RESUMEN
OBJECTIVES: Previous studies have demonstrated that obesity may impact the efficacy of anti-PD1 therapy, but the underlying mechanism remains unclear. In this study, our objective was to determine the prognostic value of obesity in patients with oral tongue squamous cell carcinoma (OTSCC) treated with pembrolizumab and establish a subtype based on fatty acid metabolism-related genes (FAMRGs) for immunotherapy. MATERIALS AND METHODS: We enrolled a total of 56 patients with OTSCC who underwent neoadjuvant anti-PD1 therapy. Univariate and multivariate Cox regression analyses, Kaplan-Meier survival analysis, and immunohistochemistry staining were performed. Additionally, we acquired the gene expression profiles of pan-cancer samples and conducted GSEA and KEGG pathway analysis. Moreover, data from TCGA, MSigDB, UALCAN, GEPIA and TIMER were utilized to construct the FAMRGs subtype. RESULTS: Our findings indicate that high Body Mass Index (BMI) was significantly associated with improved PFS (HR = 0.015; 95% CI, 0.001 to 0.477; p = 0.015), potentially attributed to increased infiltration of PD1 + T cells. A total of 91 differentially expressed FAMRGs were identified between the response and non-response groups in pan-cancer patients treated with immunotherapy. Of these, 6 hub FAMRGs (ACSL5, PLA2G2D, PROCA1, IL4I1, UBE2L6 and PSME1) were found to affect PD-1 expression and T cell infiltration in HNSCC, which may impact the efficacy of anti-PD1 therapy. CONCLUSION: This study demonstrates that obesity serves as a robust prognostic predictor for patients with OTSCC undergoing neoadjuvant anti-PD1 therapy. Furthermore, the expression of 6 hub FAMRGs (ACSL5, PLA2G2D, PROCA1, IL4I1, UBE2L6 and PSME1) plays a pivotal role in the context of anti-PD1 therapy and deserves further investigation.
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Inhibidores de Puntos de Control Inmunológico , Terapia Neoadyuvante , Obesidad , Neoplasias de la Lengua , Humanos , Neoplasias de la Lengua/tratamiento farmacológico , Neoplasias de la Lengua/metabolismo , Neoplasias de la Lengua/inmunología , Neoplasias de la Lengua/patología , Neoplasias de la Lengua/mortalidad , Neoplasias de la Lengua/genética , Femenino , Masculino , Terapia Neoadyuvante/métodos , Obesidad/metabolismo , Obesidad/complicaciones , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Pronóstico , Anciano , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Anticuerpos Monoclonales Humanizados/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Adulto , Índice de Masa Corporal , Biomarcadores de Tumor/metabolismoRESUMEN
BACKGROUND: Tongue squamous cell carcinoma (TSCC) is characterized by aggressive invasion and poor prognosis. Currently, immune checkpoint inhibitors may prolong overall survival compared with conventional treatments. However, PD1/PDL1 remain inapplicable in predicting the prognosis of TSCC; thus, it is urgent to explore the genetic characteristics of TSCC. MATERIALS AND METHODS: We utilized single-sample gene set enrichment analysis (ssGSEA) to classify TSCC patients from the TCGA database into clusters with different immune cell infiltrations. ESTIMATE (immune-related scores) and CIBERSORT (immune cell distribution) analyses were used to evaluate the immune landscape among clusters. GO, KEGG, and GSEA analyses were performed to analyze the different underlying molecular mechanisms in the clusters. Based on the immune characteristics, we applied the LASSO Cox regression to select hub genes and construct a prognostic risk model. Finally, we established an interactive network among these hub genes by using Cytoscape, and a pan-cancer analysis to further verify and decipher the innate function of these genes. RESULTS: Using ssGSEA, we constructed three functional clusters with different overall survival and immune-cell infiltration. ESTIMATE and CIBERSORT analyses revealed the different distributions of immune cells (T cells, B cells, and macrophages) with diverse immune-related scores (ESTIMATE, immune, stromal, and tumor purity scores). Moreover, pathways including those of the interferon-gamma response, hypoxia, and glycolysis of the different subtypes were investigated to elucidate their involvement in mediating the heterogeneous immune characteristics. Subsequently, after LASSO Cox regression, a signature of 15 immune-related genes was established that is more prognostically effective than the TNM stage. Furthermore, three hub genes-PGK1, GPI, and RPE-were selected using Cytoscape evaluation and verified by immunohistochemistry. PGK1, the foremost regulator, was a comprehensively profiled pan-cancer, and a PGK1-based interactive network was established. CONCLUSION: Our results suggest that immune-related genes and clusters in TSCC have the potential to guide individualized treatments.
