AUTHOR=Ding Zhuang , He Yijia , Fu Yong , Zhu Nisha , Zhao Mengxiang , Song Yuxian , Huang Xiaofeng , Chen Sheng , Yang Yan , Zhang Caihong , Hu Qingang , Ni Yanhong , Ding Liang 

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

JOURNAL=Frontiers in Oncology

VOLUME=Volume 11 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.687430

DOI=10.3389/fonc.2021.687430

ISSN=2234-943X

ABSTRACT=Background: CD38, a member of the ribosyl cyclase family, is generally expressed on various hematological cells and involved into immunosuppression and tumor promotion. Although anti-CD38 monoclonal antibody was approved for treatment for multiple myeloma, the role of CD38 in solid tumor, etc. oral squamous cell carcinoma (OSCC), has not been explored.
Methods: 92 OSCC samples were enrolled in this retrospective study, and immunohistochemistry (IHC) was performed to detect the spatial pattern of CD38. The diagnostic and prognostic value of CD38 were also assessed. Additionally, 53 OSCC preoperative peripheral blood were used to be analyzed with the 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).
Results: CD38 was widely expressed in tumor cells (TCs), fibroblast-like cells (FLCs) and tumor-infiltrating lymphocytes (TILs). Patients with higher expressed CD38 in TCs (CD38TCs) had higher TNM stage and the 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 occur postoperative metastasis and were with higher expressed CD38TILs independently predicted shorter overall and disease-free survival. Strikingly, patients with high-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 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.
Conclusion: CD38 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.