Tumor gene signatures that correlate with release of extracellular vesicles shape the immune landscape in head and neck squamous cell carcinoma

Author:

Kallinger Isabella1,Rubenich Dominique S23,Głuszko Alicja4,Kulkarni Aditi567,Spanier Gerrit1,Spoerl Steffen1,Taxis Juergen1ORCID,Poeck Hendrik8,Szczepański Mirosław J4,Ettl Tobias1,Reichert Torsten E1,Meier Johannes K1,Braganhol Elizandra23,Ferris Robert L5679,Whiteside Theresa L57910,Ludwig Nils1ORCID

Affiliation:

1. Department of Oral and Maxillofacial Surgery, University Hospital Regensburg , Regensburg , Germany

2. Programa de Pós-Graduação em Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) , Porto Alegre, RS , Brazil

3. Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária do Instituto de Cardiologia (IC-FUC) , Porto Alegre, RS , Brazil

4. Chair and Department of Biochemistry, Faculty of Medicine, Medical University of Warsaw, Warsaw , Poland

5. UPMC Hillman Cancer Center, University of Pittsburgh , Pittsburgh, PA , USA

6. Tumor Microenvironment Center, UPMC Hillman Cancer Center , Pittsburgh, PA , USA

7. Department of Otolaryngology, University of Pittsburgh , Pittsburgh, PA , USA

8. Clinic and Polyclinic for Internal Medicine III, University Hospital Regensburg and Leibniz Institute for Immunotherapy (LIT) , Regensburg , Germany

9. Department of Immunology, University of Pittsburgh , Pittsburgh, PA , USA

10. Department of Pathology, University of Pittsburgh , Pittsburgh, PA , USA

Abstract

Abstract Head and neck squamous cell carcinomas (HNSCCs) evade immune responses through multiple resistance mechanisms. Extracellular vesicles (EVs) released by the tumor and interacting with immune cells induce immune dysfunction and contribute to tumor progression. This study evaluates the clinical relevance and impact on anti-tumor immune responses of gene signatures expressed in HNSCC and associated with EV production/release. Expression levels of two recently described gene sets were determined in The Cancer Genome Atlas Head and Neck Cancer cohort (n = 522) and validated in the GSE65858 dataset (n = 250) as well as a recently published single-cell RNA sequencing dataset (n = 18). Clustering into HPV(+) and HPV(−) patients was performed in all cohorts for further analysis. Potential associations between gene expression levels, immune cell infiltration, and patient overall survival were analyzed using GEPIA2, TISIDB, TIMER, and the UCSC Xena browser. Compared to normal control tissues, vesiculation-related genes were upregulated in HNSCC cells. Elevated gene expression levels positively correlated (P < 0.01) with increased abundance of CD4(+) T cells, macrophages, neutrophils, and dendritic cells infiltrating tumor tissues but were negatively associated (P < 0.01) with the presence of B cells and CD8(+) T cells in the tumor. Expression levels of immunosuppressive factors NT5E and TGFB1 correlated with the vesiculation-related genes and might explain the alterations of the anti-tumor immune response. Enhanced expression levels of vesiculation-related genes in tumor tissues associates with the immunosuppressive tumor milieu and the reduced infiltration of B cells and CD8(+) T cells into the tumor.

Funder

German Academic Exchange Service

Medical University of Warsaw

National Institutes of Health

Walter Schulz Foundation

Publisher

Oxford University Press (OUP)

Subject

Immunology,Immunology and Allergy

Reference47 articles.

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4. Cancer-derived small extracellular vesicles promote angiogenesis by heparin-bound, bevacizumab-insensitive VEGF, independent of vesicle uptake;Ko;Commun Biol,2019

5. Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance;Mashouri;Mol Cancer,2019

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