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There are no effective treatment options for patients with poor performance status and limited liver reserve, classified as Child-Pugh Grade B and C. A 61-year-old man with a prior medical history of hepatitis C virus infection was admitted to the hospital with abdominal distension and significant abdominal ascites. He was diagnosed with stage IVB hepatocellular carcinoma (HCC), characterized by multiple metastases to lymph nodes, lungs, and bones. After receiving combined immune therapy, including dendritic cell therapy targeting WT1 and α-Galactosylceramide, natural killer cells, and Nivolumab, the patient showed significant improvement in HCC and liver reserve function and followed standard treatment. Combined immune therapy is potentially an important option for patients with advanced hepatocellular carcinoma and poor liver reserve function, especially for relatively young patients.
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Immune checkpoints are crucial molecules for the maintenance of antitumor immune responses. The activation or inhibition of these molecules is dependent on the interactions between receptors and ligands; such interactions can provide inhibitory or stimulatory signals to the various components of the immune system. Over the last 10 years, the inhibition of immune checkpoints, such as cytotoxic T lymphocyte antigen-4, programmed cell death-1, and programmed cell death ligand-1, has taken a leading role in immune therapy. This relatively recent therapy regime is based on the use of checkpoint inhibitors, which enhance the immune response towards various forms of cancer. For a subset of patients with specific forms of cancer, these inhibitors can induce a durable response to therapy; however, the medium response rate to such therapy remains relatively poor. Recent research activities have demonstrated that the disease response to this highly promising therapy resembles the response of many forms of cancer to chemotherapy, where an encouraging initial response is followed by acquired resistance to treatment and progress of the disease. That said, these inhibitors are now used as single agents or in combination with chemotherapies as first or second lines of treatment for about 50 types of cancer. The prevailing opinion regarding immune therapy suggests that for this approach of therapy to deliver on its promise, a number of challenges have to be circumvented. These challenges include understanding the resistance mechanisms to immune checkpoint blockade, the identification of more efficient inhibitors, extending their therapeutic benefits to a wider audience of cancer patients, better management of immune-related adverse side effects, and, more urgently the identification of biomarkers, which would help treating oncologists in the identification of patients who are likely to respond positively to the immune therapies and, last but not least, the prices of therapy which can be afforded by the highest number of patients. Numerous studies have demonstrated that understanding the interaction between these checkpoints and the immune system is essential for the development of efficient checkpoint inhibitors and improved immune therapies. In the present text, we discuss some of these checkpoints, their inhibitors, and some works in which mass spectrometry-based proteomic analyses were applied.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Proteómica , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/inmunología , Proteómica/métodos , Animales , Inmunoterapia/métodos , Proteínas de Punto de Control Inmunitario/metabolismoRESUMEN
Background: Distinct clinical features and molecular characteristics of left-sided colon cancer (LCC) and right-sided colon cancer (RCC) suggest significant variations in their tumor microenvironments (TME). These differences can impact the efficacy of immunotherapy, making it essential to investigate and understand these disparities. Methods: We conducted a multi-omics analysis, including bulk RNA sequencing (bulk RNA-seq), single-cell RNA sequencing (scRNA-seq), and whole-exome sequencing (WES), to investigate the constituents and characteristic differences of the tumor microenvironment (TME) in left-sided colon cancer (LCC) and right-sided colon cancer (RCC). Result: Deconvolution algorithms revealed significant differences in infiltrated immune cells between left-sided colon cancer (LCC) and right-sided colon cancer (RCC), including dendritic cells, neutrophils, natural killer (NK) cells, CD4 and CD8 T cells, and M1 macrophages (P < 0.05). Notably, whole-exome sequencing (WES) data analysis showed a significantly higher mutation frequency in RCC compared to LCC (82,187/162 versus 18,726/115, P < 0.01). Single-cell analysis identified predominant tumor cell subclusters in RCC characterized by heightened proliferative potential and increased expression of major histocompatibility complex class I molecules. However, the main CD8 + T cell subpopulations in RCC exhibited a highly differentiated state, marked by T cell exhaustion and recent activation, defined as tumor-specific cytotoxic T lymphocytes (CTLs). Immunofluorescence and flow cytometry results confirmed this trend. Additionally, intercellular communication analysis demonstrated a greater quantity and intensity of interactions between tumor-specific CTLs and tumor cells in RCC. Conclusion: RCC patients with an abundance of tumor-specific cytotoxic T lymphocytes (CTLs) and increased immunogenicity of tumor cells in the TME may be better candidates for immune checkpoint inhibitor therapy.
