RESUMO
Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.
Assuntos
Antineoplásicos , Neoplasias de Cabeça e Pescoço , Adenosina/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Modelos Animais de Doenças , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Imunoterapia , Camundongos , Fosfatidilinositol 3-Quinases , Quinolinas/uso terapêutico , Linfócitos T ReguladoresRESUMO
BACKGROUND: The immune peptidome of OPSCC has not previously been studied. Cancer-antigen specific vaccination may improve clinical outcome and efficacy of immune checkpoint inhibitors such as PD1/PD-L1 antibodies. METHODS: Mapping of the OPSCC HLA ligandome was performed by mass spectrometry (MS) based analysis of naturally presented HLA ligands isolated from tumour tissue samples (n = 40) using immunoaffinity purification. The cohort included 22 HPV-positive (primarily HPV-16) and 18 HPV-negative samples. A benign reference dataset comprised of the HLA ligandomes of benign haematological and tissue datasets was used to identify tumour-associated antigens. RESULTS: MS analysis led to the identification of naturally HLA-presented peptides in OPSCC tumour tissue. In total, 22,769 peptides from 9485 source proteins were detected on HLA class I. For HLA class II, 15,203 peptides from 4634 source proteins were discovered. By comparative profiling against the benign HLA ligandomic datasets, 29 OPSCC-associated HLA class I ligands covering 11 different HLA allotypes and nine HLA class II ligands were selected to create a peptide warehouse. CONCLUSION: Tumour-associated peptides are HLA-presented on the cell surfaces of OPSCCs. The established warehouse of OPSCC-associated peptides can be used for downstream immunogenicity testing and peptide-based immunotherapy in (semi)personalised strategies.
Assuntos
Antígenos HLA , Neoplasias Otorrinolaringológicas , Infecções por Papillomavirus , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Infecções por Papillomavirus/imunologia , Peptídeos/imunologia , Vacinação , Neoplasias Otorrinolaringológicas/imunologia , Antígenos HLA/imunologia , Antígenos de Neoplasias/imunologia , Papillomavirus Humano 16 , Papillomavirus Humano 18RESUMO
Immunotherapeutic agents are nowadays established for treatment of a wide variety of tumor entities, including squamous cell carcinoma of the head and neck region. Originally used in the palliative setting, these are increasingly administered with curative intent, e.g., as neoadjuvant treatment. Current research addresses the questions of which patients benefit from the treatment and which combination therapies are successful. The present article summarizes relevant findings of the two international cancer congresses in 2022.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Humanos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Imunoterapia , Carcinoma de Células Escamosas/terapia , Fatores Imunológicos/uso terapêutico , Terapia CombinadaRESUMO
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of cancers and patients have limited therapy options if primary treatment fails. Therefore, additional information about the biology of the tumor is essential. Here we performed a feasibility study of concurrently applying two precision diagnostic tools in a consecutive series of HNSCC patients. We analyzed tumor samples of 31 patients using a genomic (oncomine) and a proteomic, immunohistochemical approach (oncopanel) and compared the result, also in the focus on their overlapping therapeutical targets. We found no strong correlation between the two approaches and observed a higher proportion of marker expression for the immunohistochemical panel. However, both panels show in our HNSCC cohort distinct patterns with druggable targets. The data suggest that both approaches complement one another and can be applied side-by-side to identify the best targets for the development of individual treatment options for HNSCC patients.
Assuntos
Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Proteômica , GenômicaRESUMO
Demographically, the German population is aging and becoming more morbid. At the same time, urbanization trends, medical overcapacities, and increasing care costs are being observed in association with a tight healthcare budget. Centralization, specialization, and outpatient care are intended to provide a remedy and can be controlled by modifications to remuneration. This upheaval poses new challenges for patients and physicians, which were analyzed exemplarily at the Head and Neck Tumor (HNC) Center of the University Hospital Ulm. This is a retrospective, monocentric cohort study on the development of patient volume, catchment area, treatment modality, and demographics including 2070 HNC patients at the ENT clinic between the years 2011 and 2020. It was observed that the number (new diagnoses 2011: 134 vs. 2020: 204) and the average age (2011: 61.5 years vs. 2020: 65.8 years; p < 0.0001) of HNC patients increased over time. In addition, patients tended to travel longer distances (2011: 54.4 km vs. 2020: 64.4 km; p = 0.05). At the same time, the mean number of consultations and treatments per patient per 5-year follow-up interval grew (at initial diagnosis in 2011: 7.8 vs. 2016: 10.4; p = 0.0003), with the proportion of outpatient contacts increasing from 58.9 % to 62.4 % (p = 0.09) from 2011 to 2020. Accordingly, clinical centers are expected to become more important in the care of HNC patients as the healthcare system becomes more specialized, and centralized with a growing outpatient setting. The following consequences for patient care should be considered in restructuring strategies.
