Cancer cell-specific PD-L1 expression is a predictor of poor outcome in patients with locally advanced oral cavity squamous cell carcinoma

Wang, M; Qin, L; Thia, K; Nguyen, T; Macdonald, S; Belobrov, S; Kranz, S; Goode, D; Trapani, JA; Wiesenfeld, D; Neeson, PJ

Author(s): Wang, M; Qin, L; Thia, K; Nguyen, T; Macdonald, S; Belobrov, S; Kranz, S; Goode, D; Trapani, JA; Wiesenfeld, D; Neeson, PJ;
Details: Publication Year 2024-10-02,Volume 12,Issue #10,Page e009617
Journal Title: Journal for Immunotherapy of Cancer
Publication Type: Research article
Abstract: BACKGROUND: Locally advanced oral cavity squamous cell carcinoma (OCSCC) presents a significant clinical challenge despite being partially responsive to standard treatment modalities. This study investigates the prognostic implications of programmed death-ligand 1 (PD-L1) expression in these tumors, focusing on its association with treatment outcomes and the immune microenvironment. METHODS: We assessed tumor-infiltrating lymphocytes (TILs) in 132 patients with OCSCC to evaluate their impact on survival. Multiplex immunohistochemistry staining for CD3, CD68, CD11c, PD-L1, and P40 was used to explore correlations with clinical outcomes in patients with early-stage (n=22) and locally advanced (n=36) OCSCC. These initial findings were validated through differential gene expression analysis, gene set enrichment, and immune cell deconvolution in a The Cancer Genome Atlas cohort of 163 locally advanced OCSCC tumors. Additionally, single-cell RNA sequencing (scRNA-seq) on a smaller cohort (n=10) further characterized the PD-L1(hi) or PD-L1(lo) cancer cells in these tumors. RESULTS: Elevated PD-L1 expression was associated with poor outcomes in patients with locally advanced OCSCC undergoing standard adjuvant therapy, irrespective of "hot" or "cold" classification based on TILs assessment. PD-L1(hi) tumors exhibited an active immune response phenotype, enriched with M1 macrophages, CD8(+) T cells and T regulatory cells in the tumor microenvironment. Notably, the negative impact of PD-L1 expression on outcomes was primarily attributed to its expression by cancer cells, rather than immune cells. Furthermore, scRNA-seq revealed that immune interactions were not essential for PD-L1 upregulation in cancer cells, instead, complex regulatory networks were involved. Additionally, PD-L1(lo) locally advanced tumors exhibited more complex pathway enrichment and diverse T-cell populations compared with those in the early-stage. CONCLUSION: Our findings underscore the prognostic significance of PD-L1 expression in locally advanced OCSCC, and unveil the complex interplay between PD-L1 expression, immune responses, and molecular pathways in the tumor microenvironment. This study provides insights that may inform future therapeutic strategies, including the possibility of tailored immunotherapeutic approaches for patients with PD-L1(hi) locally advanced OCSCC.
Publisher: BMJ
Keywords: Humans; *B7-H1 Antigen/metabolism; *Mouth Neoplasms/pathology/immunology/metabolism/genetics; Male; Female; Middle Aged; *Tumor Microenvironment; *Lymphocytes, Tumor-Infiltrating/immunology/metabolism; Aged; Prognosis; Biomarkers, Tumor/metabolism; Carcinoma, Squamous Cell/immunology/metabolism/pathology/genetics; Adult; Squamous Cell Carcinoma of Head and; Neck/immunology/metabolism/genetics/pathology/mortality; Adjuvant; Head and Neck Cancer; Immune Checkpoint Inhibitor; Radiotherapy/Radioimmunotherapy; Tumor Microenvironment
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1136/jitc-2024-009617
Open Access at Publisher's Site: https://doi.org/10.1136/jitc-2024-009617
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-11-12 06:11:11

Last Modified: 2024-11-12 06:12:19