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Radiotherapy (RT) controls local lesions, meantime it has the capability to induce systemic response to inhibit distant, metastatic, non-radiated tumors, which is referred to as the "abscopal effect". It is widely recognized that radiotherapy can stimulate systemic immune response. This provides a compelling theoretical basis for the combination of immune therapy combined with radiotherapy(iRT). Indeed, this phenomenon has also been observed in clinical treatment, bringing significant clinical benefits to patients, and a series of basic studies are underway to amplify this effect. However, the molecular mechanisms of immune response induced by RT, determination of the optimal treatment regimen for iRT, and how to amplify the abscopal effect. In order to amplify and utilize this effect in clinical management, these key issues require to be well addressed; In this review, we comprehensively summarize the growing consensus and emphasize the emerging limitations of enhancing the abscopal effect with radiotherapy or immunotherapy. Finally, we discuss the prospects and barriers to the current clinical translational applications.
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BACKGROUND: Cluster of differentiation 24 (CD24) is a highly glycosylated glycosylphosphatidylinositol (GPI)-anchored surface protein, expressed in various tumor cells, as a "don't eat me" signaling molecule in tumor immune. This study aimed to investigate the potential features of CD24 in pan-cancer. METHODS: The correlations between 22 immune cells and CD24 expression were using TIMER analysis. R package "ESTIMATE" was used to predict the proportion of immune and stromal cells in pan-cancer. Spearman's correlation analysis was performed to evaluate the relationships between CD24 expression and immune checkpoints, chemokines, mismatch repair, tumor mutation burden and microsatellite instability, and qPCR and western blot were conducted to assess CD24 expression levels in liver hepatocellular carcinoma (LIHC). In addition, loss of function was performed for the biological evaluation of CD24 in LIHC. RESULTS: CD24 expression was positively correlated with myeloid cells, including neutrophils and myeloid-derived suppressor cells, in various tumors, such as BLCA, HNSC-HPV, HNSC, KICH, KIRC, KIRP, TGCT, THCA, THYM, and UCEC. In contrast, anti-tumor NK cells and NKT cells showed a negative association with CD24 expression in BRCA-Her2, ESCA, HNSC-HPV, KIRC, THCA, and THYM. The top three tumors with the highest correlation between CD24 and ImmuneScore were TGCT, THCA, and SKCM. Functional enrichment analysis revealed CD24 expression was negatively associated with various immune-related pathways. Immune checkpoints and chemokines also exhibited inverse correlations with CD24 in CESC, CHOL, COAD, ESCA, READ, TGCT, and THCA. Additionally, CD24 was overexpressed in most tumors, with high CD24 expression in BRCA, LIHC, and CESC correlating with poor prognosis. The TIDE database indicated tumors with high CD24 expression, particularly melanoma, were less responsive to PD1/PD-L1 immunotherapy. Finally, CD24 knockdown resulted in impaired proliferation and cell cycle progression in LIHC. CONCLUSION: CD24 participates in regulation of immune infiltration, influences patient prognosis and serves as a potential tumor marker.