Assuntos
Neoplasias de Cabeça e Pescoço , Especialização , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Estudos de Coortes , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/terapia , Assistência AmbulatorialRESUMO
Programmed-death-1 (PD1) antibodies are approved for recurrent and metastatic head and neck squamous cell carcinoma. Multiple drugs targeting costimulatory and coinhibitory immune checkpoint molecules (ICM) have been discovered. However, it remains unknown how these ICM are affected by curative conventional therapy on different immune cell subsets during the course of treatment. In the prospective noninterventional clinical study titled "Immune Response Evaluation to Curative conventional Therapy" (NCT03053661), 22 patients were prospectively enrolled. Blood samples were drawn at defined time points throughout curative conventional treatment and follow-up. Immune cells (IC) from the different time points were assessed by multicolor flow cytometry. The following ICM were measured by flow cytometry: PD1, CTLA4, BTLA, CD137, CD27, GITR, OX40, LAG3 and TIM3. Dynamics of ICM expression were assessed using nonparametric paired samples tests. Significant changes were noted for PD1, BTLA and CD27 on multiple IC types during or after radiotherapy. Nonsignificant trends for increased expression of OX40 and GITR from baseline until the end of RT were observed on CD4 T cells and CD4+ CD39+ T cells. In patients with samples at recurrence of disease, a nonsignificant increase of TIM3 and LAG3 positive CD4+ CD39+ T cells was evident, accompanied by an increase of double positive cells for TIM3/LAG3. Potential future targets to be combined with RT in the conventional treatment and anti-PD1/PD-L could be BTLA agonists, or agonistic antibodies to costimulatory ICM like CD137, OX40 or GITR. The combination of cetuximab with CD27 agonistic antibodies enhancing ADCC or the targeting of TIM3/LAG3 may be another promising strategy.
Assuntos
Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Proteínas de Checkpoint Imunológico/metabolismo , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/metabolismo , Subpopulações de Linfócitos T/metabolismo , Idoso , Antígeno CTLA-4/metabolismo , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/metabolismo , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Estudos ProspectivosRESUMO
Cytokines and immune mediators play an important role in the communication between immune cells guiding their response to infectious diseases or cancer. In this study, a comprehensive longitudinal analysis of serum cytokines and immune mediators in head and neck squamous cell carcinoma (HNSCC) patients was performed. In a prospective, non-interventional, longitudinal study, blood samples from 22 HNSCC patients were taken at defined time points (TP) before, during, and every 3 months after completion of (chemo)radio)therapy (CRT/RT) until 12 months after treatment. Serum concentrations of 17 cytokines/immune mediators and High-Mobility-Group-Protein B1 (HMGB1) were measured by fluorescent bead array and ELISA. Concentrations of sFas were significantly elevated during and after CRT/RT, whereas perforin levels were significantly decreased after CRT/RT. Levels of MIP-1ß and Granzyme B differed significantly during CRT/RT by HPV status. Increased HMGB1 levels were observed at recurrence, accompanied by high levels of IL-4 and IL-10. The sFas increase and simultaneous perforin decrease may indicate an impaired immune cell function during adjuvant radiotherapy. Increased levels of pro-inflammatory cytokines in HPV+ compared to HPV- patients seem to reflect the elevated immunogenicity of HPV-positive tumors. High levels of HMGB1 and anti-inflammatory cytokines at recurrence may be interpreted as a sign of immune evasion.
