The treatment options for patients with advanced salivary gland cancers (SGCs) are limited. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, the response to ICI immunotherapy is largely driven by the immune cell signatures within the tumor tissue and the para-tumoral tissue compartments. To date, there are no data on the expression of programed cell death protein-1/programed cell death protein-ligand 1 (PD-1/PD-L1) in SGC, which may enable the implementation of ICI immunotherapy for this disease. Thus, we performed an immunohistochemical analysis of PD-1 and PD-L1 expression in tumor cells and tumor-infiltrating immune cells (TIICs) in the tumor center and periphery of 62 SGC patients. The tumor periphery showed significantly higher expression of PD-L1 in tumor cells than in TIICs. Moreover, peripheral TIICs had significantly higher PD-1 expression than peripheral tumor cells. PD-1-positive tumor cells were detected exclusively in the tumor center of high-grade tumors, and most importantly, the presence of lymph node (LN) metastases and primary tumor stage significantly correlated with the presence of PD-L1-positive tumor cells in the tumor periphery. The PD-1/PD-L1 molecular signatures in SGC are clustered predominantly in the tumor periphery, reflect disease severity, and may predict the response to ICI immunotherapy in SGC patients.

Department of Immunology 2nd Faculty of Medicine Charles University and University Hospital Motol 15006 Prague Czech Republic

Department of Methodology Faculty of Physical Education and Sport Charles University 16252 Prague Czech Republic

Department of Otorhinolaryngology 2nd Faculty of Medicine Charles University and University Hospital Motol 15006 Prague Czech Republic

Department of Otorhinolaryngology and Head and Neck Surgery 1st Faculty of Medicine Charles University and University Hospital Motol 15006 Prague Czech Republic

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University and University Hospital Motol 15006 Prague Czech Republic

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Park S.I., Park W., Choi S., Jang Y., Kim H., Kim S.H., Noh J.M., Chung M.K., Son Y.I., Baek C.H., et al. Clinical Outcome of Minor Salivary Gland Cancers in the Oral Cavity: A Comparative Analysis With Squamous Cell Carcinomas of the Oral Cavity. Front. Oncol. 2020;10:881. doi: 10.3389/fonc.2020.00881. PubMed DOI PMC

Galdirs T.M., Kappler M., Reich W., Eckert A.W. Current aspects of salivary gland tumors—A systematic review of the literature. GMS Interdiscip. Plast. Reconstr. Surg. DGPW. 2019;8:Doc12. doi: 10.3205/iprs000138. PubMed DOI PMC

Witte H.M., Gebauer N., Lappohn D., Umathum V.G., Riecke A., Arndt A., Steinestel K. Prognostic Impact of PD-L1 Expression in Malignant Salivary Gland Tumors as Assessed by Established Scoring Criteria: Tumor Proportion Score (TPS), Combined Positivity Score (CPS), and Immune Cell (IC) Infiltrate. Cancers. 2020;12:873. doi: 10.3390/cancers12040873. PubMed DOI PMC

Wang X., Luo Y., Li M., Yan H., Sun M., Fan T. Management of salivary gland carcinomas—A review. Oncotarget. 2017;8:3946–3956. doi: 10.18632/oncotarget.13952. PubMed DOI PMC

Acauan M.D., Figueiredo M.A., Cherubini K., Gomes A.P., Salum F.G. Radiotherapy-induced salivary dysfunction: Structural changes, pathogenetic mechanisms and therapies. Arch. Oral Biol. 2015;60:1802–1810. doi: 10.1016/j.archoralbio.2015.09.014. PubMed DOI

Lagha A., Chraiet N., Ayadi M., Krimi S., Allani B., Rifi H., Raies H., Mezlini A. Systemic therapy in the management of metastatic or advanced salivary gland cancers. Head Neck Oncol. 2012;4:19. doi: 10.1186/1758-3284-4-19. PubMed DOI PMC

Sroussi H.Y., Epstein J.B., Bensadoun R.J., Saunders D.P., Lalla R.V., Migliorati C.A., Heaivilin N., Zumsteg Z.S. Common oral complications of head and neck cancer radiation therapy: Mucositis, infections, saliva change, fibrosis, sensory dysfunctions, dental caries, periodontal disease, and osteoradionecrosis. Cancer Med. 2017;6:2918–2931. doi: 10.1002/cam4.1221. PubMed DOI PMC

Waldman A.D., Fritz J.M., Lenardo M.J. 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

Vaddepally R.K., Kharel P., Pandey R., Garje R., Chandra A.B. Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence. Cancers. 2020;12:738. doi: 10.3390/cancers12030738. PubMed DOI PMC

Kato S., Elkin S.K., Schwaederle M., Tomson B.N., Helsten T., Carter J.L., Kurzrock R. Genomic landscape of salivary gland tumors. Oncotarget. 2015;6:25631–25645. doi: 10.18632/oncotarget.4554. PubMed DOI PMC