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BACKGROUND: Prostate cancer is one of the most common cancers in men with a significant proportion of patients developing biochemical recurrence (BCR) after treatment. Programmed cell death (PCD) mechanisms are known to play critical roles in tumor progression and can potentially serve as prognostic and therapeutic biomarkers in PCa. This study aimed to develop a prognostic signature for BCR in PCa using PCD-related genes. MATERIALS AND METHODS: We conducted an analysis of 19 different modes of PCD to develop a comprehensive model. Bulk transcriptomic, single-cell transcriptomic, genomic, and clinical data were collected from multiple cohorts, including TCGA-PRAD, GSE58812, METABRIC, GSE21653, and GSE193337. We analyzed the expression and mutations of the 19 PCD modes and constructed, evaluated, and validated the model. RESULTS: Ten PCD modes were found to be associated with BCR in PCa, with specific PCD patterns exhibited by various cell components within the tumor microenvironment. Through Lasso Cox regression analysis, we established a Programmed Cell Death Index (PCDI) utilizing an 11-gene signature. High PCDI values were validated in five independent datasets and were found to be associated with an increased risk of BCR in PCa patients. Notably, older age and advanced T and N staging were associated with higher PCDI values. By combining PCDI with T staging, we constructed a nomogram with enhanced predictive performance. Additionally, high PCDI values were significantly correlated with decreased drug sensitivity, including drugs such as Docetaxel and Methotrexate. Patients with lower PCDI values demonstrated higher immunophenoscores (IPS), suggesting a potentially higher response rate to immune therapy. Furthermore, PCDI was associated with immune checkpoint genes and key components of the tumor microenvironment, including macrophages, T cells, and NK cells. Finally, clinical specimens validated the differential expression of PCDI-related PCDRGs at both the gene and protein levels. CONCLUSION: In conclusion, we developed a novel PCD-based prognostic feature that successfully predicted BCR in PCa patients and provided insights into drug sensitivity and potential response to immune therapy. These findings have significant clinical implications for the treatment of PCa.
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Objective: Immune checkpoint inhibitors (ICIs) are revolutionary in oncology but may cause immune-related (IR) side effects, such as hypophysitis. Treatment with anti-PD-(L)1, anti-CTLA-4 or anti-CLTA-4/PD-1 may induce hypophysitis, but little is known about the differences in clinical presentation or need for different treatment. We analyzed the differences of anti-PD-(L)1, anti-CTLA-4 and anti-CTLA-4/PD-1 induced hypophysitis. Methods: retrospective analysis of 67 patients (27 anti-PD-(L)1, 6 anti-CLTA-4 and 34 anti-CTLA-4/PD-1 induced hypophysitis). Results: The median time between starting ICIs and IR-hypophysitis was longer after anti-PD(L)-1) therapy (22 weeks versus 11 and 14 weeks after anti-CTLA-4 and anti-CTLA-4/PD-1 therapy, respectively). The majority of patients (>90%), presented with atypical complaints such as fatigue, nausea, and muscle complaints. Headache, TSH or LH/FSH deficiency were more common in anti-CTLA-4 and anti-CLTA-4/PD-1 versus anti-PD-(L)1 induced hypophysitis (83% and 58% versus 8%, 67% and 41% versus 11%, and 83% and 48% versus 7%, respectively). Pituitary abnormalities on MRI (hypophysitis or secondary empty sella syndrome) were only seen in patients receiving anti-CTLA-4 or anti-CTLA-4/PD-1 therapy. Recovery from TSH, LH/FSH and ACTH deficiency was described in 92%, 70% and 0% of patients after a mean period of 14 and 104 days, respectively, and did not differ between patients who did or did not receive high-dose steroids. Conclusion: The clinical presentation of IR-hypophysitis varies depending on the type of ICIs. MRI abnormalities were only seen in anti-CTLA-4 or anti-CTLA-4/PD-1 induced hypophysitis. Endocrine recovery is seen for LH/FSH and TSH deficiency but not for ACTH deficiency, irrespective of the corticosteroid dose.