Assuntos
Citocinas/sangue , Neoplasias de Cabeça e Pescoço/virologia , Infecções por Papillomavirus/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Idoso , Quimiorradioterapia , Feminino , Granzimas/sangue , Proteína HMGB1/sangue , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Perforina/sangue , Estudos Prospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Receptor fas/sangueRESUMO
PURPOSE: To establish a chordoma tissue cohort (n = 43) and to correlate localization, size, metastasis, residual disease (R-status), recurrences, histological subtype, matrix content, and Ki-67 proliferation index with patients' overall survival (OS). METHODS AND RESULTS: We used routine histopathology supplemented by immunohistochemistry. In our patient cohort (median age 69 years, range 17 to 84 years) the median OS was 8.25 years. 24 chordomas were localized in the sacrum, 6 in lumbar vertebrae, 7 in thoracic and cervical vertebrae, 5 were limited to the clivus, and one was localized in the nasal septum. Ten patients had metastases, with pulmonary, nodal, and hepatic involvement. 23 patients had recurrent disease. 23 chordomas were classified as 'not otherwise specified' (NOS). Besides NOS, we found the following differentiation patterns: renal cell cancer like in six cases, chondroid in four cases, hepatoid differentiation in three cases, and anaplastic morphology in six cases. Ki-67 index of ≥10 %, presence of metastasis, and the low content of extracellular matrix were statistically linked to poor OS (p < 0.05). The matrix-poor phenotype had a higher Ki-67 index (p < 0.05). Furthermore, presence of metastasis was associated with a higher Ki-67 index in the primary lesion, a positive resection margin, and multiple recurrences (p < 0.05 each). CONCLUSION: We propose to include these parameters in the final pathologic report of the resected chordoma.
Assuntos
Cordoma , Neoplasias da Coluna Vertebral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cordoma/diagnóstico por imagem , Cordoma/epidemiologia , Cordoma/mortalidade , Cordoma/patologia , Humanos , Antígeno Ki-67/sangue , Pessoa de Meia-Idade , Metástase Neoplásica , Fenótipo , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/epidemiologia , Neoplasias da Coluna Vertebral/mortalidade , Neoplasias da Coluna Vertebral/patologia , Coluna Vertebral/diagnóstico por imagem , Adulto JovemRESUMO
PURPOSE: High numbers of tumor-infiltrating lymphocytes (TIL) are linked to better survival in patients with cancer. Tissue-resident memory T cells (TRM; CD8+CD103+) are recognized as a key player of anticancer immune response. To assess TRM cells in primary, metastatic, and recurrent head and neck squamous cell carcinoma (HNSCC), we developed a tissue microarray (TMA) and used multiplex IHC (MxIHC). EXPERIMENTAL DESIGN: Samples from primary tumors of 379 HNSCC cases treated at Southampton Hospitals between 2000 and 2016 were collected and analyzed. Of these, 105 cases had lymph node metastases and 82 recurrences. A TMA was generated with triplicate cores for each sample. MxIHC with a stain-and-strip approach was performed using CD8, CD103, and TIM3. Scanned slides were analyzed (digital image analysis) and quality checked (QC). RESULTS: After QC, 194 primary tumors, 76 lymph node metastases, and 65 recurrences were evaluable. Alcohol consumption was statistically significantly correlated with a reduction of TRM cells in primary tumors (nondrinker vs. heavy drinker: P = 0.0036). The known survival benefit of TRM cell infiltration in primary tumors was not found for lymph node metastasis. In recurrences, a high TRM cell number led to a favorable outcome after 12 months. The checkpoint molecule TIM3, was expressed significantly higher on TRM and non-TRM cells in the lymph node compared with primary tumors (P < 0.0001), which was also seen in recurrences (P = 0.0134 and P = 0.0007, respectively). CONCLUSIONS: We confirm the prognostic impact of TIL in primary tumors and in recurrences. TRM cell density in lymph node metastases was not linked to outcome. The role of TIM3, as a therapeutic target remains to be defined.
