Background Despite the importance of immune checkpoints in immunotherapy, the prognostic value of these molecules remains controversial in oral squamous cell carcinoma (OSCC). We performed a systematic review to investigate the prognostic significance of the immune checkpoints in OSCC. Materials A systematic search was conducted in Ovid Medline, Scopus and Cochrane libraries, and all studies that evaluated the prognostic significance of immune checkpoints in OSCC were systematically retrieved. Results Twelve immune checkpoints/modulators were studied for their prognostic values in OSCC patients between 1985 and 2017. Seven immune checkpoints (FKBP51, B7‐H4, B7‐H6, ALHD1, PD‐L1, B7‐H3 and IDO1) were reported to be associated with poor patients’ survival in at least one study, and five (CTLA‐4, TLT‐2, VISTA, PD‐L2 and PD‐1) did not have a significant prognostic value. PD‐L1 results were controversial as it was reported to be associated with both better and worse patients’ survival. Conclusions Even though immune checkpoint markers had high expectation for OSCC prognostication, our systematic review revealed that the majority of them had been studied only once. The other molecules, which had been studied more than once, had controversial findings, except B7‐H3.
Extracellular mast cell-derived IL-17F is antitumorigenic in oral tongue SCC. It separates patients with early-stage disease who are at high risk from patients who are at low risk. Furthermore, when analyzing tentative prognostic molecules, we conclude that in addition to the staining intensity, attention must be paid to the cellular source, distribution, and location of the molecule.
Immune checkpoint molecules IDO1 and PD-L1 are modulated during oral epithelial dysplastic changes, and their expression is associated with inflammatory cell infiltration in the lamina propria. As immune checkpoint molecules expression fluctuates over time, these molecules are not useful as biomarkers for oral mucosal dysplasia progression.
BackgroundImmune checkpoint inhibitors (ICIs), primarily anti-PD-1, are currently used to treat patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, only a minority of patients benefit from these costly therapies. Therefore, there is an unmet need to better understand the effect of ICIs on immune effector cells. This study aimed to investigate the effect of a PD-1 antibody and an IDO1 inhibitor on different lymphocyte populations (NK, CD4+, and CD8+ T cells) in term of migration, cytotoxicity, and cytokine release in the presence of HNSCC cells.MethodsUsing a microfluidic chip, we injected HSC-3 cells (an oral tongue squamous cell carcinoma cell line) embedded in a human tumor-derived matrix “myogel/fibrin” together with NK, CD4+, and CD8+ T cells in separate channels. The two channels were connected with microchannels. The PD-1 antibody nivolumab and IDO1 inhibitor epacadostat were added to the microfluidic chips. Lymphocyte migration and cytotoxicity were examined under fluorescent microscopy and cytokine release was measured using a FirePlex Human Discovery Cytokines Immunoassay.ResultsEpacadostat significantly increased the migration and infiltration of NK and CD4+ T cells, but not CD8+ T cells, towards the cancer cells. Nivolumab did not exhibit a similar effect. While CD8+ T cells alone showed near to no migration, adding CD4+ T cells enhanced migration towards the cancer cells. There was a mild nonsignificant increase in apoptosis of HSC-3 cells after adding epacadostat to lymphocytes. In contrast, HSC-3 proliferation was not affected by lymphocytes regardless of ICIs. Nivolumab significantly increased release of MIP1-α, IL-6, and IL-8 from NK, CD4+, and CD8+ T cells, respectively.ConclusionsThis study revealed that each subpopulation of lymphocytes respond differently to ICIs. We also revealed the subpopulation of lymphocytes responsible for the increases in specific serum cytokines after ICI treatment.
Tongue squamous cell carcinoma (TSCC) has a poor prognosis due to its early metastasis through blood and lymphatic vessels. We undertook a systematic review to investigate the prognostic significance of blood microvessel density (MVD) and lymphatic vessel density (LVD) in TSCC patients. We carried out a systematic search in Ovid Medline, Scopus, and Cochrane libraries. All studies that evaluated the prognostic significance of MVD/LVD markers in TSCC were systematically retrieved. Our results showed that MVD/LVD markers, CD31, CD34, CD105, factor VIII, lymphatic vessel endothelial hyaluronan receptor‐1, and D2‐40 were evaluated in TSCC patients until 28 June 2018. Six out of 13 studies reported markers that were associated with poor prognosis in TSCC. Two out of three studies suggested that a high number of D2‐40+ vessels predicated low overall survival (OS); the third study reported that the ratio of D2‐40+ over factor VIII+ vessels is associated with low OS. Most of the other markers had controversial results for prognostication. We found higher expression of MVD/LVD markers were commonly, but not always, associated with shorter survival in TSCC patients. It is therefore not currently possible to recommend implementation of these markers as reliable prognosticators in clinical practice. More studies (especially for D2‐40) with larger patient cohorts are needed.
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