Background Tumor-infiltrating lymphocytes include tumor-reactive lymphocytes and regulatory T-cells. However, the prognostic value of tumor-infiltrating lymphocytes in oral squamous cell carcinoma ...(OSCC) remains unclear. Methods We used immunohistochemistry to evaluate the presence of tumor-infiltrating FoxP3#226;#186; T-cells and CTLA-4#226;#186; cells in four distinct histological compartments (tumor parenchyma and stroma at the tumor center, and parenchyma and stroma at the invasive front) and assessed the association between the prevalence of these cells and the histopathological status of 137 patients with OSCC. Results Five-year overall survival, disease-specific survival, and recurrence-free survival were favorable in patients with high numbers of FoxP3#226;#186; T-cells in the parenchyma of the invasive front. Recurrence-free survival and metastasis-free survival were decreased in patients with high numbers of CTLA-4#226;#186; cells in the parenchyma of the invasive front. Conclusions The presence of FoxP3#226;#186; T-cells in the parenchyma of the invasive front may be a useful prognostic factor. Our results indicate that FoxP3#226;#186; T-cells may exert site-specific anti-tumor effects but may not play an immunosuppressive role in OSCC. In addition, our results suggest that CTLA-4.sup.+ cells suppress the function of FoxP3.sup.+ T-cells and promote anti-tumor immunity in OSCC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human leukocyte antigen (HLA) class Ⅰ molecules play a central role in anticancer immunity, but their prognostic value in oral squamous cell carcinoma (OSCC) remains unclear. We examined HLA class I ...expression in 2 distinct tumor compartments, namely, the tumor center and invasive front, and evaluated the association between its expression pattern and histopathological status in 137 cases with OSCC. Human leukocyte antigen class Ⅰ expression was graded semiquantitatively as high, low, and negative. At the invasive front of the tumor, HLA class I expression was high in 72 cases (52.6%), low in 44 cases (32.1%), and negative in 21 cases (15.3%). The HLA class I expression in the tumor center was high in 48 cases (35.0%), low in 58 cases (42.4%), and negative in 31 cases (22.6%). The 5‐year overall survival and disease‐specific survival rates were good in cases with high HLA class I expression at the invasive front; however, there was no significant difference in survival based on HLA class I expression in the tumor center. In addition, high HLA class I expression was correlated with high CD8+ T cell density, whereas negative HLA class I expression was correlated with low CD8+ T cell density at the invasive front. These results suggest that it is easier for CD8+ T cells to recognize presented peptides in the case of high HLA class Ⅰ expression at the tumor invasive front and could be a prognostic factor for OSCC.
Human leukocyte antigen class Ⅰ expression at the tumor invasive front could be a useful prognostic factor for oral squamous cell carcinoma.
Immune checkpoint inhibitor‐based cancer immunotherapy has provided an additional therapeutic option for oral squamous cell carcinoma (OSCC) with recurrence or distant metastases. However, further ...improvement of OSCC treatment is required to develop the optimal combination or order for chemoradiotherapy and immunotherapy. Along with the accumulation of clinical knowledge and evidence, it is also essential to clarify the biological impact of chemo‐radiotherapeutic agents on the cancer immune microenvironment. In this study, we investigated the effects of cisplatin (CDDP), a key therapeutic agent for OSCC, on programmed death‐ligand 1 (PD‐L1) expression in OSCC lines. Although CDDP treatment increased the surface levels of PD‐L1 on OSCC cell lines, the gene and total protein expression levels of PD‐L1 were not altered. We also demonstrated that the phosphorylation of heat shock factor 1 and heat shock protein 90 was involved in this process. In addition, CDDP‐induced PD‐L1 attenuated the target‐specific cytotoxic T lymphocyte reaction to OSCC. These results provide an immunobiological basis for the response of OSCC to CDDP and will contribute to our biological understanding of the action of novel combination therapy including immunotherapy together with platinum‐based chemotherapy for OSCC.
In this report, we demonstrated that CDDP increased the cell surface expression of PD‐L1 on HSC2 OSCC cells and was mediated by HSF1 and HSP90.
