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

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.

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Hypofractionated Radiotherapy Upregulates Several Immune Checkpoint Molecules in Head and Neck Squamous Cell Carcinoma Cells Independently of the HPV Status While ICOS-L Is Upregulated Only on HPV-Positive Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22179114 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9114

Author(s):

Sebastian Wimmer ◽

Lisa Deloch ◽

Michael Hader ◽

Anja Derer ◽

Fridolin Grottker ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Tumor Cells ◽

Squamous Cell ◽

Immune Checkpoint ◽

Patient Specific ◽

Immune Checkpoint Molecules ◽

Hpv Status ◽

The Impact

While the treatment of squamous cell carcinoma of the head and neck (HNSCC) with radiotherapy (RT) is complemented more and more by immunotherapy in clinical trials, little is known about the impact of the human papillomavirus (HPV) status or the applied RT scheme on the immune phenotype of the tumor cells. Therefore, we aimed to examine the impact of the HPV status of four human HNSCC cell lines on cell death and the expression of immune checkpoint molecules (ICMs) after RT with either hypofractionation irradiation (5x3.0Gy) or a high single dose (1x19.3Gy) via multicolor flow cytometry and quantitative PCR at an early time point after therapy. In our study, 5x3.0Gy RT induced high numbers of early and late apoptotic cells independent of the HPV status, but necrosis was only increased in the HPV-positive UM-Scc-47 cells. Generally, the immune stimulatory ICMs (CD70, CD137-L, ICOS-L) were less affected by RT compared to the immune suppressive ones (PD-L1, PD-L2, and the herpesvirus entry mediator (HVEM)). A significant higher surface expression of the analyzed ICMs was found after hypofractionated RT compared to a single high dose; however, regardless of the HPV status, with the exception of ICOS-L. Here, HPV-positive HNSCC tumor cells showed a stronger response to 5x3.0Gy than HPV-negative ones. On the RNA level, only minor alterations of ICMs were observed following RT, with the exception of the HPV negative cell line CAL33 treated with 5x3.0Gy, where PD-L2, HVEM and CD70 were significantly increased. We conclude that the HPV status may not distinctly predict immunological responses following RT, and thus cannot be used as a single predictive marker for therapy responses in HNSCC. In contrast, the patient-specific individual expression of ICMs following RT is preferable for the targeted patient selection for immune therapy directed against distinct ICM.

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RANK Ligand Modulation of Autophagy in Oral Squamous Cell Carcinoma Tumor Cells

Journal of Cellular Biochemistry ◽

10.1002/jcb.25255 ◽

2015 ◽

Vol 117 (1) ◽

pp. 118-125 ◽

Cited By ~ 11

Author(s):

Yuvaraj Sambandam ◽

Sashank Sakamuri ◽

Sundaravadivel Balasubramanian ◽

Azizul Haque

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Tumor Cells ◽

Squamous Cell ◽

Rank Ligand ◽

Squamous Cell Carcinoma Tumor ◽

Carcinoma Tumor

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Heat shock protein 90 as a molecular target for therapy in oral squamous cell carcinoma: Inhibitory effects of 17‑DMAG and ganetespib on tumor cells

Oncology Reports ◽

10.3892/or.2020.7873 ◽

2020 ◽

Vol 45 (2) ◽

pp. 448-458

Author(s):

Naoki Shiraishi ◽

Takeshi Onda ◽

Kamichika Hayashi ◽

Kaoru Onidani ◽

Katsuhito Watanabe ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Heat Shock ◽

Oral Squamous Cell Carcinoma ◽

Heat Shock Protein ◽

Cell Carcinoma ◽

Tumor Cells ◽

Squamous Cell ◽

Heat Shock Protein 90 ◽

Molecular Target ◽

Inhibitory Effects

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MET ectodomain shedding is associated with poor disease-free survival of patients diagnosed with oral squamous cell carcinoma

Modern Pathology ◽

10.1038/s41379-019-0426-2 ◽

2019 ◽

Vol 33 (6) ◽

pp. 1015-1032 ◽

Cited By ~ 1

Author(s):

Maria J. De Herdt ◽

Senada Koljenović ◽

Berdine van der Steen ◽

Stefan M. Willems ◽

Rob Noorlag ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Disease Free Survival ◽

Ectodomain Shedding ◽

Free Survival ◽

Disease Free

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Lymphatic Vessels and High Endothelial Venules are Increased in the Sentinel Lymph Nodes of Patients with Oral Squamous Cell Carcinoma Before the Arrival of Tumor Cells

Annals of Surgical Oncology ◽

10.1245/s10434-011-2154-9 ◽

2011 ◽

Vol 19 (5) ◽

pp. 1595-1601 ◽

Cited By ~ 24

Author(s):