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Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/inmunología , Neoplasias de la Lengua/genética , Neoplasias de la Lengua/inmunología , Algoritmos , Biomarcadores de Tumor/genética , Bases de Datos Genéticas , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Pronóstico , Análisis de Supervivencia , Microambiente Tumoral/inmunologíaRESUMEN
Despite the many successes and opportunities presented by PD-1 blockade in cancer therapies, anti-PD-1 monoclonal antibodies still face multiple challenges. Herein we report a strategy based on a nanobody (Nb) to circumvent these obstacles. A new PD-1-blocking Nb (PD-1 Nb20) in combination with tumor-specific dendritic cell (DC)/tumor-fusion cell (FC) vaccine that aims to improve the activation, proliferation, cytokine secretion, and tumor cell cytotoxicity of CD8+ T-cells. This combination was found to effectively enhance the in vitro cytotoxicity of CD8+ T-cells to kill human non-small cell lung cancer (NSCLC) HCC827 cells, hepatocellular carcinoma (HCC) HepG2 cells, and tongue squamous cell carcinoma (TSCC) Tca8113 cells. Moreover, CD8+ T-cells pre-treated with PD-1 Nb20 and tumor-specific DC/tumor-FCs significantly suppressed the growth of NSCLC-, HCC- and TSCC-derived xenograft tumors and prolonged the survival of tumor-bearing mice, through promoting T-cell infiltration to kill tumor cells and inhibiting tumor angiogenesis. These data demonstrate that PD-1 Nb20 in synergy with DC/tumor-FC vaccine augment the broad spectrum of antitumor activity of CD8+ T-cells, providing an alternative and promising immunotherapeutic strategy for tumor patients who are T-cell-dysfunctional or not sensitive to anti-PD-1 therapy.
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Vacunas contra el Cáncer/farmacología , Células Dendríticas/trasplante , Receptor de Muerte Celular Programada 1/inmunología , Anticuerpos de Dominio Único/farmacología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Células Hep G2 , Xenoinjertos , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Ratones , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anticuerpos de Dominio Único/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Neoplasias de la Lengua/tratamiento farmacológico , Neoplasias de la Lengua/genética , Neoplasias de la Lengua/inmunología , Neoplasias de la Lengua/patologíaRESUMEN
Increasing clinical evidence indicates that Th17 cells may promote or inhibit tumor progression, however the exact role of these cells in Oral Squamous Cell Carcinoma (OSCCs) pathogenesis and progression remains unclear. Tumor associated macrophages are highly plastic phenotype cells which can differentiate as M1 or M2. The mechanism and cellular phenotype of IL-17 expressing macrophages are unknown. 40 cases of lip and 28 of tongue SCCs were submitted to immunohistochemical analysis, and histologically graded. In tongue cases TNM was analyzed. The number of IL-17+ T cells was higher in lip SCC (p = 0.028). IL-17+ macrophages was greater in tongue SCC (p = 0.014). There were more IL-17+ macrophages in the high-grade malignancy oral tongue SCCs (p = 0.016), yet there was no significant difference in the numbers of RORγt+ lymphocytes by histopathological or TNM analysis. This study provides evidence concerning IL-17's pleiotropic roles, being possibly dependent on its cellular sources in the tumor microenvironment.
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Interleucina-17/inmunología , Neoplasias de los Labios , Linfocitos Infiltrantes de Tumor , Proteínas de Neoplasias/inmunología , Células Th17 , Neoplasias de la Lengua , Macrófagos Asociados a Tumores , Femenino , Humanos , Neoplasias de los Labios/inmunología , Neoplasias de los Labios/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Masculino , Células Th17/inmunología , Células Th17/patología , Neoplasias de la Lengua/inmunología , Neoplasias de la Lengua/patología , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/patologíaRESUMEN
BACKGROUND: Host immune microenvironment is a key component of anti-tumoral immune response, influencing tumor progression, regression, and treatment responses. There is a need for simple and reliable histologic measurements of host immune response in routine histopathologic diagnosis. METHODS: The prognostic value of lymphocytic host response (LHR), a qualitative histologic grading scheme, was compared to stromal/intratumoral TIL (sTIL/iTIL) percentage, a quantitative measurement in a retrospective study of 329 patients with oral tongue squamous cell carcinoma (OTSCC) of 4 cm or less in size. RESULTS: High sTIL predicted improved distant recurrence free survival on univariate survival analysis and was an independent prognostic factor for better overall survival on multivariate analysis. LHR and iTIL were not associated with the risk of nodal metastasis or outcome. CONCLUSIONS: sTIL appears to be a superior quantitative histologic measurement for the host immune microenvironment compared with the qualitative LHR grading scheme. sTIL is an independent prognostic factor for overall survival in OTSCC.
