 2.203 | 27/44 (61.4) | 2.183 | ||||
No | 20/33 (60.6) | 1.000 | 1.134–4.280 | 0.015 | 25/33 (75.8) | 1.000 | 0.938–5.080 | 0.058 |
The level of smoking—Brinkman index b | ||||||||
≤520 | 23/37 (62.2) | 1.000 | 29/37 (78.4) | 1.000 | ||||
>520 | 14/40 (35.0) | 1.929 | 1.004–3.999 | 0.042 | 23/40 (57.5) | 2.295 | 0.989–5.323 | 0.044 |
The level of drinking | ||||||||
Low | 23/34 (67.6) | 1.000 | 28/34 (82.3) | 1.000 | ||||
High | 14/43 (32.6) | 2.356 | 1.174–4.726 | 0.012 | 24/43 (55.8) | 2.962 | 1.180–7.432 | 0.013 |
active HPV16 infection | ||||||||
Present | 16/24 (66.7) | 1.000 | 15/24 (79.2) | 1.000 | ||||
Absent | 18/49 (36.7) | 2.389 | 1.075–5.303 | 0.023 | 29/49 (59.1) | 2.630 | 0.941–7.348 | 0.049 |
Tumor STING immunoexpression | ||||||||
Yes | 27/55 (49.1) | 1.000 | 42/55 (76.4) | 1.000 | ||||
No | 10/22 (45.4) | 1.047 | 0.532–2.060 | 0.891 | 10/22 (45.4) | 2.282 | 1.040–5.004 | 0.031 |
Microenvironment STING immunoexpression | ||||||||
Yes | 25/55 (45.5) | 1.376 | 38/55 (69.1) | 1.000 | ||||
No | 12/22 (54.5) | 1.000 | 0.672–2.818 | 0.362 | 14/22 (63.6) | 1.063 | 0.458–2.467 | 0.883 |
Treatment | ||||||||
Definitive CRT or surgery + CRT | 17/28 (60.7) | 1.000 | 24/28 (85.7) | 1.000 | ||||
Definitive RT or surgery + RT | 14/30 (46.7) | 1.484 | 0.688–3.201 | 19/30 (63.3) | 2.015 | 1.127–3.602 | ||
Induction CT + definitive RT | 6/19 (31.6) | 1.730 | 0.956–3240 | 0.356 | 9/19 (47.4) | 2.865 | 0.910–9.006 | 0.059 |
Characteristics | HR | 95% CI | p-Value a |
---|---|---|---|
Overall survival | |||
Gender | |||
Female | 1.000 | ||
Male | 4.501 | 1.363–14.865 | 0.014 |
T stage | |||
1 + 2 | 1.000 | ||
3 + 4 | 2.466 | 1.293–4.701 | 0.006 |
Disease-free survival | |||
T stage | |||
1 + 2 | 1.000 | ||
3 + 4 | 3.616 | 1.627–8.036 | 0.002 |
Tumor STING expression | |||
Yes | 1.000 | ||
No | 3.912 | 1.915–9.443 | 0.042 |
Overall Survival | Disease-Free Survival | ||||||||
---|---|---|---|---|---|---|---|---|---|
Response n (%) | HR | 95% CI | Log-Rank p | Response n (%) | HR | 95% CI | Log-Rank p | ||
Active HPV16 infection | Tumor STING immunoexpression | ||||||||
Yes | 12/18 (66.7) | 1.055 | 0.213–5.234 | 0.946 | 17/18 (94.4) | 1.000 | 0.701–15.217 | 0.047 | |
No | 4/6 (66.7) | 1.000 | 3/6 (50.0) | 4.206 | |||||
Stromal STING immunoexpression | |||||||||
Yes | 7/12 (58.3) | 1.916 | 0.547–8.035 | 0.363 | 11/12 (91.7) | 1.000 | 0.397–12.025 | 0.225 | |
No | 9/12 (75.0) | 1.000 | 8/12 (66.7) | 3.566 | |||||
Lack of active HPV16 infection | Tumor STING immunoexpression | ||||||||
Yes | 13/34 (38.2) | 1.000 | 0.503–2.275 | 0.853 | 24/35 (68.6) | 1.000 | 1.040–5.004 | 0.130 | |
No | 5/15 (33.3) | 1.070 | 6/15 (40.0) | 2.282 | |||||
Stromal STING immunoexpression | |||||||||
Yes | 16/41 (39.0) | 1.000 | 0.484–2.880 | 0.706 | 25/41 (61.0) | 1.000 | 0.365–3.278 | 0.869 | |
No | 2/8 (25.0) | 1.180 | 4/8 (50.0) | 1.093 |
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Biesaga, B.; Smolarczyk, R.; Mucha-Małecka, A.; Czapla, J.; Ryś, J.; Małecki, K. Prognostic Significance of STING Immunoexpression in Relation to HPV16 Infection in Patients with Squamous Cell Carcinomas of Oral Cavity and Oropharynx. Biomedicines 2022, 10, 2538. https://doi.org/10.3390/biomedicines10102538
Biesaga B, Smolarczyk R, Mucha-Małecka A, Czapla J, Ryś J, Małecki K. Prognostic Significance of STING Immunoexpression in Relation to HPV16 Infection in Patients with Squamous Cell Carcinomas of Oral Cavity and Oropharynx. Biomedicines. 2022; 10(10):2538. https://doi.org/10.3390/biomedicines10102538
Chicago/Turabian StyleBiesaga, Beata, Ryszard Smolarczyk, Anna Mucha-Małecka, Justyna Czapla, Janusz Ryś, and Krzysztof Małecki. 2022. "Prognostic Significance of STING Immunoexpression in Relation to HPV16 Infection in Patients with Squamous Cell Carcinomas of Oral Cavity and Oropharynx" Biomedicines 10, no. 10: 2538. https://doi.org/10.3390/biomedicines10102538