Transporter associated with antigen processing 1 (TAP1) and TAP2 serve pivotal roles in adaptive immunity. Tumor cells often show reduced antigen presentation on their surface as one mechanism to escape immune recognition. Whether downregulation of TAPs is a common mechanism of tumor immune evasion in squamous cell carcinoma of the oral tongue (SCCOT) is unclear. In the present study, samples from 78 patients with SCCOT and 17 patients with benign hyperplastic tongue lesions were analyzed for TAP1 and TAP2 expression by immunohistochemistry. The percentage of positive cells and staining intensity were scored. Associations with clinicopathological variables and survival outcome were also investigated. The results demonstrated that TAP1 and TAP2 levels were highly associated with each other in individual samples and were upregulated in SCCOT compared with benign lesions (P<0.001). The proportion of TAP1- or TAP2-positive tumor cells was >80% in all but two of the tumors, whereas 25.6 and 23.0% of the tumors showed weak intensity of TAP1 and TAP2, respectively. There were no significant associations with clinicopathological variables or survival outcomes between TAP-intermediate/strong and TAP-weak tumors. However, in patients <70 years old and with early stage SCCOT, male patients had better outcomes than female patients (log-rank P<0.05), and the best outcome was observed in male patients with intermediate/strong TAP expression. In conclusion, loss of TAP was not a frequent event in SCCOT and stronger TAP expression in male patients was associated with improved survival, providing further evidence for sex-specific immune modulation in cancer.

Department of Clinical Sciences Division of Ear Nose and Throat Diseases Umeå University Umeå 901 87 Sweden

Department of Medical Biosciences Pathology Umeå University Umeå 901 87 Sweden

Regional Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Brno 656 53 Czech Republic

Zobrazit více v PubMed

Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. 2020;6:92. doi: 10.1038/s41572-020-00224-3. PubMed DOI PMC

Chow LQM. Head and neck cancer. N Engl J Med. 2020;382:60–72. doi: 10.1056/NEJMra1715715. PubMed DOI

Martincorena I, Raine KM, Gerstung M, Dawson KJ, Haase K, Van Loo P, Davies H, Stratton MR, Campbell PJ. Universal patterns of selection in cancer and somatic tissues. Cell. 2017;171:1029–1041.e21. doi: 10.1016/j.cell.2017.09.042. PubMed DOI PMC

Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: Insights into tumour immunogenicity and immune evasion. Nat Rev Cancer. 2021;21:298–312. doi: 10.1038/s41568-021-00339-z. PubMed DOI

Leone P, Shin EC, Perosa F, Vacca A, Dammacco F, Racanelli V. MHC class I antigen processing and presenting machinery: Organization, function, and defects in tumor cells. J Natl Cancer Inst. 2013;105:1172–1187. doi: 10.1093/jnci/djt184. PubMed DOI

Dhatchinamoorthy K, Colbert JD, Rock KL. Cancer immune evasion through loss of MHC class I antigen presentation. Front Immunol. 2021;12:636568. doi: 10.3389/fimmu.2021.636568. PubMed DOI PMC

Cai L, Michelakos T, Yamada T, Fan S, Wang X, Schwab JH, Ferrone CR, Ferrone S. Defective HLA class I antigen processing machinery in cancer. Cancer Immunol Immunother. 2018;67:999–1009. doi: 10.1007/s00262-018-2131-2. PubMed DOI PMC

Mantel I, Sadiq BA, Blander JM. Spotlight on TAP and its vital role in antigen presentation and cross-presentation. Mol Immunol. 2022;142:105–119. doi: 10.1016/j.molimm.2021.12.013. PubMed DOI PMC

Johnsen AK, Templeton DJ, Sy M, Harding CV. Deficiency of transporter for antigen presentation (TAP) in tumor cells allows evasion of immune surveillance and increases tumorigenesis. J Immunol. 1999;163:4224–4231. PubMed

Feenstra M, Veltkamp M, van Kuik J, Wiertsema S, Slootweg P, van den Tweel J, de Weger R, Tilanus M. HLA class I expression and chromosomal deletions at 6p and 15q in head and neck squamous cell carcinomas. Tissue Antigens. 1999;54:235–245. doi: 10.1034/j.1399-0039.1999.540304.x. PubMed DOI

Meissner M, Reichert TE, Kunkel M, Gooding W, Whiteside TL, Ferrone S, Seliger B. Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: Association with clinical outcome. Clin Cancer Res. 2005;11:2552–2560. doi: 10.1158/1078-0432.CCR-04-2146. PubMed DOI

Bandoh N, Ogino T, Katayama A, Takahara M, Katada A, Hayashi T, Harabuchi Y. HLA class I antigen and transporter associated with antigen processing downregulation in metastatic lesions of head and neck squamous cell carcinoma as a marker of poor prognosis. Oncol Rep. 2010;23:933–939. doi: 10.3892/or_00000717. PubMed DOI

Ogino T, Shigyo H, Ishii H, Katayama A, Miyokawa N, Harabuchi Y, Ferrone S. HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker. Cancer Res. 2006;66:9281–9289. doi: 10.1158/0008-5472.CAN-06-0488. PubMed DOI