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Linfocitos Infiltrantes de Tumor , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Neoplasias de la Lengua/inmunología , Microambiente Tumoral/inmunología , Humanos , Pronóstico , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neoplasias de la Lengua/patologíaRESUMEN
OBJECTIVES/HYPOTHESIS: Occult lymph metastasis is an important prognosticator for the treatment of early oral tongue squamous cell carcinoma (SCC). The objective of this study was to evaluate the prognostic significance of tumor-infiltrating lymphocytes (TILs) in early oral tongue SCC. The combination of the TIL subtype and intermediate- or high-grade budding scores was investigated as a prognostic marker for occult neck metastases. STUDY DESIGN: Retrospective study. METHODS: Specimens from 62 patients with early oral tongue SCC treated with only primary surgery were analyzed by immunohistochemistry for CD4+, CD8+, FoxP3+, and CD45RO+ T cells and CD163+ macrophages. The highest number of each TIL subtype was counted in two areas of parenchyma and stroma in the tumor (Tumor) and peripheral stroma of the invasion margin. RESULTS: Based on multivariate analysis, a high density of Tumor CD163+ macrophages served as the poorest prognostic factor for regional control (RC) and disease-free survival (DFS). Patients with both a high density of Tumor CD163+ macrophages and an intermediate- or a high-grade budding score had a poor prognosis for RC according to the log-rank test. CONCLUSIONS: In summary, each TIL subtype may use different mechanisms during early and advanced stages of oral tongue SCC. A high density of Tumor CD163+ macrophages was determined to be a risk factor for RC and DFS as well as an additional stratification factor for RC in patients with intermediate- or high-grade budding scores. Therefore, identifying TIL subtypes in daily clinical practice can help determine a more successful and individualized therapeutic approach for early oral tongue SCC. LEVEL OF EVIDENCE: Step 4 (Level 4) Laryngoscope, 131:2512-2518, 2021.
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Neoplasias de Cabeza y Cuello/mortalidad , Linfocitos Infiltrantes de Tumor/inmunología , Recurrencia Local de Neoplasia/epidemiología , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Neoplasias de la Lengua/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Metástasis Linfática/inmunología , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/cirugía , Lengua/inmunología , Lengua/patología , Lengua/cirugía , Neoplasias de la Lengua/diagnóstico , Neoplasias de la Lengua/inmunología , Neoplasias de la Lengua/cirugía , Microambiente Tumoral/inmunologíaAsunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Nivolumab/efectos adversos , Paclitaxel/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Terapia Recuperativa , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de la Lengua/tratamiento farmacológico , Adulto , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/inmunología , Enfermedad de Hashimoto/inducido químicamente , Enfermedad de Hashimoto/inmunología , Humanos , Masculino , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Inducción de Remisión , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/secundario , Factores de Tiempo , Neoplasias de la Lengua/inmunología , Neoplasias de la Lengua/metabolismo , Neoplasias de la Lengua/patología , Insuficiencia del TratamientoRESUMEN
B7-H3 was the only molecule identified with prognostic potential from a recent systematic review of the prognostic value of immune checkpoints in oral cancer. We aimed to validate this finding in a multicenter international cohort. We retrospectively retrieved 323 oral tongue squamous cell carcinoma (OTSCC) samples from three different countries (Brazil, Finland, and Norway) for immunostaining and scoring for B7-H3. We evaluated tumor immunogenicity by analyzing the amount of tumor-infiltrating lymphocytes and divided the tumors into immune hot and cold. To increase the reliability of the results, both digital and manual visual scoring were used. Survival curves were constructed based on the Kaplan-Meier method, and the Cox proportional hazard model was utilized for univariate and multivariate survival analysis. B7-H3 expression was not significantly associated with overall or disease-specific survival in the whole OTSCC cohort. When divided into immune hot and cold tumors, high B7-H3 expression was significantly associated with poor disease-specific and overall survival in the immune hot group, depending on the scoring method and the country of the cohort. This was achieved only in the univariate analysis. In conclusion, B7-H3 was a negative prognosticator for OTSCC patient survival in the subgroup of immune hot tumors, and was not validated as a prognosticator in the full cohort. Our findings suggest that the immune activity of the tumor should be considered when testing immune checkpoints as biomarkers.