Assuntos
Neoplasias de Cabeça e Pescoço , Segunda Neoplasia Primária , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Células T de Memória , Metástase Linfática , Receptor Celular 2 do Vírus da Hepatite A , Memória Imunológica , Recidiva Local de Neoplasia , Linfócitos T CD8-Positivos , Linfócitos do Interstício TumoralRESUMO
Patients with oropharyngeal squamous cell carcinoma (OPSCC) caused by human papilloma virus (HPV) exhibit a better prognosis than those with HPV-negative OPSCC. This study investigated the distinct molecular pathways that delineate HPV-negative from HPV-positive OPSCC to identify biologically relevant therapeutic targets. Bulk mRNA from 23 HPV-negative and 39 HPV-positive OPSCC tumors (n = 62) was sequenced to uncover the transcriptomic profiles. Differential expression followed by gene set enrichment analysis was performed to outline the top enriched biological process in the HPV-negative compared with HPV-positive entity. INHBA, the highest overexpressed gene in the HPV-negative tumor, was knocked down. Functional assays (migration, proliferation, cell death, stemness) were conducted to confirm the target's oncogenic role. Correlation analyses to reveal its impact on the tumor microenvironment were performed. We revealed that epithelial-to-mesenchymal transition (EMT) is the most enriched process in HPV-negative compared with HPV-positive OPSCC, with INHBA (inhibin beta A subunit) being the top upregulated gene. INHBA knockdown downregulated the expression of EMT transcription factors and attenuated migration, proliferation, stemness, and cell death resistance of OPSCC cells. We uncovered that INHBA associates with a pro-tumor microenvironment by negatively correlating with antitumor CD8+ T and B cells while positively correlating with pro-tumor M1 macrophages. We identified three miRNAs that are putatively involved in repressing INHBA expression. Our results indicate that the upregulation of INHBA is tumor-promoting. We propose INHBA as an attractive therapeutic target for the treatment of INHBA-enriched tumors in patients with HPV-negative OPSCC to ameliorate prognosis. SIGNIFICANCE: Patients with HPV-negative OPSCC have a poorer prognosis due to distinct molecular pathways. This study reveals significant transcriptomic differences between HPV-negative and HPV-positive OPSCC, identifying INHBA as a key upregulated gene in HPV-negative OPSCC's oncogenic pathways. INHBA is crucial in promoting EMT, cell proliferation, and an immunosuppressive tumor environment, suggesting its potential as a therapeutic target for HPV-negative OPSCC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Subunidades beta de Inibinas , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/complicações , Neoplasias Orofaríngeas/genética , Infecções por Papillomavirus/genética , Carcinoma de Células Escamosas/genética , Processos Neoplásicos , Neoplasias de Cabeça e Pescoço/complicações , Microambiente Tumoral/genéticaRESUMO
Introduction: The human leukocyte antigen complex (HLA) is essential for inducing specific immune responses to cancer by presenting tumor-associated peptides (TAP) to T cells. Overexpressed tumor associated antigens, mainly cancer-testis antigens (CTA), are outlined as essential targets for immunotherapy in oropharyngeal squamous cell carcinoma (OPSCC). This study assessed the degree to which presentation, gene expression, and antibody response (AR) of TAP, mainly CTA, are correlated in OPSCC patients to evaluate their potential as immunotherapy targets. Materials and methods: Snap-frozen tumor (NLigand/RNA=40), healthy mucosa (NRNA=6), and healthy tonsils (NLigand=5) samples were obtained. RNA-Seq was performed using Illumina HiSeq 2500/NovaSeq 6000 and whole exome sequencing (WES) utilizing NextSeq500. HLA ligands were isolated from tumor tissue using immunoaffinity purification, UHPLC, and analyzed by tandem MS. Antibodies were measured in serum (NAb=27) utilizing the KREX™ CT262 protein array. Data analysis focused on 312 proteins (KREX™ CT262 panel + overexpressed self-proteins). Results: 183 and 94 of HLA class I and II TAP were identified by comparative profiling with healthy tonsils. Genes from 26 TAP were overexpressed in tumors compared to healthy mucosa (LFC>1; FDR<0.05). Low concordance (r=0.25; p<0.0001) was found between upregulated mRNA and class I TAP. The specific mode of correlation of TAP was found to be dependent on clinical parameters. A lack of correlation was observed both between mRNA and class II TAP, as well as between class II tumor-unique TAP (TAP-U) presentation and antibody response (AR) levels. Discussion: This study demonstrates that focusing exclusively on gene transcript levels fails to capture the full extent of TAP presentation in OPSCC. Furthermore, our findings reveal that although CTA are presented at relatively low levels, a few CTA TAP-U show potential as targets for immunotherapy.