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Hipofisitis , Inhibidores de Puntos de Control Inmunológico , Receptor de Muerte Celular Programada 1 , Humanos , Hipofisitis/inducido químicamente , Hipofisitis/diagnóstico por imagen , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Antígeno CTLA-4/antagonistas & inhibidores , Anciano de 80 o más Años , Antígeno B7-H1/antagonistas & inhibidores , Neoplasias/tratamiento farmacológicoRESUMEN
Immune checkpoint inhibitor-based cancer immunotherapy has shown promise as a potential treatment in the clinic. It has been reported that anti-PD-L1 combined with cisplatin treatment can improve the antitumor effect. However, the therapeutic outcome is limited due to the abundance of tumor stroma in pancreatic cancer (PC), which prevented the penetration of cisplatin and anti-PD-L1 into tumor regions, thus impeding the effectiveness in the treatment of PC. In this study, a nanocarrier-mediated codelivery system of hyaluronidase and cisplatin was constructed, which can degrade the stroma and promote cisplatin and anti-PD-L1 to penetrate the tumor stroma into the deep tumor, so as to suppress PC effectively. When combined the cisplatin nanocarrier system BPEI-SS-Pt/HAase@CaP (BSP/H@CaP) with an immune checkpoint inhibitor to overcome the poor therapeutic outcome of PC, the results indicated that the therapeutic effect of BSP/H@CaP combined with anti-PD-L1 was better than that of BSP/H@CaP and single anti-PD-L1 group. Because the stroma is degrading, a higher amount of BPEI-SS-Pt and anti-PD-L1 can enter the tumor stroma and reach the inner depths of the tumor for immune stimulation, leading to a synergistically augmented chemotherapy and immunotherapy for PC. The above combination therapy is useful for clinical translation to overcome the treatment resistance of matrix-rich PC.
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Antígeno B7-H1 , Cisplatino , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pancreáticas , Cisplatino/farmacología , Cisplatino/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/terapia , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Animales , Humanos , Ratones , Línea Celular Tumoral , Portadores de Fármacos/química , Nanopartículas , Inmunoterapia/métodos , Hialuronoglucosaminidasa , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Femenino , Ratones Endogámicos BALB CRESUMEN
Heart failure (HF) is a terminal condition of multiple cardiovascular disorders. Cancer is a deadly disease worldwide. The relationship between HF and cancer remains poorly understood. The Gene Expression Omnibus database was used to download the RNA sequencing data of 356 patients with hypertrophic cardiomyopathy-induced HF and non-HF. A co-expression network was established through the weighted correlation network analysis (WGCNA) to identify hub genes of HF and cancer. Cox risk analysis was performed to predict the prognostic risks of HF hub genes in pan-cancer. HF was linked to immune response pathway by the analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). A positive correlation was observed between the expression levels of 4 hub genes and the infiltration of CD8+T-cells in pan-cancer. 4 hub genes were identified as beneficial prognostic factors in several cancers. Western blotting and real-time polymerase chain reaction validated the high expression of GZMM, NKG7, and ZAP70 in both mice and patients with HF compared to control groups. Our study highlights the shared immune pathogenesis of HF and cancer and provides valuable insights for developing novel therapeutic strategies, offering new opportunities for improving the management and treatment outcomes of both HF and cancer.
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Linfocitos T CD8-positivos , Insuficiencia Cardíaca , Neoplasias , Humanos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Neoplasias/genética , Neoplasias/inmunología , Animales , Ratones , Insuficiencia Cardíaca/genética , Redes Reguladoras de Genes , Pronóstico , Perfilación de la Expresión Génica , Masculino , Proteína Tirosina Quinasa ZAP-70/genética , Proteína Tirosina Quinasa ZAP-70/metabolismo , Regulación Neoplásica de la Expresión Génica , FemeninoRESUMEN
Immune checkpoint inhibitor (ICI) therapies for tumors of different systems have attained significant achievements and have changed the current situation of tumor treatment due to their therapeutic characteristics of high specificity and low side effects. The immune checkpoint Programmed death 1/Programmed cell death-Ligand 1 (PD-1/PD-L1) axis exerts a vital role in the immune escape of tumor cells. As a result, it has become a key target for tumor immunotherapy. Therefore, to perfect research into potential regulatory factors for the PD-1/PD-L1 axis, in order to understand and illustrate tumor ICI therapy mechanisms, is a significant goal. Moreover, ncRNA has been verified to regulate the PD-1/PD-L1 axis in the tumor immune microenvironment to regulate tumor genesis and development. ncRNAs can improve or decrease the efficacy of ICI therapy by modulating PD-L1 expression. This review aimed to investigate the mechanisms of action of ncRNA in regulating the PD-1/PD-L1 axis in ICI therapy, to provide more efficient immunotherapy for tumors of different systems.
