CD38 Multi-Functionality in Oral Squamous Cell Carcinoma: Prognostic Implications, Immune Balance, and Immune Checkpoint

Abstract

BackgroundCD38 belongs to the ribosyl cyclase family and is expressed on various hematological cells and involved in immunosuppression and tumor promotion. Although targeting CD38 antibodies has been approved for treatment of multiple myeloma, the function of CD38 in solid tumor, oral squamous cell carcinoma (OSCC) etc., has not been investigated.MethodsThis retrospective study included 92 OSCC samples and analyzed the spatial distribution of CD38 by immunohistochemistry (IHC). The values of diagnosis and prognosis of CD38 were evaluated. Additionally, 53 OSCC preoperative peripheral blood samples were used to be analyzed by flow cytometry. Tumor Immune Estimation Resource (TIMER) and cBioPortal databases were used to study CD38 level in various tumors and its correlation with tumor immune microenvironment in head and neck squamous cell carcinoma (HNSCC).ResultsCD38 ubiquitously presented in tumor cells (TCs), fibroblast-like cells (FLCs), and tumor-infiltrating lymphocytes (TILs). Patients with highly expressed CD38 in TCs (CD38TCs) had higher TNM stage and risk of lymph node metastasis. Upregulation of CD38 in FLCs (CD38FLCs) was significantly associated with poor WPOI. Escalated CD38 in TILs (CD38TILs) led to higher Ki-67 level of tumor cells. Moreover, patients with enhanced CD38TCs were susceptible to postoperative metastasis occurrence, and those with highly expressed CD38TILs independently predicted shorter overall and disease-free survival. Strikingly, patients with highly expressed CD38TILs, but not CD38TCs and CD38FLCs, had significantly lower CD3+CD4+ T cells and higher ratio of CD3−CD16+CD56+NK cells. The imbalance of immune system is attributed to dysregulated immune checkpoint molecules (VISTA, PD-1, LAG-3, CTLA-4, TIGIT, GITR) as well as particular immune cell subsets, which were positively correlated with CD38 expression in HNSCC.ConclusionCD38 is a poor prognostic biomarker for OSCC patients and plays a vital role in governing immune microenvironment and circulating lymphocyte homeostasis. Co-expression between CD38 and immune checkpoint molecules provides new insight into immune checkpoint therapy.

Peripheral blood lymphocyte subsets predict the efficacy of TACE with or without PD-1 inhibitors in patients with hepatocellular carcinoma: a prospective clinical study

“…In HCC, a high frequency of CD38+PD-1+CD8+ T cells is associated with high histopathological grades (III and IV), thereby indicating that CD38, a T-cell co-exhaustion marker, is linked to tumor aggressiveness (27). A recent study has revealed that a heightened level of CD38 expression in TILs promotes increases in the levels of Ki-67 in tumor cells, and that highly expressed CD38+ TILs independently predict shorter OS and PFS (47). The findings of further studies have indicated that the progression of prostate cancer is associated with increases in CD38+ tumor-infiltrating immune cell density, which is independently associated with a worse OS (48).…”

Identification and Validation of PLOD2 as an Adverse Prognostic Biomarker for Oral Squamous Cell Carcinoma

“…We also used bioinformatic analysis to confirm our results. Since OSCC is the most common type of epithelial malignant tumor in the head and neck, using the HNSCC cases in TCGA database for OSCC study is frequently applied by researchers [ 17 , 33 ]. In this study, by using the HNSCC cases in TCGA database, we found significant increases of PLOD2 mRNA levels in tumor tissues compared with normal tissues ( Figure 2 ), and highly expressed PLOD2 was associated with poor OS and DFS ( Figure 5 i,j).…”