The objective of the current study was to elucidate the clinicopathological significance and appearance of in vitro three-dimension (3D) spheroid models of oral malignant tumors that were prepared ...from four pathologically different squamous cell carcinoma (OSCC; low-grade; SSYP and MO-1000, intermediate-grade; LEM2) and oral adenosquamous carcinoma (OASC; high-grade; Mesimo) obtained from patients with different malignant stages. To characterize the biological significance of these cell lines themselves, two-dimensional (2D) cultured cells were subjected to cellular metabolic analysis by a Seahorse bioanalyzer alongside the measurement of the cytotoxicity of cisplatin (CDDP). The appearance of their 3D spheroids was then observed by phase contrast microscopy, and both 2D and 3D cultured cells were subject to trypsin digestion and qPCR analysis of factors related to oncogenic signaling and other related analyses. ATP-linked respiration and proton leaking were significantly different among the four cell lines, and the malignant stages of these cultures were significantly associated with increased ATP-linked respiration and decreased proton leakage. Alternatively, the appearances of these 3D spheroids were also significantly diverse among them, and their differences increased in the order of LEM2, MO-1000, SSYP, and Mesimo. Interestingly, these orders were exactly the same in that the efficacies of CDDP-induced cytotoxicity increased in the same order. qPCR analysis indicated that the levels of expression of oncogenic signaling-related factors varied among these four cell lines, and the values for fibronectin and a key regulator of mitochondrial biogenesis, PGC-1α, were prominently elevated in cultures of the worst malignant Mesimo cells. In addition, although 0.25% trypsin-induced destruction was comparable among all four 2D cultured cells, the values for the 3D spheroids were also substantially varied among these cultures. The findings reported herein indicate that cellular metabolic functions and 3D spheroid architectures may be valuable and useful indicators for estimating the pathological and drug-sensitive aspects of OSCC and OASC malignancies.
Intravascular papillary endothelial hyperplasia is an unusual benign lesion of vascular origin. A 56-year-old man presented with a mass in the right side of the lower lip. Before visiting our ...hospital, he had undergone 3 surgical procedures for recurrence of the mass in a short period of time. Clinical examination revealed a painless, soft, elastic, dark purple obscure mass measuring 17 × 11 mm in the right lower lip. Ultrasonography and magnetic resonance imaging suggested a hemangioma-like lesion. The possibility of malignant transformation could not be ruled out because of the clinical course up to that point, even though it had been histopathologically diagnosed as hemangioma. The lesion was surgically resected and the defect was reconstructed using a vermilion advancement flap combined with a V-Y advancement flap. The histopathological diagnosis was intravascular papillary endothelial hyperplasia. The patient has had no symptoms or any evidence of recurrence in the 4 years since the operation. His postoperative progress has been favorable both functionally and aesthetically.
Background
Aberrant Notch signaling pathway has been related with the tumorigenesis in head and neck region, involving oral cavity. Here, we report the correlation between mutations in the Notch ...signaling pathway and CD8+ T‐cell infiltration via PD‐L1, which lead to enhanced antitumor immunity and may target for immune‐checkpoint inhibitors (ICIs) therapy.
Methods
This retrospective study analyzed the results of immunohistochemical staining for PD‐L1 and CD8+ T‐cell infiltration in 10 patients and whole‐exome sequencing (WES) was conducted on five of these patients to identify frequently mutated genes.
Results
Four of 10 patients were positive for PD‐L1 and CD8+ T. By analyzing WES in three of these four patients, we notably identified the mutations of NOTCH1, FBXW7, and noncoding RNA intronic mutation in NOTCH2NLR in two of these three patients. This study may enable better selection of ICI therapy with CD8+ T‐cell infiltration via PD‐L1 expression for oral squamous cell carcinoma patients with mutations in Notch signaling pathway.
Cholesterol embolism is a condition in which the atheroma in a large vessel wall collapses and cholesterol crystals leak into the bloodstream, causing periphery embolization, which may be caused by ...catheterization or cardiovascular surgery. In this paper, we describe a case of cholesterol embolism after superselective intra-arterial chemotherapy. The patient was an 81-year-old man with right oral-floor carcinoma （T2N1M0, stage Ⅲ）. Since the patient strongly desired to preserve organ function, he underwent a total of four superselective intra-arterial chemotherapy courses by the Seldinger method combined with radiotherapy （66Gy）. Before the fifth superselective intra-arterial chemotherapy course, right toe pain, purple-red spots, and sudden renal function decrease （serum Cr level; 1.92mg/dl, eGFR level; 26.9ml/min） were observed, and a histopathological diagnosis of cholesterol embolism was obtained from the tissue biopsy performed at the department of dermatology. Oral administration of steroids and prostacyclin preparations improved the right toe pain; however, renal function did not improve. After completing steroid therapy, the patient was followed up in the outpatient clinic. After 3 months, cervical lymph node resurgence was observed, and systemic drug therapy was initiated. After 10 months, the patient died of pneumonia. Reportedly, the Seldinger method causes cerebral infarction in approximately 1％ of cases. Conversely, cholesterol embolism, although extremely rare, is a disease with a poor prognosis and high probability of transitioning to hemodialysis. It is suggested that the disease should be fully considered when selecting treatment options.
