Head and neck squamous cell carcinoma: Genomics and emerging biomarkers for immunomodulatory cancer treatments

Solomon, Benjamin; Young, Richard J.; Rischin, Danny

doi:10.1016/j.semcancer.2018.01.008

Cited by 366 publications

(287 citation statements)

References 101 publications

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“…By contrast, HNSCC samples presented with IDO1 but only on a small fraction of tumorinfiltrating lymphocytes (Figure 2). Although not analyzed systematically, the only HPV positive case in this small cohort showed highest IDO1 abundance, nicely reflecting the tumors' immunogenicity (11,37). Using five individual GBM cell lines, IDO1 expression was inducible in all cases ( Figure 3A).…”

Section: Basal Ido1 and Related Genes In Gbm And Hnscc Cell Linesmentioning

confidence: 80%

“…IDO1 activity inhibits T-cell activation and proliferation and even mediates regulatory T-cell recruitment to the tumor microenvironment, provoking local immune tolerance. In head and neck squamous cell carcinomas (HNSCCs), IDO1 inversely correlates with programmed cell death protein ligand 1, which constitutes an important prognostic biomarker for immune-checkpoint inhibition (11). The increased IDO1 activation decreases intratumoral TRP levels, resulting in tumor starvation and increase in kynurenine (KYN) metabolites (which are toxic to lymphocytes) (12).…”

Section: Introductionmentioning

confidence: 99%

“…In the KP, most studies focused on IDO1 because this molecule is amenable to pharmacological intervention (19)(20)(21)(22), and a couple of specific and global IDO inhibitors [including natural compounds (17,23,24)] already entered clinical trials, mostly reporting safe application and efficacy (stable disease at best outcome) (25). Current trials are evaluating the efficacy of IDO1 inhibitors in combination with chemotherapy, radiotherapy, and other immunotherapies including cytotoxic T-lymphocyteassociated protein 4 blockade (11,22). The latter is based on the observation of an enhanced lytic ability of tumor-antigenspecific T cells upon IDO1 inhibition and decreased numbers of local immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells (20,26).…”

Section: Introductionmentioning

confidence: 99%

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Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

et al. 2020

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Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2) are the key enzymes of tryptophan (TRP) metabolism in the kynurenine pathway (KP). Both enzymes function as indicators of immunosuppression and poor survival in cancer patients. Direct or indirect targeting of either of these substances seems thus reasonable to improve therapy options for patients. In this study, glioblastoma multiforme (GBM) as well as head and neck squamous cell carcinomas (HNSCC) were examined because of their different mechanisms of spontaneous and treatment-induced immune escape. Effects on gene expression and protein levels were examined. Accompanying assessment of TRP metabolites from treated GBM cell culture supernatants was conducted. Our results show a heterogeneous and inversely correlated expression profile of TRP-metabolizing genes among GBM and HNSCC cells, with low, but inducible IDO1 expression upon IFNγ treatment. TDO2 expression was higher in GBM cells, while genes encoding kynurenine aminotransferases were mainly confined to HNSCC cells. These data indicate that the KP is active in both entities, with however different enzymes involved in TRP catabolism. Upon treatment with Temozolomide, the standard of care for GBM patients, IDO1 was upregulated. Comparable, although less pronounced effects were seen in HNSCC upon Cetuximab and conventional drugs (i.e., 5-fluorouracil, Gemcitabine). Here, IDO1 and additional genes of the KP (KYAT1, KYAT2, and KMO) were induced. Vice versa, the novel yet experimental cyclin-dependent kinase inhibitor Dinaciclib suppressed KP in both entities. Our comprehensive data imply inhibition of the TRP catabolism by Dinaciclib, while conventional chemotherapeutics tend to activate this pathway. These data point to limitations of conventional therapy and highlight the potential of targeted therapies to interfere with the cells' metabolism more than anticipated.

