Download PDF
CC BY 4.0 · Eur J Dent 2024; 18(01): 236-242
DOI: 10.1055/s-0043-1764419
Original Article

High 4-1BB Expression in PBMCs and Tumor Infiltrating Lymphocytes (TILs) in Patients with Head and Neck Squamous Cell Carcinoma

Fardeela Bin-Alee   *
1   Faculty of Medicine, Princess of Naradhiwas University, Narathiwat, Thailand
,
Nattharee Chunthagonesupawit   *
2   Master of Science Program in Medical Sciences, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
,
Tamonwan Meesakul
2   Master of Science Program in Medical Sciences, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
,
Areeya Diloktaweewattana
3   Division of Dengue Hemorrhagic Fever Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
4   Siriraj Center of Research Excellence in Dengue and Emerging Pathogens, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
,
Patnarin Mahattanasakul
5   Department of Otolaryngology, Head and Neck Surgery, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
6   Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
,
Apiwat Mutirangura
7   Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
,
Komkrit Ruangritchankul
8   Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
,
Somboon Keelawat
8   Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
,
Nakarin Kitkumthorn
9   Department of Oral Biology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
› Author Affiliations
› Further Information
   Permissions and Reprints

Abstract

Objective 4-1BB is a costimulatory immune-activating molecule. Increased amounts of this protein have previously been found in the plasma of patients with oropharyngeal and oral cancer. Here, we focused on this molecule that functions as part of the immune system. We investigated 4-1BB in the peripheral blood mononuclear cells (PBMCs) and tumor infiltrating lymphocytes (TILs) of patients with head and neck squamous cell cancer (HNSCC).

Materials and Methods The expression level of 4-1BB in the PBMCs was determined using real-time polymerase chain reaction (PCR). The TIMER (Tumor Immune Estimation Resource) web server was utilized to approximate the 4-1BB level in HNSCC TILs. Moreover, 4-1BB immunohistochemistry (IHC) was used to validate TILs in four organs of HNSCC, including oral cancer (OC), oropharyngeal cancer (OPC), sinonasal cancer (SNC), and laryngeal cancer (LC), in both the tumor area and adjacent normal epithelium. The difference in 4-1BB expression levels in various groups was assessed using a Kruskal-Wallis test and an independent sample t-test.

Results The level of 4-1BB expression in PBMCs was highest in OPC, followed by OC and healthy controls (HC). Significant differences were discovered between HC and OPC and between OC and OPC. Bioinformatics revealed a substantial correlation between 4-1BB expression level and lymphocyte infiltration in HNSCC, including B cells, CD8+ T cells, and CD4+ T cells. IHC validation in HNSCC tissue revealed that the average number of 4-1BB positive TILs in all four HNSCC subtypes was considerably greater than the number of lymphocytes seen in adjacent normal tissue. Interestingly, the number of lymphocytes that were 4-1BB positive increased in relation to the TIL level.

Conclusion A higher number of 4-1BB expression levels were found in the PBMCs and TILs of HNSCC patients, implying that 4-1BB may be a promising approach for HNSCC patients to improve their immune function. It is important to study and create a treatment that uses 4-1BB medicine as well as existing drugs.

Keywords

4-1BB - head and neck cancer - PBMCs - TILs

* Co-first author


Supplementary Material



Publication History

Article published online:
02 May 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

 