Assuntos
Antígenos de Neoplasias , Neoplasias Orofaríngeas , Humanos , Neoplasias Orofaríngeas/imunologia , Neoplasias Orofaríngeas/genética , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/genética , Masculino , Feminino , Pessoa de Meia-Idade , Apresentação de Antígeno/imunologia , Idoso , Regulação Neoplásica da Expressão Gênica , Formação de Anticorpos/genética , Formação de Anticorpos/imunologia , Adulto , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Sequenciamento do Exoma , MultiômicaRESUMO
Junctional adhesion molecule-like protein (JAML) serves as a co-stimulatory molecule in γδ T cells. While it has recently been described as a cancer immunotherapy target in mice, its potential to cause toxicity, specific mode of action with regard to its cellular targets, and whether it can be targeted in humans remain unknown. Here, we show that JAML is induced by T cell receptor engagement, reveal that this induction is linked to cis-regulatory interactions between the CD3D and JAML gene loci. When compared with other immunotherapy targets plagued by low target specificity and end-organ toxicity, we find JAML to be mostly restricted to and highly expressed by tissue-resident memory CD8+ T cells in multiple cancer types. By delineating the key cellular targets and functional consequences of agonistic anti-JAML therapy in a murine melanoma model, we show its specific mode of action and the reason for its synergistic effects with anti-PD-1.
Assuntos
Moléculas de Adesão Celular , Neoplasias , Humanos , Animais , Camundongos , Moléculas de Adesão Juncional , Moléculas de Adesão Celular/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Imunoterapia , Linfócitos do Interstício Tumoral/metabolismoRESUMO
BACKGROUND: Demographic development in rural and urban areas differs substantially. Demographics and access to specialized head and neck cancer centers may affect head and neck cancer patients' (HNCP) outcomes. Here, we compare epidemiological indicators and outcomes of HNCP in rural and urban Germany. PATIENTS AND METHODS: In a retrospective analysis of data from the Center for Cancer Registry Data (ZfKD) between 2002 and 2017, 212,920 HNCP were included. Incidence, demographics, travel distance to specialized centers, and ground values were compared between rural and urban areas with a focus on their association with patient outcomes. RESULTS: The mean age of HNCP was significantly higher in urban areas (mean difference = 1.4 years; p < 0.0001), but increased at a comparable rate (p = 0.26) in rural and urban areas during the observation period. Gender imbalance was higher in rural areas (mean ratio of men/women: 4.1 vs. 3.1; p < 0.0001), but showed a comparable trend toward equilibration in both, rural and urban districts (p = 0.46). The portion of HNCP of the entire HNCP population living in urban areas increased from 55.9% in the year 2002 to 76.4% in the year 2017. There was no significant difference or change in the ratio of advanced to low UICC stage during the observation period (p = 0.26). However, travel distances to medical centers were higher in rural areas, especially (p < 0.0001) in East Germany. Median survival of HNCP in rural areas was significantly lower than in urban areas (42 months [SEM = 0.7; CI: 40.5-43.5] vs. 54 months [SEM = 1.2; CI: 51.7-56.3]; p < 0.0001) in East Germany, whereas in West Germany no significant difference was observed (59 months [SEM = 0.8; CI: 57.4-60.6] vs. 60 months [SEM = 0.5; CI: 59.0-61.0]; p = 0.15). CONCLUSIONS: Place of residence contributes to survival outcome of HNCP. Access to specialized care and socioeconomic factors could be improved in East Germany.
RESUMO
INTRODUCTION: Demographics are important prognostic factors in malignant diseases. A nationwide analysis concerning the prognostic impact of demographics in head and neck cancer (HNC) patients (HNCP) has not been performed previously. METHODS: A retrospective analysis of data from the Center for Cancer Registry Data (ZfKD) and the Federal Statistical Office (Destatis) between 2002 and 2017 was performed. A total of 212'920 HNCP were included. Incidence, tumor stage, age development, sex distribution, age-, residence-, and diagnosis-time-specific survival were examined. RESULTS: Mean age of HNCP increased more rapidly than in the general population (slope coefficient: 0.29 vs. 0.20; p < 0.0001). Higher age and male sex were associated with a worse prognosis. Whereas overall survival (OS) increased from the early to the later observation period for HNCP <70 years, no OS improvement for HNCP >70 years was found. Furthermore, an OS disadvantage was observed for East Germany compared to West Germany (median 47 vs. 60 months; p < 0.0001). This disparity was associated with a disproportionately high ratio of men in East Germany (men/women: 4.4 vs. 3.1; p < 0.0001) and a lower mean age (61 vs. 63 years; p < 0.0001). In addition to stage, age and sex, residence in East Germany were confirmed as an independent factor for OS in a multivariate analysis. CONCLUSION: Finally, three decades after the German reunion, a survival disadvantage for patients in East Germany still exists. This discrepancy may be a result of socioeconomic disparities.