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Antígenos B7/metabolismo , Biomarcadores de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neoplasias de la Lengua/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos B7/análisis , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Neoplasias de la Lengua/inmunología , Adulto JovenRESUMEN
PURPOSE: Immune checkpoint proteins programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are important therapeutic targets for head and neck cancer. This large-scale case study aimed to analyze tongue squamous cell carcinomas (SCCs) and evaluate the correlation between PD-L1 expression and clinical prognosis. So far, this study is the largest case study on PD-L1 expression in tongue SCCs. METHODS: This is a case-control study that analyzed 121 tongue SCCs. Paraffin-embedded sections and clinical data were obtained retrospectively and immunohistochemistry with PD-L1 was performed. RESULTS: 11.6% contained ≥ 50% of PD-L1-positive cells, 57.1% of these cases had a poor prognosis with nodal metastasis. Among cases of T1/2 primary lesions with nodal metastasis, cases of high PD-L1 expression had a significantly shorter disease-free survival than cases of no PD-L1 expression (p = 0.018). The hazard ratio for high PD-L1 expression was 3.21 (95 per cent CI, 1.26-8.72) compared with no PD-L1 expression after adjusting for other factors. CONCLUSIONS: These data indicate that PD-L1 upregulation in tongue SCCs is associated with a more advanced stage and shorter disease-free survival. PD-1/PD-L1 inhibitors might hence constitute potential adjuvant therapy for tongue SCCs with PD-L1 upregulation.
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Antígeno B7-H1/metabolismo , Recurrencia Local de Neoplasia/epidemiología , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Neoplasias de la Lengua/mortalidad , Lengua/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/análisis , Antígeno B7-H1/antagonistas & inhibidores , Quimioterapia Adyuvante/métodos , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Lengua/cirugía , Neoplasias de la Lengua/diagnóstico , Neoplasias de la Lengua/inmunología , Neoplasias de la Lengua/terapia , Regulación hacia Arriba/inmunología , Adulto JovenRESUMEN
The tumor immune microenvironment of oral tongue squamous cell carcinoma may be accountable for differences in clinical behavior, particularly between different age groups. We performed RNA expression profiling and evaluated tumor infiltrating lymphocytes (TILs) and their T-cell subsets in order to assess the functional status of oral tongue squamous cell carcinoma tumor microenvironment and detect potentially clinically useful associations. Archival surgical pathology material from sixteen oral tongue squamous cell carcinoma patients was microscopically evaluated for TIL densities. RNA was extracted from macrodissected whole tumor sections and normal controls and RNA expression profiling was performed by the NanoString PanCancer IO 360 Gene Expression Panel. Immunostains for CD4, CD8 and FOXP3 were evaluated manually and by digital image analysis. Oral tongue squamous cell carcinomas had increased TIL densities, numerically dominated by CD4 + T cells, followed by CD8 + and FOXP3 + T cells. RNA expression profiling of tumors versus normal controls showed tumor signature upregulation in inhibitory immune signaling (CTLA4, TIGIT and PD-L2), followed by inhibitory tumor mechanisms (IDO1, TGF-ß, B7-H3 and PD-L1). Patients older than 44 years showed a tumor microenvironment with increased Tregs and CTLA4 expression. Immunohistochemically assessed CD8% correlated well with molecular signatures related to CD8 + cytotoxic T-cell functions. FOXP3% correlated significantly with CTLA4 upregulation. CTLA4 molecular signature could be predicted by FOXP3% assessed by immunohistochemistry (R2 = 0.619, p = 0.026). Oral tongue squamous cell carcinoma hosts a complex inhibitory immune microenvironment, partially reflected in immunohistochemically quantified CD8 + and FOXP3 + T-cell subsets. Immunohistochemistry can be a useful screening tool for detecting tumors with upregulated expression of the targetable molecule CTLA4.