Ross J.S., Gay L.M., Wang K., Vergilio J.A., Suh J., Ramkissoon S., Somerset H., Johnson J.M., Russell J., Ali S., et al. Comprehensive genomic profiles of metastatic and relapsed salivary gland carcinomas are associated with tumor type and reveal new routes to targeted therapies. Ann. Oncol. Off. J. Eur. Soc. Med Oncol. ESMO. 2017;28:2539–2546. doi: 10.1093/annonc/mdx399. PubMed DOI PMC

Lee H.T., Lee S.H., Heo Y.S. Molecular Interactions of Antibody Drugs Targeting PD-1, PD-L1, and CTLA-4 in Immuno-Oncology. Molecules. 2019;24:1190. doi: 10.3390/molecules24061190. PubMed DOI PMC

Barrueto L., Caminero F., Cash L., Makris C., Lamichhane P., Deshmukh R.R. Resistance to Checkpoint Inhibition in Cancer Immunotherapy. Transl. Oncol. 2020;13:100738. doi: 10.1016/j.tranon.2019.12.010. PubMed DOI PMC

Nowicki T.S., Hu-Lieskovan S., Ribas A. Mechanisms of Resistance to PD-1 and PD-L1 Blockade. Cancer J. 2018;24:47–53. doi: 10.1097/PPO.0000000000000303. PubMed DOI PMC

Vital D., Ikenberg K., Moch H., Rossle M., Huber G.F. The expression of PD-L1 in salivary gland carcinomas. Sci. Rep. 2019;9:12724. doi: 10.1038/s41598-019-49215-9. PubMed DOI PMC

Hamza A., Roberts D., Su S., Weber R.S., Bell D., Ferrarotto R. PD-L1 expression by immunohistochemistry in salivary duct carcinoma. Ann. Diagn. Pathol. 2019;40:49–52. doi: 10.1016/j.anndiagpath.2019.04.001. PubMed DOI PMC

Xu B., Jungbluth A.A., Frosina D., Alzumaili B., Aleynick N., Slodkowska E., Higgins K., Ho A., Morris L., Ghossein R., et al. The immune microenvironment and expression of PD-L1, PD-1, PRAME and MHC I in salivary duct carcinoma. Histopathology. 2019;75:672–682. doi: 10.1111/his.13944. PubMed DOI PMC

Alame M., Cornillot E., Cacheux V., Tosato G., Four M., De Oliveira L., Gofflot S., Delvenne P., Turtoi E., Cabello-Aguilar S., et al. The molecular landscape and microenvironment of salivary duct carcinoma reveal new therapeutic opportunities. Theranostics. 2020;10:4383–4394. doi: 10.7150/thno.42986. PubMed DOI PMC

Chang H., Kim J.S., Choi Y.J., Cho J.G., Woo J.S., Kim A., Kim J.S., Kang E.J. Overexpression of PD-L2 is associated with shorter relapse-free survival in patients with malignant salivary gland tumors. Onco Targets Ther. 2017;10:2983–2992. doi: 10.2147/OTT.S134589. PubMed DOI PMC

Eveson J.W., Auclair P., Gnepp D.R., El-Naggar A.K. Tumours of the salivary glands. In: Barnes L., Eveson J.W., Reichart P., Sidransky D., editors. World Health Organization Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. IARC press; Lyon, France: 2005. pp. 209–281.

Huang S.H., O’Sullivan B. Overview of the 8th Edition TNM Classification for Head and Neck Cancer. Curr. Treat. Options Oncol. 2017;18:40. doi: 10.1007/s11864-017-0484-y. PubMed DOI

O’Kane G., Lynch M., Hooper S., Aird J., Muldoon C., Mulligan N., Loscher C., Gallagher D.J. Zonal differences in PD-1 expression in centre of tumour versus periphery in microsatellite stable and unstable colorectal cancer. J. Clin. Oncol. 2015;33:3574. doi: 10.1200/jco.2015.33.15_suppl.3574. DOI

Emancipator K., Huang L., Aurora-Garg D., Bal T., Cohen E.E.W., Harrington K., Soulieres D., Le Tourneau C., Licitra L., Burtness B., et al. Comparing programmed death ligand 1 scores for predicting pembrolizumab efficacy in head and neck cancer. Mod. Pathol. 2020:1–10. doi: 10.1038/s41379-020-00710-9. PubMed DOI

de Ruiter E.J., Mulder F.J., Koomen B.M., Speel E.J., van den Hout M., de Roest R.H., Bloemena E., Devriese L.A., Willems S.M. Comparison of three PD-L1 immunohistochemical assays in head and neck squamous cell carcinoma (HNSCC) Mod. Pathol. 2020:1–8. doi: 10.1038/s41379-020-0644-7. PubMed DOI