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Tumor-associated macrophages (TAMs) and other myelomonocytic cells are implicated in regulating responsiveness to immunotherapies, including immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis. We have developed an ex vivo high-throughput approach to discover modulators of macrophage-mediated T cell suppression, which can improve clinical outcomes of ICIs. We screened 1,430 Food and Drug Administration (FDA)-approved small-molecule drugs using a co-culture assay employing bone-marrow-derived macrophages (BMDMs) and splenic-derived T cells. This identified 57 compounds that disrupted macrophage-mediated T cell suppression. Seven compounds exerted prominent synergistic T cell expansion activity when combined with αPD-L1. These include four COX1/2 inhibitors and two myeloid cell signaling inhibitors. We demonstrate that the use of cyclooxygenase (COX)1/2 inhibitors in combination with αPD-L1 decreases tumor growth kinetics and enhances overall survival in triple-negative breast cancer (TNBC) tumor models in a CD8+ T cell-dependent manner. Altogether, we present a rationalized approach for identifying compounds that synergize with ICI to potentially enhance therapeutic outcomes for patients with solid tumors.
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Antígeno B7-H1 , Macrófagos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Animales , Humanos , Ratones , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Femenino , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Línea Celular Tumoral , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Ratones Endogámicos C57BL , Inmunoterapia/métodos , Inhibidores de la Ciclooxigenasa/farmacologíaRESUMEN
Although multiple myeloma is an incurable disease, the past decade has witnessed significant improvement in patient outcomes. This was brought about by the development of T-cell redirection therapies such as chimeric antigen receptor (CAR) T-cells, which can leverage the natural ability of the immune system to fight myeloma cells. The approval of the B-cell maturation antigen (BCMA)-directed CAR T, idecabtagene vicleucel (ide-cel), and ciltacabtagene autoleucel (cilta-cel) has resulted in a paradigm shift in the treatment of relapsed/refractory multiple myeloma. Overall response rates ranging from 73 to 97% are currently achievable. However, the limitations of KarMMa-1 and CARTITUDE-1 studies spurred the generation of real-world data to provide some insights into the effectiveness of ide-cel and cilta-cel among patients who were excluded from clinical trials, particularly those who received prior BCMA-targeted or other T-cell redirection therapies. Despite their unprecedented clinical efficacy in heavily pretreated patients, responses to CAR T remain non-durable. Although the underlying mechanisms of resistance to these agents haven't been fully elucidated, studies have suggested that resistance patterns could be multifaceted, implicating T-cell exhaustion and tumor intrinsic mechanisms such as BCMA target loss, upregulation of gamma-secretase, and others. Herein, we provide a succinct overview of the development of CAR T-cells, manufacturing process, and associated toxicities/complications. In this review, we also recapitulate the existing literature pertaining MM CAR-T as well as emerging data from some of the ongoing clinical trials designed to mitigate the shortcomings of these agents, and improve the clinical efficacy of CAR T, especially in the relapsed/refractory setting.
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PURPOSE: Central nervous system (CNS) metastases from lung cancers and melanoma, significantly contribute to morbidity and mortality. Despite advances in local therapies, there is a need for effective systemic treatments. Pembrolizumab, a PD-1 inhibitor, has shown promise for some patients with untreated brain metastases from melanoma and non-small cell lung cancer (NSCLC). This study aims to analyze the response of brain metastasis to pembrolizumab and associate characteristics like size and location with treatment outcome. METHODS: This retrospective study used imaging data from a phase II trial of pembrolizumab in melanoma or NSCLC patients with untreated brain metastases. MRI evaluations were conducted at 2 month intervals, with each brain metastasis treated as a distinct tumor for response assessment, based on modified RECIST criteria (maximum 5 lesions, 5 mm target lesions). RESULTS: Of 130 individual target metastases (> 5 mm), in 65 patients with NSCLC (90 metastases) and Melanoma (40 metastases), 32 (24.6%) demonstrated complete resolution, 24 (18.5%) had partial resolution, 32 (24.6%) were SD and 42 (32.3%) demonstrated PD. Those smaller than 10 mm were more likely to show complete resolution (p = 0.0218), while those ≥ 10 mm were more likely to have PR. There was no significant association between size, number or location (supratentorial vs. infratentorial) and lesion progression. The median time to metastatic lesion progression in the brain was 5.7-7 weeks. CONCLUSION: Pembrolizumab is effective in brain metastases from NSCLC and melanoma, showing response (CR + PR) in 43% and progression (PD) in 32% of metastases. With the median time to CNS progression of 5.7-7 weeks, careful radiographic monitoring is essential to guide timely local treatment decisions.