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Linfocitos Infiltrantes de Tumor/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Neoplasias de la Lengua/inmunología , Microambiente Tumoral/inmunología , Adulto , Anciano , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neoplasias de la Lengua/patología , TranscriptomaRESUMEN
BACKGROUND: Nivolumab has been associated with immune-related adverse events, including nephritis, with acute interstitial nephritis being the most commonly reported renal manifestation. CASE: We describe the first case to our knowledge of minimal change disease with nephrotic syndrome associated with the PD-1 checkpoint inhibitor, Nivolumab. Minimal change disease has been reported with other immune checkpoint inhibitors; however, this is the first reported case with Nivolumab. We report development of nephrotic syndrome with acute kidney injury in a 57-year-old man, 1 month after commencement of Nivolumab for metastatic squamous cell carcinoma of the tongue. Minimal change disease was confirmed by renal biopsy. Management with corticosteroids and cessation of Nivolumab failed to improve kidney function or nephrosis. CONCLUSION: This case adds to current literature identifying minimal change as an additional complication of immune checkpoint inhibitor-associated acute kidney injury. Given the increasing use of immune checkpoint inhibitors for a range of malignancies, nephrologists, oncologist and generalists should be aware of the spectrum of kidney pathologies associated with their use.
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Autoinmunidad/efectos de los fármacos , Nefrosis Lipoidea/diagnóstico , Nivolumab/efectos adversos , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Neoplasias de la Lengua/terapia , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Resultado Fatal , Humanos , Masculino , Persona de Mediana Edad , Nefrosis Lipoidea/inducido químicamente , Nefrosis Lipoidea/inmunología , Cuidados Paliativos/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/secundario , Neoplasias de la Lengua/inmunología , Neoplasias de la Lengua/patologíaRESUMEN
BACKGROUND: In patients with squamous cell carcinoma of the oral tongue (OTSCC), current tumor node metastasis staging system fails to identify at-risk patients associated with early relapse and poor prognosis despite complete surgical resection. Given the importance of tumor-infiltrating lymphocytes (TILs) in the development of cancers, here we investigated the prognostic significance of the immune phenotype in OTSCC. METHODS: Hematoxylin-eosin stained sections of OTSCCs from 211 patients were evaluated. Cancers were classified as (a) immune-inflamed when TILs were found next to tumor cell nests; (b) immune-excluded when TILs were found in the stroma, outside the tumor; and (c) immune-desert for tumors lacking lymphocyte infiltrate. The prognostic significance of these immune phenotypes classes was investigated. Data were further validated on an independent cohort from The Cancer Genome Atlas database. RESULTS: Immune-desert phenotype was the least represented group of OTSCCs in our cohort (11.8%) and served as an independent prognostic factor. Patients with immune-desert tumors exhibited worse disease-specific survival (HR = 2.673; [CI: 95% 1.497-4.773]; P = .001), overall survival (HR = 2.591; [CI: 95% 1.468-4.572]; P = .001), and disease-free survival (HR = 2.313; [CI: 95% 1.118-4.786]; P = .024) at multivariate analysis. CONCLUSIONS: We identified a specific subgroup of OTSCCs with poor prognosis. Tumor-infiltrating lymphocytes density and localization could serve as an integrative parameter to the current staging system and inform the selection of most appropriate treatments. In particular, the tumor immune phenotype could improve the stratification of patients with more aggressive disease.