Rasmussen J.H., Lelkaitis G., Hakansson K., Vogelius I.R., Johannesen H.H., Fischer B.M., Bentzen S.M., Specht L., Kristensen C.A., von Buchwald C., et al. Intratumor heterogeneity of PD-L1 expression in head and neck squamous cell carcinoma. Br. J. Cancer. 2019;120:1003–1006. doi: 10.1038/s41416-019-0449-y. PubMed DOI PMC

Ferrata M., Schad A., Zimmer S., Musholt T.J., Bahr K., Kuenzel J., Becker S., Springer E., Roth W., Weber M.M., et al. PD-L1 Expression and Immune Cell Infiltration in Gastroenteropancreatic (GEP) and Non-GEP Neuroendocrine Neoplasms With High Proliferative Activity. Front. Oncol. 2019;9:343. doi: 10.3389/fonc.2019.00343. PubMed DOI PMC

Phillips T., Simmons P., Inzunza H.D., Cogswell J., Novotny J., Jr., Taylor C., Zhang X. Development of an automated PD-L1 immunohistochemistry (IHC) assay for non-small cell lung cancer. Appl. Immunohistochem. Mol. Morphol. 2015;23:541–549. doi: 10.1097/PAI.0000000000000256. PubMed DOI PMC

Igarashi T., Teramoto K., Ishida M., Hanaoka J., Daigo Y. Scoring of PD-L1 expression intensity on pulmonary adenocarcinomas and the correlations with clinicopathological factors. ESMO Open. 2016;1:e000083. doi: 10.1136/esmoopen-2016-000083. PubMed DOI PMC

Cedres S., Ponce-Aix S., Zugazagoitia J., Sansano I., Enguita A., Navarro-Mendivil A., Martinez-Marti A., Martinez P., Felip E. Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM) PLoS ONE. 2015;10:e0121071. doi: 10.1371/journal.pone.0121071. PubMed DOI PMC

Derwinger K., Kodeda K., Bexe-Lindskog E., Taflin H. Tumour differentiation grade is associated with TNM staging and the risk of node metastasis in colorectal cancer. Acta Oncol. 2010;49:57–62. doi: 10.3109/02841860903334411. PubMed DOI

Tabibi A., Parvin M., Abdi H., Bashtar R., Zamani N., Abadpour B. Correlation between size of renal cell carcinoma and its grade, stage, and histological subtype. Urol. J. 2007;4:10–13. PubMed

Murciano-Goroff Y.R., Warner A.B., Wolchok J.D. The future of cancer immunotherapy: Microenvironment-targeting combinations. Cell Res. 2020;30:507–519. doi: 10.1038/s41422-020-0337-2. PubMed DOI PMC

Kim S., Kim A., Shin J.Y., Seo J.S. The tumor immune microenvironmental analysis of 2,033 transcriptomes across 7 cancer types. Sci. Rep. 2020;10:9536. doi: 10.1038/s41598-020-66449-0. PubMed DOI PMC

Huo M., Zhang Y., Chen Z., Zhang S., Bao Y., Li T. Tumor microenvironment characterization in head and neck cancer identifies prognostic and immunotherapeutically relevant gene signatures. Sci. Rep. 2020;10:11163. doi: 10.1038/s41598-020-68074-3. PubMed DOI PMC

Giraldo N.A., Becht E., Pages F., Skliris G., Verkarre V., Vano Y., Mejean A., Saint-Aubert N., Lacroix L., Natario I., et al. Orchestration and Prognostic Significance of Immune Checkpoints in the Microenvironment of Primary and Metastatic Renal Cell Cancer. Clin. Cancer Res. 2015;21:3031–3040. doi: 10.1158/1078-0432.CCR-14-2926. PubMed DOI

Fridman W.H., Zitvogel L., Sautes-Fridman C., Kroemer G. The immune contexture in cancer prognosis and treatment. Nat. Rev. Clin. Oncol. 2017;14:717–734. doi: 10.1038/nrclinonc.2017.101. PubMed DOI

Davis A.A., Patel V.G. The role of PD-L1 expression as a predictive biomarker: An analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J. Immunother. Cancer. 2019;7:278. doi: 10.1186/s40425-019-0768-9. PubMed DOI PMC

Sharpe A.H., Pauken K.E. The diverse functions of the PD1 inhibitory pathway. Nat. Rev. Immunol. 2018;18:153–167. doi: 10.1038/nri.2017.108. PubMed DOI

Wang X., Yang X., Zhang C., Wang Y., Cheng T., Duan L., Tong Z., Tan S., Zhang H., Saw P.E., et al. Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy. Proc. Natl. Acad. Sci. USA. 2020;117:6640–6650. doi: 10.1073/pnas.1921445117. PubMed DOI PMC