  • References

  • 1 Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers 2020; 6 (01) 92
    CrossrefPubMedGoogle Scholar
  • 2 Sung H, Ferlay J, Siegel RL. et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71 (03) 209-249
    CrossrefPubMedGoogle Scholar
  • 3 Chester C, Ambulkar S, Kohrt HE. 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer Immunol Immunother 2016; 65 (10) 1243-1248
    CrossrefPubMedGoogle Scholar
  • 4 Chester C, Sanmamed MF, Wang J, Melero I. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood 2018; 131 (01) 49-57
    CrossrefPubMedGoogle Scholar
  • 5 Cheuk AT, Mufti GJ, Guinn BA. Role of 4-1BB:4-1BB ligand in cancer immunotherapy. Cancer Gene Ther 2004; 11 (03) 215-226
    CrossrefPubMedGoogle Scholar
  • 6 Buranapraditkun S, Mahattanasakul P, Diloktaweewattana A. et al. Immune-associated plasma proteins in oral and oropharyngeal cancer patients. Heliyon 2022; 8 (09) e10753
    CrossrefPubMedGoogle Scholar
  • 7 Doescher J, Veit JA, Hoffmann TK. The 8th edition of the AJCC Cancer Staging Manual: updates in otorhinolaryngology, head and neck surgery. HNO 2017; 65 (12) 956-961
    PubMedGoogle Scholar
  • 8 Li T, Fan J, Wang B. et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res 2017; 77 (21) e108-e110
    CrossrefPubMedGoogle Scholar
  • 9 Li T, Fu J, Zeng Z. et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res 2020; 48 (W1): W509-W514
    CrossrefPubMedGoogle Scholar
  • 10 Ruangritchankul K, Sandison A, Warburton F. et al. Clinical evaluation of tumour-infiltrating lymphocytes as a prognostic factor in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma. Histopathology 2019; 75 (01) 146-150
    CrossrefPubMedGoogle Scholar
  • 11 Zhang GB, Dong QM, Hou JQ. et al. Characterization and application of three novel monoclonal antibodies against human 4-1BB: distinct epitopes of human 4-1BB on lung tumor cells and immune cells. Tissue Antigens 2007; 70 (06) 470-479
    CrossrefPubMedGoogle Scholar
  • 12 Glorieux C, Huang P. Regulation of CD137 expression through K-Ras signaling in pancreatic cancer cells. Cancer Commun (Lond) 2019; 39 (01) 41
    CrossrefPubMedGoogle Scholar
  • 13 Kim AMJ, Nemeth MR, Lim S-O. 4-1BB: A promising target for cancer immunotherapy. Front Oncol 2022; 12: 968360
    CrossrefPubMedGoogle Scholar
  • 14 Suzuki S, Ogawa T, Sano R. et al. Immune-checkpoint molecules on regulatory T-cells as a potential therapeutic target in head and neck squamous cell cancers. Cancer Sci 2020; 111 (06) 1943-1957
    CrossrefPubMedGoogle Scholar
  • 15 Wen T, Bukczynski J, Watts TH. 4-1BB ligand-mediated costimulation of human T cells induces CD4 and CD8 T cell expansion, cytokine production, and the development of cytolytic effector function. J Immunol 2002; 168 (10) 4897-4906
    CrossrefPubMedGoogle Scholar
  • 16 Curran MA, Kim M, Montalvo W, Al-Shamkhani A, Allison JP. Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production. PLoS One 2011; 6 (04) e19499
    CrossrefPubMedGoogle Scholar
  • 17 Chapman CH, Yom SS. Oropharyngeal Cancer. In: Hansen EK, Roach IM. eds. Handbook of Evidence-Based Radiation Oncology. Cham: Springer International Publishing; 2018: 171-192
    Google Scholar
  • 18 Sankaranarayanan R, Ramadas K, Amarasinghe H, Subramanian S, Johnson N. Oral cancer: prevention, early detection, and treatment. In: Gelband H, Jha P, Sankaranarayanan R, Horton S. eds. Cancer: Disease Control Priorities. 3rd ed. Vol. 3. Washington, DC: The International Bank for Reconstruction and Development/The World Bank; 2015
    Google Scholar
  • 19 Llorente JL, López F, Suárez C, Hermsen MA. Sinonasal carcinoma: clinical, pathological, genetic and therapeutic advances. Nat Rev Clin Oncol 2014; 11 (08) 460-472
    CrossrefPubMedGoogle Scholar
  • 20 Pacini L, Cabal VN, Hermsen MA, Huang PH. EGFR Exon 20 insertion mutations in sinonasal squamous cell carcinoma. Cancers (Basel) 2022; 14 (02) 394
    CrossrefPubMedGoogle Scholar
  • 21 Liu C, Wang M, Zhang H. et al. Tumor microenvironment and immunotherapy of oral cancer. Eur J Med Res 2022; 27 (01) 198
    CrossrefPubMedGoogle Scholar
  • 22 Locati LD, Serafini MS, Carenzo A. et al. complete response to nivolumab in recurrent/metastatic HPV-positive head and neck squamous cell carcinoma patient after progressive multifocal leukoencephalopathy: a case report. Front Oncol 2022; 11: 799453
    CrossrefPubMedGoogle Scholar
  • 23 Chu DT, Bac ND, Nguyen KH. et al. An update on anti-CD137 antibodies in immunotherapies for cancer. Int J Mol Sci 2019; 20 (08) 1822
    CrossrefPubMedGoogle Scholar
  • 24 Segal NH, He AR, Doi T. et al. Phase I study of single-agent Utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res 2018; 24 (08) 1816-1823
    CrossrefPubMedGoogle Scholar
  • 25 Cohen EEW, Pishvaian MJ, Shepard DR. et al. A phase Ib study of utomilumab (PF-05082566) in combination with mogamulizumab in patients with advanced solid tumors. J Immunother Cancer 2019; 7 (01) 342
    CrossrefPubMedGoogle Scholar
  • 26 Hamid O, Chiappori AA, Thompson JA. et al. First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors. J Immunother Cancer 2022; 10 (10) e005471
    CrossrefPubMedGoogle Scholar
  • 27 Hong DS, Gopal AK, Shoushtari AN. et al. Utomilumab in patients with immune checkpoint inhibitor-refractory melanoma and non-small-cell lung cancer. Front Immunol 2022; 13: 897991
    CrossrefPubMedGoogle Scholar
  • 28 Gao Y, Yang T, Liu H, Song N, Dai C, Ding Y. Development and characterization of a novel human CD137 agonistic antibody with anti-tumor activity and a good safety profile in non-human primates. FEBS Open Bio 2022; 12 (12) 2166-2178
    CrossrefPubMedGoogle Scholar
  • 29 Shindo Y, Yoshimura K, Kuramasu A. et al. Combination immunotherapy with 4-1BB activation and PD-1 blockade enhances antitumor efficacy in a mouse model of subcutaneous tumor. Anticancer Res 2015; 35 (01) 129-136
    Google Scholar