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Linfocitos Infiltrantes de Tumor/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Neoplasias de la Lengua/inmunología , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Fenotipo , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/cirugía , Factores de Tiempo , Neoplasias de la Lengua/mortalidad , Neoplasias de la Lengua/cirugía , Microambiente TumoralRESUMEN
OBJECTIVE: To determine the tumor genomic, immunologic expression, and risk factors of treatment outcomes for patients with double head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC). METHODS: We reviewed patients with double HNSCC and ESCC between 1995 and 2014. The TP53 genomic mutation, CD8+ tumor infiltrating lymphocytes (TIL) and tumor programmed cell death ligand 1 (PD-L1) expression of paired HNSCC and ESCC were analyzed. RESULTS: A total of 116 patients (57 metachronous and 59 synchronous) were included. There were 88 (75.86%) patients with HNSCC and 80 (68.97%) with ESCC harboured TP53 disruptive mutation. Nearly 106 (91.38%) patients had different clonality of TP53 mutation in paired HNSCC and ESCC. The immunologic expression of synchronous and metachronous patients was significantly different. Compared to the metachronous patients, the synchronous patients had significantly higher HNSCC CD8+ TIL (p = 0.03), ESCC CD8+ TIL (p < 0.001), HNSCC PD-L1+ tumor proportion score (TPS, p = 0.04), and ESCC PD-L1+ TPS (p = 0.04). Furthermore, among the synchronous patients, the immunologic expression between HNSCC and ESCC was significantly correlated. The CD8+ TIL and PD-L1 TPS had strongly (r = 0.63, p < 0.0001) and moderately (r = 0.42, p = 0.001) positive correlations, respectively. Finally, advanced stage (III/IV) HNSCC was a significant factor for disease-free (p = 0.03) and overall survival (p = 0.005). CONCLUSION: In patients with double HNSCC and ESCC, nearly all HNSCC and ESCC were of multicentric origin. For the synchronous patients, there was more adaptive immune resistance in HNSCC and ESCC. The immunologic expression between paired HNSCC and ESCC was also significantly correlated.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Genes p53/genética , Neoplasias de Cabeza y Cuello , Mutación/genética , Neoplasias Primarias Múltiples , Carcinoma de Células Escamosas de Cabeza y Cuello , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/citología , Supervivencia sin Enfermedad , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/mortalidad , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/inmunología , Carcinoma de Células Escamosas de Esófago/mortalidad , Femenino , Técnicas de Genotipaje , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Neoplasias Hipofaríngeas/genética , Neoplasias Hipofaríngeas/inmunología , Inmunidad Celular , Linfocitos Infiltrantes de Tumor/citología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/mortalidad , Fenotipo , Estudios Retrospectivos , Factores de Riesgo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Neoplasias de la Lengua/genética , Neoplasias de la Lengua/inmunología , Resultado del TratamientoRESUMEN
We wanted to evaluate the prognostic value of common histopathological variables in a large cohort of patients with cancer in the mobile tongue as such information can be important for treatment stratification of the individual patient, especially for patients with low-stage disease. In addition, we wanted to investigate whether an alternative scoring model with fewer options would compromise the prognostic value. One hundred fifty patients with oral tongue squamous cell carcinomas that were treated in curative intent and with available HE-stained tumor sections were included. We reclassified all tumors and performed univariate and multivariate survival analyses of histopathological and clinical variables. For the complete cohort, lymph node status, grade of differentiation, perineural infiltration, and lymphocytic infiltration were independent prognosticators. In the low-stage disease group, independent prognostic factors were tumor size, grade of differentiation, and lymphocytic infiltrate. For patients with low-stage disease, a histo-score combining the scores for tumor differentiation and lymphocytic infiltrate identified a group of patients with particularly low survival, as patients with moderately or poorly differentiated tumors and little lymphocytic infiltrate had a less favorable 5-year survival outcome than patients in the high-stage disease group. This study shows that a histo-score combining tumor differentiation and lymphocytic infiltration should be given special consideration in treatment planning. Our results also illustrate that many variables can be scored with fewer options than previously suggested to increase their reproducibility, and still maintain their prognostic value.
Asunto(s)
Linfocitos Infiltrantes de Tumor/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neoplasias de la Lengua/inmunología , Neoplasias de la Lengua/patología , Adulto , Anciano , Anciano de 80 o más Años , Diferenciación Celular , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Persona de Mediana Edad , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Neoplasias de la Lengua/mortalidadRESUMEN
INTRODUCTION: Several studies regarding tumor-stroma ratio (TSR) in colorectal, esophageal, breast, endometrial, and cervical carcinomas have been done in the past with significant results. OBJECTIVES: The objectives of this study were to (1) study and grade TSR in buccal mucosa and tongue squamous cell carcinoma (SCC), (2) grade inflammatory cell infiltrate surrounding the tumor, and (3) correlate the above two parameters with tumor grade, lymph node metastasis, lymphovascular invasion (LVI), and perineural invasion (PNI). MATERIALS AND METHODS: Totally, 25 patients of buccal SCC and 16 cases of tongue SCC were included in the study. TSR was assessed visually on the hematoxylin and eosin-stained tissue sections by two independent observers. Cases were categorized into two groups: One with high TSR >50% (stroma poor) and the other with low TSR <50% as the stroma-rich group. TSR was correlated with tumor size, lymph node metastasis, inflammatory cell infiltrate, LVI, and PNI. Data were analyzed by the Statistical Package for the Social Sciences version 16.0 (Chicago, IL, USA) for Windows. The Chi-square and Fischer's exact tests were applied in the analysis of categorical variable. RESULTS AND CONCLUSION: SCC of buccal mucosa showed a significant correlation between TSR and size of the tumor (P = 0.001). We found that smaller the tumor size ≤2 cm (Stage T1), lesser the TSR, and size >2 cm was found to be associated with higher TSR. Hence, higher TSR (stroma poor) was associated with an adverse pathological characteristic, i.e., advanced T significantly. There was no significant correlation between TSR and inflammatory infiltrate with grade of the tumor, lymph node metastasis, LVI, and PNI. In 16 cases of SCC of the tongue; no correlation was observed between TSR and inflammatory infiltrate with tumor size, grade of the tumor, lymph node metastasis, LVI, and PNI. TSR has been studied in various malignancies (mostly adenocarcinomas) including laryngeal SCCs; however, it has never been studied on oral SCCs.