Gooden M.J., de Bock G.H., Leffers N., Daemen T., Nijman H.W. The prognostic influence of tumour-infiltrating lymphocytes in cancer: A systematic review with meta-analysis. Br. J. Cancer. 2011;105:93–103. doi: 10.1038/bjc.2011.189. PubMed DOI PMC

Hendry S., Salgado R., Gevaert T., Russell P.A., John T., Thapa B., Christie M., van de Vijver K., Estrada M.V., Gonzalez-Ericsson P.I., et al. Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors. Adv. Anat. Pathol. 2017;24:311–335. doi: 10.1097/PAP.0000000000000161. PubMed DOI PMC

Linxweiler M., Kuo F., Katabi N., Lee M., Nadeem Z., Dalin M.G., Makarov V., Chowell D., Dogan S., Ganly I., et al. The Immune Microenvironment and Neoantigen Landscape of Aggressive Salivary Gland Carcinomas Differ by Subtype. Clin. Cancer Res. 2020;26:2859–2870. doi: 10.1158/1078-0432.CCR-19-3758. PubMed DOI PMC

Belulescu I.C., Margaritescu C., Dumitrescu C.I., DĂGUCI L., Munteanu C., Margaritescu O.C. Adenoid Cystic Carcinoma of Salivary Gland: A Ten-Year Single Institute Experience. Curr. Health Sci. J. 2020;46:56–65. doi: 10.12865/CHSJ.46.01.08. PubMed DOI PMC

Schmitt N.C., Kang H., Sharma A. Salivary duct carcinoma: An aggressive salivary gland malignancy with opportunities for targeted therapy. Oral Oncol. 2017;74:40–48. doi: 10.1016/j.oraloncology.2017.09.008. PubMed DOI PMC

Gershkovitz M., Yajuk O., Fainsod-Levi T., Granot Z. The pd-l1/pd-1 axis blocks neutrophil cytotoxicity in cancer. bioRxiv. 2020:969410. doi: 10.1101/2020.02.28.969410. PubMed DOI PMC

Alsaab H.O., Sau S., Alzhrani R., Tatiparti K., Bhise K., Kashaw S.K., Iyer A.K. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front. Pharmacol. 2017;8:561. doi: 10.3389/fphar.2017.00561. PubMed DOI PMC

Furuse M., Kuwabara H., Ikeda N., Hattori Y., Ichikawa T., Kagawa N., Kikuta K., Tamai S., Nakada M., Wakabayashi T., et al. PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma. BMC Cancer. 2020;20:277. doi: 10.1186/s12885-020-06755-y. PubMed DOI PMC

Heinhuis K.M., Ros W., Kok M., Steeghs N., Beijnen J.H., Schellens J.H.M. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. ESMO. 2019;30:219–235. doi: 10.1093/annonc/mdy551. PubMed DOI

Lamichhane P., Deshmukh R., Brown J.A., Jakubski S., Parajuli P., Nolan T., Raja D., Badawy M., Yoon T., Zmiyiwsky M., et al. Novel Delivery Systems for Checkpoint Inhibitors. Medicines. 2019;6:74. doi: 10.3390/medicines6030074. PubMed DOI PMC

Havel J.J., Chowell D., Chan T.A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer. 2019;19:133–150. doi: 10.1038/s41568-019-0116-x. PubMed DOI PMC

Park C.K., Kim S.K. Clinicopathological significance of intratumoral and peritumoral lymphocytes and lymphocyte score based on the histologic subtypes of cutaneous melanoma. Oncotarget. 2017;8:14759–14769. doi: 10.18632/oncotarget.14736. PubMed DOI PMC

Strizova Z., Snajdauf M., Stakheev D., Taborska P., Vachtenheim J., Jr., Biskup J., Lischke R., Bartunkova J., Smrz D. The paratumoral immune cell signature reveals the potential for the implementation of immunotherapy in esophageal carcinoma patients. J. Cancer Res. Clin. Oncol. 2020;146:1979–1992. doi: 10.1007/s00432-020-03258-y. PubMed DOI

Schnell A., Schmidl C., Herr W., Siska P.J. The Peripheral and Intratumoral Immune Cell Landscape in Cancer Patients: A Proxy for Tumor Biology and a Tool for Outcome Prediction. Biomedicines. 2018;6:25. doi: 10.3390/biomedicines6010025. PubMed DOI PMC

Strizova Z., Taborska P., Stakheev D., Partlova S., Havlova K., Vesely S., Bartunkova J., Smrz D. NK and T cells with a cytotoxic/migratory phenotype accumulate in peritumoral tissue of patients with clear cell renal carcinoma. Urol. Oncol. 2019;37:503–509. doi: 10.1016/j.urolonc.2019.03.014. PubMed DOI

The expression profiles of CD47 in the tumor microenvironment of salivary gland cancers: a next step in histology-driven immunotherapy