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Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos , Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Melanoma , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/diagnóstico por imagen , Masculino , Estudios Retrospectivos , Femenino , Melanoma/tratamiento farmacológico , Melanoma/patología , Persona de Mediana Edad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Anciano , Antineoplásicos Inmunológicos/uso terapéutico , Adulto , Inmunoterapia/métodos , Resultado del Tratamiento , Estudios de Seguimiento , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Melanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as "triple wild-type" (tWT) melanomas. They constitute 5-10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date. METHODS: Targeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV. RESULTS: 184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4-9) and mOS was 24.8 months (95 % CI: 14.2-53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9-8.5) and mOS was 29.18 months (95 % CI: 17.5-46.2). CONCLUSIONS: While known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations.
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Inhibidores de Puntos de Control Inmunológico , Melanoma , Mutación , Proteínas Proto-Oncogénicas B-raf , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/mortalidad , Melanoma/patología , Melanoma/inmunología , Masculino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Femenino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas B-raf/genética , Anciano , Adulto , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Neurofibromina 1/genética , Estudios Prospectivos , Supervivencia sin Progresión , Anciano de 80 o más Años , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Telomerasa/genética , GTP Fosfohidrolasas/genética , Regiones Promotoras Genéticas , Proteínas de la MembranaRESUMEN
Elevated levels of miR-155 in solid and liquid malignancies correlate with aggressiveness of the disease. In this manuscript, we show that miR-155 targets transcripts encoding IcosL, the ligand for Inducible T-cell costimulator (Icos), thus impairing the ability of T cells to recognize and eliminate malignant cells. We specifically found that overexpression of miR-155 in B cells of Eµ-miR-155 mice causes loss of IcosL expression as they progress toward malignancy. Similarly, in mice where miR-155 expression is controlled by a Cre-Tet-OFF system, miR-155 induction led to malignant infiltrates lacking IcosL expression. Conversely, turning miR-155 OFF led to tumor regression and emergence of infiltrates composed of IcosL-positive B cells and Icos-positive T cells forming immunological synapses. Therefore, we next engineered malignant cells to express IcosL, in order to determine whether IcosL expression would increase tumor infiltration by cytotoxic T cells and reduce tumor progression. Indeed, overexpressing an IcosL-encoding cDNA in MC38 murine colon cancer cells before injection into syngeneic C57BL6 mice reduced tumor size and increased intratumor CD8+ T cell infiltration, that formed synapses with IcosL-expressing MC38 cells. Our results underscore the fact that by targeting IcosL transcripts, miR-155 impairs the infiltration of tumors by cytotoxic T cells, as well as the importance of IcosL on enhancing the immune response against malignant cells. These findings should lead to the development of more effective anticancer treatments based on maintaining, increasing, or restoring IcosL expression by malignant cells, along with impairing miR-155 activity.
