CD3D: a prognostic biomarker associated with immune infiltration and immunotherapeutic response in head and neck squamous cell carcinoma

Abstract

Recent studies have demonstrated that CD3D activates T-cell-related signal transduction and is associated with the antitumor immune response in several cancers. This study explored the role of CD3D in head and neck squamous cell carcinoma (HNSCC). A total of 499 HNSCC tissues and 44 normal controls were acquired from The Cancer Genome Atlas as the training cohort. GSE65858 included 270 HNSCC patients and was obtained from the Gene Expression Omnibus database as the test cohort. Overall, 172 HNSCC patients were collected as the validation cohort. CD3D expression in the validation cohort was measured by quantitative real-time polymerase chain reaction. The Kaplan–Meier plot revealed that high CD3D expression was associated with longer overall survival in HNSCC patients. Univariate and multivariate analyses showed that CD3D expression was an independent prognostic factor for HNSCC patients, which was confirmed in the test cohort and validation cohort. Furthermore, GO, KEGG, and GSEA analyses revealed the association of CD3D with immune-related pathways. Subsequently, ESTIMATE analysis showed the association between CD3D and the tumor microenvironment, while ssGSEA showed a remarkable positive link between CD3D and immune-related functions. Multiple algorithms demonstrated that high CD3D expression was associated with more immune effector cell infiltration. Finally, the tumor immune dysfunction and exclusion (TIDE) score and immunophenoscore (IPS) showed that patients with high CD3D could benefit from immunotherapy. In summary, CD3D was an independent favorable prognostic biomarker and correlated with immune cell infiltration and immune-related function, as well as an efficient indicator of immunotherapy response for HNSCC patients.

Exploring the frontiers: tumor immune microenvironment and immunotherapy in head and neck squamous cell carcinoma

“…Similarly, the KEYNOTE-048 trial, a randomized Phase III study, compared pembrolizumab alone or in combination with chemotherapy (cisplatin or carboplatin with 5-FU) against the EXTREME regimen (Erbitux with platinum-based chemotherapy and 5-FU) in patients with R/MHNSCC. It was observed that while the overall response rate (ORR) for the pembrolizumab monotherapy arm was lower than the chemotherapy arm, pembrolizumab demonstrated a significantly longer OS in patients with a combined positive score (CPS) of 1 or more, compared to the chemotherapy arm [ 63 ]. Additionally, pembrolizumab monotherapy was found to be as effective as the EXTREME regimen in the general population, irrespective of CPS [ 65 ].…”

“…In preclinical studies, radiation and chemotherapy have been observed to up-regulate the expression of immune checkpoints in tumor-associated lymphocytes, including PD-1, TIM-3, and CTLA-4. Additionally, an increase in both CD4 + and CD8 + T cells was noted in response to treatment with radiation and chemotherapy [ 63 – 65 ].…”

“…Overall response rates (ORRs) were also similar across the three groups. However, the duration of response to the combination immunotherapy regimen was more sustained than in the SOC group, with 7.4 months in the D + T group, 2.9 months in the D group, and 3.7 months in the chemotherapy group [ 62 , 63 ]. Previous studies combining anti-PD-1 and anti-CTLA-4 therapies have not demonstrated the superiority of dual immune checkpoint blockade in patients with R/MHNSCC who progressed after platinum-based chemotherapy [ 58 , 64 – 67 ].…”

Hypomethylation of CD3D promoter induces immune cell infiltration and supports malignant phenotypes in uveal melanoma

“…18 In addition, high CD3D expression is associated with more immune effector cell infiltration and functions as an independent favorable prognostic biomarker in patients with head and neck squamous cell carcinoma. 19 Meanwhile, CD3D has been identified as a CD8 + T cell co-expression gene capable of promoting the infiltration of CD8 + T cells in liver cancer. 20 Moreover, increased expression of CD3D is suggestive of more prolonged overall survival in melanoma.…”

“…CD3D is also correlated with immune checkpoint and immune‐infiltrated cells; colon cancer patients with high expression of CD3D show better clinical outcomes 18 . In addition, high CD3D expression is associated with more immune effector cell infiltration and functions as an independent favorable prognostic biomarker in patients with head and neck squamous cell carcinoma 19 …”