Assuntos
Neoplasias de Cabeça e Pescoço , Humanos , Masculino , Feminino , Estudos Retrospectivos , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/terapia , Alemanha/epidemiologia , Prognóstico , Distribuição por SexoRESUMO
Chemoradiotherapy (CRT) is a standard treatment for advanced head and neck squamous cell carcinoma (HNSCC). Unfortunately, not all patients respond to this therapy and require further treatment, either salvage surgery or palliative therapy. The addition of immunotherapy to CRT is currently being investigated and early results describe a mixed response. Therefore, it is important to understand the impact of CRT on the tumor microenvironment (TME) to be able to interpret the results of the clinical trials. Paired biopsies from 30 HNSCC patients were collected before and three months after completion of primary CRT and interrogated for the expression of 1392 immune- and cancer-related genes. There was a relevant difference in the number of differentially expressed genes between the total cohort and patients with residual disease. Genes involved in T cell activation showed significantly reduced expression in these tumors after therapy. Furthermore, gene enrichment for several T cell subsets confirmed this observation. The analysis of tissue resident memory T cells (TRM) did not show a clear association with impaired response to therapy. CRT seems to lead to a loss of T cells in patients with incomplete response that needs to be reversed. It is not clear whether the addition of anti-PD-1 antibodies alone to CRT can prevent treatment failure, as no upregulation of the targets was measurable in the TME.
RESUMO
BACKGROUND: Cancer is characterized by an accumulation of somatic mutations, of which a significant subset can generate cancer-specific neoepitopes that are recognized by autologous T cells. Such neoepitopes are emerging as important targets for cancer immunotherapy, including personalized cancer vaccination strategies. METHODS: We used whole-exome and RNA sequencing analysis to identify potential neoantigens for a patient with non-small cell lung cancer. Thereafter, we assessed the autologous T-cell reactivity to the candidate neoantigens using a long peptide approach in a cultured interferon gamma ELISpot and tracked the neoantigen-specific T-cells in the tumor by T-cell receptor (TCR) sequencing. In parallel, identified gene variants were incorporated into a Modified Vaccinia Ankara-based vaccine, which was evaluated in the human leucocyte antigen A*0201 transgenic mouse model (HHD). RESULTS: Sequencing revealed a tumor with a low mutational burden: 2219 sequence variants were identified from the primary tumor, of which 23 were expressed in the transcriptome, involving 18 gene products. We could demonstrate spontaneous T-cell responses to 5/18 (28%) mutated gene variants, and further analysis of the TCR repertoire of neoantigen-specific CD4+ and CD8+ T cells revealed TCR clonotypes that were expanded in both blood and tumor tissue. Following vaccination of HHD mice, de novo T-cell responses were generated to 4/18 (22%) mutated gene variants; T cells reactive against two variants were also evident in the autologous setting. Subsequently, we determined the major histocompatibility complex restriction of the T-cell responses and used in silico prediction tools to determine the likely neoepitopes. CONCLUSIONS: Our study demonstrates the feasibility of efficiently identifying tumor-specific neoantigens that can be targeted by vaccination in tumors with a low mutational burden, promising successful clinical exploitation, with trials currently underway.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Antígenos de Neoplasias/genética , Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Camundongos , VacinaçãoRESUMO
BACKGROUND: Primary platinum-based chemoradiotherapy (CRT) remains the treatment of choice for nonresectable squamous cell carcinoma of the head and neck (HNSCC). Immune-checkpoint modulators are used as palliative therapy and studied in combination with definitive CRT. However, the immunological changes by CRT need yet to be understood. METHODS: A cohort consisting of 67 paired tissue biopsies (N = 134) of HNSCC patients before and after CRT was created. The expression of PD-1, PD-L1, and CD27 of tumor and immune cells by immunohistochemistry was evaluated. RESULTS: PD-L1 expression on immune cells of non-responders was significantly lower before CRT (P = .008). CD27 was expressed only on immune cells and not on cancer cells. A significant lower CD27-expression score was observed following CRT (P = .019). CONCLUSIONS: Conventional CRT changes the expression of CD27 in the tumor microenvironment. Whether this is due to a loss of expression or a reduction of CD27+ cells must be evaluated in further analyses.
