Increased tumor-infiltrating plasmacytoid dendritic cells express high levels of PD-L2 and affect CD8+ T lymphocyte infiltration in human laryngeal squamous cell carcinoma

Yangyang Ji; Yu Heng; Xiaoke Zhu; Duo Zhang; Di Tang; Jian Zhou; Hanqing Lin; Jingyu Ma; Xuping Ding; Lei Tao; Liming Lu

doi:10.1016/j.tranon.2024.101936

Increased tumor-infiltrating plasmacytoid dendritic cells express high levels of PD-L2 and affect CD8⁺ T lymphocyte infiltration in human laryngeal squamous cell carcinoma

Transl Oncol. 2024 Apr 27:45:101936. doi: 10.1016/j.tranon.2024.101936. Online ahead of print.

Authors

Yangyang Ji¹, Yu Heng¹, Xiaoke Zhu¹, Duo Zhang¹, Di Tang¹, Jian Zhou¹, Hanqing Lin², Jingyu Ma¹, Xuping Ding³, Lei Tao⁴, Liming Lu⁵

Affiliations

¹ Department of Otolaryngology, Shanghai Key Clinical Disciplines of otorhinolaryngology, Eye Ear Nose & Throat Hospital, Fudan University, 83 Fenyang Road, Shanghai 200031, PR China.
² Department of Otorhinolaryngology, Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, PR China.
³ Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
⁴ Department of Otolaryngology, Shanghai Key Clinical Disciplines of otorhinolaryngology, Eye Ear Nose & Throat Hospital, Fudan University, 83 Fenyang Road, Shanghai 200031, PR China. Electronic address: lei.tao@fdeent.org.
⁵ Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China. Electronic address: youlanda2009@sjtu.edu.cn.

Abstract

The infiltration and prognostic significance of tumor-infiltrating plasmacytoid dendritic cells (TI-pDC) have been elucidated in various human solid cancers. However, the infiltrating patterns and functional importance of TI-pDC in laryngeal squamous cell carcinoma (LSCC) remain unknown. In this study, flow cytometric analyses were conducted to characterize the infiltration of dendritic cells and T lymphocytes, along with their respective subgroups in tumor tissues (TT), para-carcinoma tissues (PT), and peripheral blood (PB) from LSCC patients. Immunohistochemical staining for CD4 and CD8, as well as immunofluorescence staining for CD123, were performed on serial tissue sections to investigate the co-localization of TI-pDC and tumor-infiltrating T lymphocytes (TIL) within the tumor microenvironment (TME). Our results demonstrated significantly lower percentages of all three DC subsets in PB compared to TT and PT. Notably, the pDC percentage was markedly higher in TT than in PT. Moreover, TI-pDC percentage was significantly elevated in N⁺ stage patients compared to those with N0 stage. The results of survival analysis consistently demonstrated that high levels of TI-pDC infiltration were indicative of a poor prognosis. Further investigation revealed a significant negative correlation between TI-pDC and CD8⁺ TILs; notably, pDCs expressed an inhibitory surface molecule PD-L2 rather than PD-L1 within PT. Collectively, our findings suggest that increased TI-pDC is associated with adverse outcomes in LSCC patients while exhibiting an inhibitory phenotype that may play a crucial role in suppressing CD8⁺ TILs within LSCC tumors. These results highlight the potential therapeutic strategy targeting PD-L2⁺ pDCs for immunotherapies against LSCC.

Keywords: Immunosuppression; Laryngeal squamous cell carcinoma; Plasmacytoid dendritic cells; Programmed cell death pathway; Tumor microenvironment; Tumor-infiltrating T lymphocytes.