Ferris RL, Hunt JL, Ferrone S. Human leukocyte antigen (HLA) class I defects in head and neck cancer: Molecular mechanisms and clinical significance. Immunol Res. 2005;33:113–133. doi: 10.1385/IR:33:2:113. PubMed DOI

Attaran N, Gu X, Coates PJ, Fåhraeus R, Boldrup L, Wilms T, Wang L, Sgaramella N, Zborayova K, Nylander K. Downregulation of TAP1 in tumor-free tongue contralateral to squamous cell carcinoma of the oral tongue, an indicator of better survival. Int J Mol Sci. 2020;21:6220. doi: 10.3390/ijms21176220. PubMed DOI PMC

Taylor BC, Balko JM. Mechanisms of MHC-I downregulation and role in immunotherapy response. Front Immunol. 2022;13:844866. doi: 10.3389/fimmu.2022.844866. PubMed DOI PMC

Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: From T cell basic science to clinical practice. Nat Rev Immunol. 2020;20:651–668. doi: 10.1038/s41577-020-0306-5. PubMed DOI PMC

Detre S, Saclani Jotti G, Dowsett M. A ‘quickscore’ method for immunohistochemical semiquantitation: Validation for oestrogen receptor in breast carcinomas. J Clin Pathol. 1995;48:876–878. doi: 10.1136/jcp.48.9.876. PubMed DOI PMC

Brandwein-Gensler M, Teixeira MS, Lewis CM, Lee B, Rolnitzky L, Hille JJ, Genden E, Urken ML, Wang BY. Oral squamous cell carcinoma: Histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol. 2005;29:167–178. doi: 10.1097/01.pas.0000149687.90710.21. PubMed DOI

Garrido F, Cabrera T, Accolla RS, Bensa JC, Bodmer W, Dohr G, Drouet M, Fauchet R, Ferrara GB, Ferrone S, et al. HLA and cancer: 12th international histocompatibility workshop study. Workshop. 1997;Vol. I:445–452. Hla-genetic diversity of Hla functional and medical implication, proceedings of the twelfth international histocompatibility workshop and conference (12th Ihwc)

Boldrup L, Coates PJ, Laurell G, Nylander K. Differences in p63 expression in SCCHN tumours of different sub-sites within the oral cavity. Oral Oncol. 2011;47:861–865. doi: 10.1016/j.oraloncology.2011.07.002. PubMed DOI

Frohwitter G, Buerger H, Korsching E, van Diest PJ, Kleinheinz J, Fillies T. Site-specific gene expression patterns in oral cancer. Head Face Med. 2017;13:6. doi: 10.1186/s13005-017-0138-0. PubMed DOI PMC

Montesion M, Murugesan K, Jin DX, Sharaf R, Sanchez N, Guria A, Minker M, Li G, Fisher V, Sokol ES, et al. Somatic HLA class I loss is a widespread mechanism of immune evasion which refines the use of tumor mutational burden as a biomarker of checkpoint inhibitor response. Cancer Discov. 2021;11:282–292. doi: 10.1158/2159-8290.CD-20-0672. PubMed DOI

Garrido MA, Perea F, Vilchez JR, Rodriguez T, Anderson P, Garrido F, Ruiz-Cabello F, Aptsiauri N. Copy neutral LOH affecting the entire chromosome 6 is a frequent mechanism of HLA class I alterations in cancer. Cancers (Basel) 2021;13:5046. doi: 10.3390/cancers13205046. PubMed DOI PMC

Ciani Y, Fedrizzi T, Prandi D, Lorenzin F, Locallo A, Gasperini P, Franceschini GM, Benelli M, Elemento O, Fava LL, et al. Allele-specific genomic data elucidate the role of somatic gain and copy-number neutral loss of heterozygosity in cancer. Cell Syst. 2022;13:183–193.e7. doi: 10.1016/j.cels.2021.10.001. PubMed DOI PMC

Garavello W, Spreafico R, Somigliana E, Gaini L, Pignataro L, Gaini RM. Prognostic influence of gender in patients with oral tongue cancer. Otolaryngol Head Neck Surg. 2008;138:768–771. doi: 10.1016/j.otohns.2008.02.026. PubMed DOI

Roberts JC, Li G, Reitzel LR, Wei Q, Sturgis EM. No evidence of sex-related survival disparities among head and neck cancer patients receiving similar multidisciplinary care: A matched-pair analysis. Clin Cancer Res. 2010;16:5019–5027. doi: 10.1158/1078-0432.CCR-10-0755. PubMed DOI PMC

Mazul AL, Naik AN, Zhan KY, Stepan KO, Old MO, Kang SY, Nakken ER, Puram SV. Gender and race interact to influence survival disparities in head and neck cancer. Oral Oncol. 2021;112:105093. doi: 10.1016/j.oraloncology.2020.105093. PubMed DOI

Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16:626–638. doi: 10.1038/nri.2016.90. PubMed DOI

Castro A, Pyke RM, Zhang X, Thompson WK, Day CP, Alexandrov LB, Zanetti M, Carter H. Strength of immune selection in tumors varies with sex and age. Nat Commun. 2020;11:4128. doi: 10.1038/s41467-020-17981-0. PubMed DOI PMC