Background/Aim: The role of tumour-infiltrating CD45Ro+ T-cells in oral squamous cell carcinoma (OSCC) is unclear. This study aimed to evaluate prognostic biomarkers for OSCC. Patients and Methods: ...We determined the density of tumour-infiltrating CD45Ro+ T cells in the parenchyma and stroma at the tumour centre (TCe) and invasive front (IF) and examined the association between the density of these cells and histopathological status in 142 patients. Results: Five-year overall survival (OS) and recurrence-free survival were favourable in patients with high CD45Ro+ T-cell density in the TCe stroma. OS was favourable in patients with high CD45Ro+ T-cell density in the IF stroma. Stepwise Cox regression model analysis indicated that CD45Ro+ T-cells in the stroma of the IF and TCe were an independent prognostic factor for OS. Conclusion: CD45Ro+ T-cells in the stroma of the IF and TCe play a role in cancer immune surveillance and may be a useful prognostic factor.
The mortality rate of oral cancer has not improved over the past three decades despite remarkable advances in cancer therapies. Oral cancers contain a subpopulation of cancer stem cells (CSCs) that ...share characteristics associated with normal stem cells, including self‐renewal and multi‐differentiation potential. CSCs are tumorigenic, play a critical role in cancer infiltration, recurrence, and distant metastasis, and significantly contribute to drug resistance to current therapeutic strategies, including immunotherapy. Cytotoxic CD8+ T lymphocytes (CTLs) are key immune cells that effectively recognize peptide antigens presented by the major histocompatibility complex class I molecules. Increasing evidence suggests that cancer antigen‐specific targeting by CTLs effectively regulates CSCs that drive cancer progression. In this study, we utilized data from public domains and performed various bioassays on human oral squamous cell carcinoma clinical samples and cell lines, including HSC‐2 and HSC‐3, to investigate the potential role of olfactory receptor family 7 subfamily C member 1 (OR7C1), a seven transmembrane G‐protein‐coupled olfactory receptor that is also expressed in nonolfactory tissues and was previously reported as a novel marker and target of colon cancer initiating cell‐targeted immunotherapy, in CSC‐targeted treatment against oral cancer. We found that the OR7C1 gene was expressed only in oral CSCs, and that CTLs reacted with human leukocyte antigen‐A24‐restricted OR7C1 oral CSC‐specific peptides. Taken together, our findings suggest that OR7C1 represents a novel target for potent CSC‐targeted immunotherapy in oral cancer.
OR7C1 was found to be preferentially expressed in oral cancer stem cells (CSCs). OR7C1‐specific cytotoxic CD8+ T lymphocyte (CTL) clones could recognize HLA‐A24+ and OR7C1+ oral cancer cells and specifically lyse oral CSCs. The results indicate that OR7C1 is a reasonable candidate for treatment‐resistant CSC.
Background/Aim: The tumor microenvironment (TME) balances tumor growth and suppression through humoral factors and cell-cell interactions. In oral squamous cell carcinoma (OSCC), TMEs have been ...associated with prognosis of cancer patients and are evaluated by microscopy; however, these methods of evaluation vary among studies. Materials and Methods: To evaluate the TME, borderline microenvironment fibrosis (bMF) was evaluated histologically in 236 OSCC cases and used to determine the clinicopathological status. Results: bMF was observed in 47% (110 in 236 cases) of OSCC cases and associated with higher T category, N category, stage, histological grade and mode of invasion. bMF-positive was related to overall survival (OS) and progression-free survival (PFS). Multivariate analysis revealed that bMF-positive was an independent factor for OS in all cases n=226; HR=1.683 (1.018–2.781); p=0.042, especially in T1+T2 cases n=186; HR=1.926 (1.079–3.440); p=0.024, and PFS in all cases n=226; HR=2.254 (1.397–3.637); p=0.001. Conclusion: bMF may act as a novel biomarker for OSCC.
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