Asunto(s)
Carcinoma de Células Escamosas/patología , Mucosa Bucal/patología , Neoplasias de la Boca/patología , Células del Estroma/patología , Neoplasias de la Lengua/patología , Lengua/patología , Adulto , Anciano , Carcinoma de Células Escamosas/inmunología , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Mucosa Bucal/inmunología , Neoplasias de la Boca/inmunología , Clasificación del Tumor , Estadificación de Neoplasias , Estudios Retrospectivos , Factores de Riesgo , Células del Estroma/inmunología , Lengua/inmunología , Neoplasias de la Lengua/inmunología , Adulto JovenRESUMEN
To discover the effect of tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) on the oral tongue squamous cell carcinoma (OTSCC) via affecting FoxP3+ regulatory T (Treg) cells. Immunohistochemistry was conducted to examine TIPE2 and FoxP3 expressions in OTSCC tumor tissues and corresponding oral mucosa. Tca8113 cells were transfected with TIPE2/control lentiviral activation particles followed by the detection with qRT-PCR, Western blotting, MTT assay, Wound healing, Transwell assay and Annexin V-FITC/PI staining. In vivo experiment was carried out on the nude mice xenografts of OTSCC with TIPE2 overexpression to observe the tumor volume and survival, and the CD4+ T cell subgroups were detected by flow cytometry. TIPE2 was lower in the OTSCC tissues than the corresponding oral mucosa, which was correlated with T stage, N stage, TNM stage, and differentiation of patients. Patients with TIPE2-positive expression had worse prognosis and lower expression of FoxP3+ Treg cells than the negative ones. Furthermore, TIPE2 overexpression curbed proliferation, invasion and migration of Tca8113 cells, while cell apoptosis was increased. Besides, TIPE2 suppressed the tumor growth and extended the survival of OTSCC mice, with the decreased proportion of FoxP3+ Treg cells in the spleen and tumor-infiltrated lymphocytes (TILs). The clinical results showed the down-regulation of TIPE2 in OTSCC tissues. Meanwhile TIPE2 overexpression affected OTSCC cells biological behavior in vitro, as well as exhibited strong tumor-growth suppressive effects in vivo, which may be a potential therapeutic target in OTSCC via regulating FoxP3+ Treg cells.
Asunto(s)
Factores de Transcripción Forkhead/inmunología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Linfocitos T Reguladores/inmunología , Neoplasias de la Lengua/inmunología , Adulto , Anciano , Animales , Apoptosis/fisiología , Carcinogénesis , Movimiento Celular/fisiología , Progresión de la Enfermedad , Femenino , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Neoplasias de la Lengua/metabolismo , Neoplasias de la Lengua/patologíaRESUMEN
We investigated whether a unique immune response was instigated with the development of oral tongue squamous cell carcinomas (OTSCC), with/without nodal involvement, with/without recurrent metastatic disease, or within tumor involved nodes. One hundred and ten formalin-fixed paraffin-embedded samples were collected from a retrospective cohort of 67 OTSCC patients and 10 non-cancerous tongue samples. Targets including CD4, CD8, FOXP3, PD-L1, and PD-1 were analyzed by immunohistochemistry. The Nanostring PanCancer Immune Profiling Panel was used for gene expression profiling. Data were externally validated in the The Cancer Genome Atlas (TCGA) head and neck (HNSCC), melanoma and lung squamous cell carcinoma (LSCC) cohorts. A 24-immune gene signature was identified that discriminated more aggressive OTSCC cases, and although not prognostic in HNSCC was associated with survival in other TCGA cohorts (improved survival for melanoma, P < .001 and worse survival for LSCC, P = .038). OTSCC exhibited concordant gene and immunohistochemical (IHC) features characterized by a TH-2 biased, proinflammatory profile with upregulated B cell and neutrophil gene activity and increased CD4, FOXP3, and PD-L1 expression (P < .001 for all by IHC). Compared to less advanced disease, nodal involvement and recurrent OTSCC did not induce a different immune response although recurrent disease was characterized by significantly higher PD-L1 expression (P = .004 by SP263, P = .013 by 22C3, P = .004 for gene expression). Identification of a gene signature associated with different prognostic effects in other cancers highlights common pathways of immune dysregulation that are impacted by the tumor origin. The significant immunosuppressive signaling in OTSCC indicates primary failure of immune system to control carcinogenesis emphasizing the need for early, combination therapeutic approaches.