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Section: Basal Ido1 and Related Genes In Gbm And Hnscc Cell Linesmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

et al. 2020

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“…SCCHN represents a heterogeneous group of tumors arising from the squamous epithelium of the oral cavity, oropharynx, larynx, and hypopharynx. Despite being grouped as a single cancer type, distinct clinical, biological features and response to treatment have been seen between tumors from different subsites . To characterize the immune microenvironment in SCCOT, the most common SCCHN subtype, we used transcriptome data analysis to estimate immune cell fractions and evaluated cytolytic activity according to mRNA levels of GZMA and PFR1 .…”

Section: Introductionmentioning

confidence: 99%

High immune cytolytic activity in tumor‐free tongue tissue confers better prognosis in patients with squamous cell carcinoma of the oral tongue

Boldrup

Coates

et al. 2019

The Journal of Pathology CR

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Immune cells and cytolytic activity within the tumor microenvironment are being intensively studied. Through transcriptome profiling, immune cell enumeration using the xCell tool and cytolytic activity quantification according to granzyme A (GZMA) and perforin (PRF1) mRNA levels, we investigated immunoreactivity in tumor and/or tumor‐free tongue tissue samples from 31 patients with squamous cell carcinoma of the oral tongue and 14 healthy individuals (control tongue tissues). We found significantly altered immune cell compositions (p < 0.001) and elevated cytolytic activity (p < 0.001) in tumor compared to tumor‐free samples, and altered infiltration of a subset of immune cells (e.g. CD8+ T cells, p < 0.01) as well as increased cytolytic activity (p < 0.001) in tumor‐free compared to control samples. Controlling for patient age at diagnosis and tumor stage, Cox regression analysis showed that high cytolytic activity in tumor‐free samples associated with improved disease‐free survival (hazard ratio= 4.20, 95% CI = 1.09–16.20, p = 0.037). However, the degree of cytolytic activity in tumor samples did not provide prognostic information. Taken together, our results show the presence of cancer‐related immune responses in clinically tumor‐free tongue in patients with squamous cell carcinoma of the oral tongue. Measuring cytolytic activity in tumor‐free tongue samples contralateral to tumor might thus be an effective approach to predict clinical outcome.

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“…However, it was expressed in some PD‐L1 negative cases . In OSCC, systematic assessment of PD‐L2 expression is missing …”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of PD‐L2 expression in patients with oral squamous cell carcinoma—A comparison to the PD‐L1 expression profile

et al. 2019

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Background Despite the observed association of increased PD‐L1 expression in peripheral blood of oral squamous cell carcinoma (OSCC) patients with histomorphologic parameters, the role of the PD1 ligands—PD‐L1 and PD‐L2—is insufficiently understood. Aim of the study was to investigate whether the alterations of PD‐L1 and PD‐L2 expression in blood are associated with survival and could serve as immune monitoring parameter. Moreover, it should be analyzed if PD‐L2 is differentially expressed in tissue and blood samples of OSCC patients compared to healthy controls and if there is an association of PD‐L2 expression with histomorphologic and prognostic tumor parameters. Methods PD‐L2 mRNA expression was analyzed in tumors and healthy oral mucosa specimens and in corresponding peripheral blood samples of 48 OSCC patients and 26 healthy controls using RT‐qPCR. A cutoff point (COP) was determined and a chi‐square test (χ2 test) was carried out. Survival analysis of PD‐L2 and previously reported PD‐L1 expression data was performed using Kaplan‐Meier analysis (Log‐rank test). Results PD‐L2 expression in tissue samples was significantly (P < 0.001) higher in OSCC patients compared to healthy controls. A significant association of PD‐L2 expression above the COP (positive) with malignancy was ascertained (P < 0.001). A significant (P = 0.01) association of previously reported PD‐L1 expression rates in peripheral blood with survival could be shown. Conclusion Peripheral blood PD‐L1 expression might be a prognostic marker for OSCC patients and a possible parameter to monitor immune dysfunction in malign diseases. In the peripheral blood, PD‐L1 might be more relevant for immune tolerance than PD‐L2. Local PD‐L2 expression in tissue samples might be useful as a diagnostic parameter for malignancy and could contribute to the immunosuppressive local microenvironment in OSCC.

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Head and neck squamous cell carcinoma: Genomics and emerging biomarkers for immunomodulatory cancer treatments

Cited by 366 publications

References 101 publications

Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

High immune cytolytic activity in tumor‐free tongue tissue confers better prognosis in patients with squamous cell carcinoma of the oral tongue

Prognostic significance of PD‐L2 expression in patients with oral squamous cell carcinoma—A comparison to the PD‐L1 expression profile

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