Man Ki Chung ◽

In-Gu Do ◽

Eunwook Jung ◽

Young-Ik Son ◽

Han-Sin Jeong ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Lymph Nodes ◽

Cell Carcinoma ◽

Tumor Cells ◽

Squamous Cell ◽

Lymphatic Vessels ◽

Sentinel Lymph Nodes ◽

High Endothelial Venules

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Combined effects of hyperthermia and chemotherapy on the regulate autophagy of oral squamous cell carcinoma cells under a hypoxic microenvironment

Cell Death Discovery ◽

10.1038/s41420-021-00538-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Fan Shi ◽

Dan Luo ◽

Xuexiao Zhou ◽

Qiaozhen Sun ◽

Pei Shen ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Tumor Microenvironment ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Tumor Cells ◽

Squamous Cell ◽

Tumor Hypoxia ◽

Combined Use ◽

Migration Capacity

AbstractAutophagy has a complex dual role in tumor survival or cell death owning to that is an evolutionarily conserved catabolic mechanism and provides the cells with a sustainable source of biomolecules and energy for the maintenance of homeostasis under stressful conditions such as tumor microenvironment. Hyperthermia is a rapidly growing field in cancer therapy and many advances have been made in understanding and applying the mechanisms of hyperthermia. The shallow oral and maxillofacial position and its abundant blood supply are favorable for the use of hyperthermia. However, the relationship between hyperthermia and autophagy has not been examined of oral squamous cell carcinoma (OSCC) in the tumor hypoxia microenvironment. Here, the expression level of autophagy relative genes is examined to explore autophagy effect on the responses of hyperthermia, hypoxia, and innutrition tumor microenvironment. It is founded that hyperthermia and hypoxia cause autophagy in starvation conditions; further, in hypoxia and innutrition tumor microenvironment, hyperthermia combines YC-1 and 3-MA could inhibit HIF-1α/BNIP3/Beclin1 signal pathway and decrease the secretion of HMGB1; moreover, the cell apoptosis rate increases with an inhibited of cell migration capacity. Thus, the present study demonstrated that combined use of YC-1 and 3-MA might increase the death of tumor cells in physiological and hyperthermic conditions, which could be relevant with the inhibition of autophagy in OSCC tumor cells under hypoxia microenvironment in vitro, which offers new insight into the therapy of OSCC and its application in treating others study carcinomas.

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TPF induction chemotherapy and pathologic response for patients with locally advanced and resectable oral squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.5593 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 5593-5593

Author(s):

Lai-ping Zhong ◽

Chen-ping Zhang ◽

Zhi-yuan Zhang ◽

Guo-xin Ren ◽

Wei Guo ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Tumor Cells ◽

Induction Chemotherapy ◽

Squamous Cell ◽

Positive Response ◽

Locally Advanced ◽

Negative Response ◽

Control Group

5593 Background: The role of induction chemotherapy in locally advanced and resectable oral squamous cell carcinoma has not been well issued. Methods: A prospective, open label, parallel, and interventional randomized control trail has been performed to evaluate the induction chemotherapy of TPF protocol in resectable oral squamous cell carcinoma (OSCC) patients at clinical stage III and IVA. The patients received two cycles of TPF induction chemotherapy (75 mg/m2 docetaxel d1, 75mg/m2 cisplatin d1, and 750mg/m2 5-fluorouracil d1-5) followed by radical surgery and post-operative radiotherapy with a dose from 54 to 66 Gy (the experimental group) or surgery and post-operative radiotherapy (the control group). Post-surgical pathologic examination was performed to determine a positive response or negative response. A positive response was defined as absence of any tumor cells (pathologic complete response) or presence of scattered foci of a few tumor cells (minimal residual disease with <10% viable tumor cells). The primary endpoint is the survival rate; the secondary endpoint is the local control and safety. This study has been approved by institutional ethics committee at Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University. Survival analysis was conducted with the Kaplan-Meier method. Results: 256 patients were enrolled in this trail and 224 patients (111 in experiment group and 113 in control group) finished the whole treatment protocol. After a median follow-up of 21 months (ranging 6-43 m). The pathologic positive response rate was 29.7% (33/111), and negative response rate was 70.3% (78/111). The patients with positive response had a better disease free survival (38.5±2.1m, 95%CI 34.4-42.6m, P=0.003) compared with those with negative response (24.6±2.1m, 95%CI 20.6-28.7m) and control group (31.0±1.6m, 95%CI 27.9-34.1m). The toxicity of induction chemotherapy could be tolerated. Conclusions: Pathologic positive response to TPF induction chemotherapy could benefit the patients with locally advanced and resectable OSCC. However, further long-term follow-up is needed to confirm the benefit on survival and local control.

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