Assuntos
Quimiorradioterapia , Neoplasias de Cabeça e Pescoço , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Imuno-Histoquímica , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Microambiente TumoralRESUMO
BACKGROUND: The impact of demographic change on the age at diagnosis in German head and neck cancer (HNC) patients is unclear. Here we present an evaluation of aging trends in HNC at a tertiary referral center. METHODS: Retrospective cohort study on aging trends at the initial diagnosis of newly diagnosed patients with HNC between 2004 and 2018 at the head and neck cancer center Ulm in relation to demographic data of the catchment area. RESULTS: The study population consisted of 2450 individuals diagnosed with HNC with a mean age of 62.84 (±11.67) years. We observed a significant increase in annual incidence rates and mean age over time. Mean age among HNC patients increased significantly more than among the population in the catchment area. Whereas the incidence rate of patients <50 years did not change, the incidence of HNC patients aged ≥70 years increased the most. The mean patient age in the main tumor sites increased significantly. Surprisingly, HPV-positive patients were not younger than HPV-negative patients, but showed a non-significant trend towards a higher mean age (63.0 vs. 60.7 years). CONCLUSIONS: Increasing incidence rates in older patients pose a challenge for health care systems. A nationwide study is needed to assess the dynamics and impact of aging on the incidence of HNC.
RESUMO
Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignant tumours typically caused by alcohol and tobacco consumption, although an increasing number of HNSCC arise due to persistent infection with high-risk human papilloma virus (HPV). The treatment of HNSCC remains challenging, and the first-line setting is focused on surgery and chemoradiotherapy. A substantial proportion of HNSCC patients die from their disease, especially those with recurrent and metastatic disease. Among factors linked with good outcome, immune cell infiltration appears to have a major role. HPV-driven HNSCC are often T-cell rich, reflecting the presence of HPV antigens that are immunogenic. Tumour-associated antigens that are shared between patients or that are unique to an individual person may also induce varying degrees of immune response; studying these is important for the understanding of the interaction between the host immune system and the cancer. The resulting knowledge is critical for the design of better immunotherapies. Key questions are: Which antigens lead to an adaptive immune response in the tumour? Which of these are exploitable for immunotherapy? Here, we review the current thinking regarding tumour antigens in HNSCC and what has been learned from early phase clinical trials.
Assuntos
Antígenos Virais de Tumores/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Papillomaviridae/imunologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Linfócitos T/imunologiaRESUMO
INTRODUCTION: Human papillomavirus 16 (HPV16) is the main cause of oropharyngeal squamous cell carcinoma (OPSCC). To date, the links between HPV16 gene expression and adaptive immune responses have not been investigated. We evaluated the correlation of HPV16 DNA, RNA transcripts and features of adaptive immune response by evaluating antibody isotypes against E2, E7 antigens and density of tumor-infiltrating lymphocytes (TIL). MATERIAL AND METHODS: FFPE-tissue from 27/77 p16-positive OPSCC patients was available. DNA and RNA were extracted and quantified using qPCR for all HPV16 genes. The TIL status was assessed. Immune responses against E2 and E7 were quantified by ELISA (IgG, IgA, and IgM; 77 serum samples pre-treatment, 36 matched post-treatment). RESULTS: Amounts of HPV16 genes were highly correlated at DNA and RNA levels. RNA co-expression of all genes was detected in 37% (7/19). E7 qPCR results were correlated with higher anti-E7 antibody (IgG, IgA) level in the blood. Patients with high anti-E2 IgG antibody (>median) had better overall survival (p=0.0311); anti-E2 and anti-E7 IgA levels had no detectable effect. During the first 6 months after treatment, IgA but not IgG increased significantly, and >6 months both antibody classes declined over time. Patients with immune cell-rich tumors had higher levels of circulating antibodies against HPV antigens. CONCLUSION: We describe an HPV16 qPCR assay to quantify genomic and transcriptomic expression and correlate this with serum antibody levels against HPV16 oncoproteins. Understanding DNA/RNA expression, relationship to the antibody response in patients regarding treatment and outcome offers an attractive tool to improve patient care.