Asunto(s)
Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Neoplasias de la Lengua/inmunología , Anciano , Antígeno B7-H1/análisis , Antígenos CD4/análisis , Antígenos CD8/análisis , Femenino , Factores de Transcripción Forkhead/análisis , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Ganglios Linfáticos/patología , Masculino , Melanoma/inmunología , Melanoma/mortalidad , Persona de Mediana Edad , Pronóstico , Receptor de Muerte Celular Programada 1/análisis , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Lengua/inmunología , Neoplasias de la Lengua/genética , Neoplasias de la Lengua/mortalidad , Neoplasias de la Lengua/patologíaRESUMEN
CA9 is a member of the carbonic anhydrases' family, that is often expressed in cancer cells under hypoxic condition. However, the role of CA9 in the molecular mechanisms of tongue squamous cell carcinoma (TSCC) pathogenesis remains unclear. CA9 expression was analysed using the TCGA database, and its influence on survival was performed using Kaplan-Meier, LASSO and COX regression analyses. The correlation between CA9 and immune infiltration was investigated by CIBERSORT and ESTIMATE. Moreover, the relationship between CA9 expression and downstream molecular regulation pathways was analysed by GSEA, GO and WGCNA. CA9 expression correlated with clinical prognosis and tumour grade in TSCC. Moreover, CA9 expression potentially contributes to the regulation of cancer cell differentiation and mediates tumour-associated genes and signalling pathways, including apoptosis, hypoxia, G2M checkpoint, PI3K/AKR/mTOR signalling and TGF-beta signalling pathways. However, the follicular helper T cells, regulatory T cells, immune and stromal scores showed no significance between high and low CA9 expression groups. These findings suggested that CA9 plays a critical role of TSCC prognosis and tumour grade. CA9 expression significantly correlated with the regulation of cell differentiation, various oncogenes and cancer-associated pathways.
Asunto(s)
Antígenos de Neoplasias/genética , Anhidrasa Carbónica IX/genética , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Lengua/enzimología , Neoplasias de la Lengua/genética , Transcripción Genética , Antígenos de Neoplasias/metabolismo , Anhidrasa Carbónica IX/metabolismo , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Humanos , Estimación de Kaplan-Meier , Análisis Multivariante , Clasificación del Tumor , Pronóstico , Factores de Riesgo , Neoplasias de la Lengua/inmunología , Neoplasias de la Lengua/patologíaRESUMEN
The immunological, and especially T cell, status of the tumor microenvironment affects tumor development and the efficacy of cancer treatment. To devise suitable combination therapies based on the results of murine tumor models, a more realistic orthotopic model is required. In this study, we generated a murine model of tongue squamous cell carcinoma (SCC), in which the tumor-immune cell interactions were recapitulated, and examined tumor- and T-cell status compared to a skin-transplanted SCC model by multiplex immunofluorescence staining for epidermal growth factor receptor, CD31, CD8, CD4, and Foxp3. Administration of SCCVII cells did not induce undesirable tissue damage or inflammation. In tongue SCC, abundant T-cell infiltration was observed at the tumor margin, but not in the core. Tongue SCC predominantly showed CD8+ T or Foxp3+ regulatory T cell (Treg)-infiltration. In contrast, skin-transplanted SCC showed abundant infiltration of T cells in the whole tumor area, which was dominated by Tregs. An orthotopic tongue SCC model showed differences in tumor and T-cell status compared to the skin-transplanted SCC model. Our tongue SCC model may enhance understanding of tumor-host interactions and enable evaluation of therapeutic efficacy.