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Ligando Coestimulador de Linfocitos T Inducibles , MicroARNs , MicroARNs/genética , MicroARNs/metabolismo , Animales , Ratones , Ligando Coestimulador de Linfocitos T Inducibles/metabolismo , Ligando Coestimulador de Linfocitos T Inducibles/genética , Linfocitos B/inmunología , Linfocitos B/metabolismo , Línea Celular Tumoral , Ratones Endogámicos C57BL , Humanos , Linfocitos T Citotóxicos/inmunología , Regulación Neoplásica de la Expresión Génica , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Proteína Coestimuladora de Linfocitos T Inducibles/genética , Neoplasias/inmunología , Neoplasias/genética , Neoplasias/patologíaRESUMEN
INTRODUCTION: While available systemic treatments have modest long term efficacy in advanced angiosarcoma, immunotherapy represents an interesting new therapeutic opportunity. To establish its benefit, it is required to conduct a clinical trial assessing its efficacy and toxicity compared to standard treatments. MATERIAL AND METHODS: This is a literature review from PubMed search. RESULTS: Several systemic treatments (chemotherapy and TKI) are currently used in advanced angiosarcoma with ORR ranging from 12.5 to 68 % and PFS from 2 to 7 months. However, few randomized trials, mainly phase II, has been conducted to compare these treatments. While most centers propose doxorubicin containing regimens or paclitaxel in 1st or 2nd line, a high heterogeneity of regimens administered in this setting is observed even across sarcoma specialized centers with no consensual standard treatment. Encouraging signals of immunotherapy activity have been reported in angiosarcoma from several retrospective and phase II studies assessing anti-PD1 either alone or in combination with anti CTLA4 or TKI. Although cutaneous and head and neck location seems to benefit more from immunotherapy, response may be observed in any angiosarcoma subtype. In sarcoma in general and AS in particular, no biomarker has been clearly established to predict the efficacy of immunotherapy: high tumor mutational burden and presence of tertiary lymphoid structures are under assessment. DISCUSSION: Even essential, developing a randomized clinical trial in AS struggles with the heterogeneity of the disease, the lack of consensual standard regimen, the uncertainty on optimal immunotherapy administration and the absence of established predictive biomarkers. CONCLUSION: International collaboration is essential to run randomized trial in advanced AS and asses the efficacy of immune therapy in this rare and heterogeneous disease.
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Hemangiosarcoma , Humanos , Hemangiosarcoma/terapia , Hemangiosarcoma/tratamiento farmacológico , Hemangiosarcoma/patología , Inmunoterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos como Asunto , Inhibidores de Puntos de Control Inmunológico/uso terapéuticoRESUMEN
BACKGROUND: Chromatin regulators (CRs) are capable of causing epigenetic alterations, which are significant features of cancer. However, the function of CRs in controlling Clear Cell Renal Cell Carcinoma (ccRCC) is not well understood. This research aims to discover a CRs prognostic signature in ccRCC and to elucidate the roles of CRs-related genes in tumor microenvironment (TME). METHODS: Expression profiles and relevant clinical annotations were retrieved from the Cancer Genome Atlas (TCGA) and UCSC Xena platform for progression-free survival (PFS) data. The R package "limma" was used to identify differentially expressed CRs. A predictive model based on five CRs was developed using LASSO-Cox analysis. The model's predictive power and applicability were validated using K-M curves, ROC curves, nomograms, comparisons with other models, stratified survival analyses, and validation with the ICGC cohort. GO and GSEA analyses were performed to investigate mechanisms differentiating low and high riskScore groups. Immunogenicity was assessed using Tumor Mutational Burden (TMB), immune cell infiltrations were inferred, and immunotherapy was evaluated using immunophenogram analysis and the expression patterns of human leukocyte antigen (HLA) and checkpoint genes. Differentially expressed CRs (DECRs) between low and high riskScore groups were identified using log2|FC|> 1 and FDR < 0.05. AURKB, one of the high-risk DECRs and a component of our prognostic model, was selected for further analysis. RESULTS: We constructed a 5 CRs signature, which demonstrated a strong capacity to predict survival and greater applicability in ccRCC. Elevated immunogenicity and immune infiltration in the high riskScore group were associated with poor prognosis. Immunotherapy was more effective in the high riskScore group, and certain chemotherapy medications, including cisplatin, docetaxel, bleomycin, and axitinib, had lower IC50 values. Our research shows that AURKB is critical for the immunogenicity and immune infiltration of the high riskScore group. CONCLUSION: Our study produced a reliable prognostic prediction model using only 5 CRs. We found that AURKB promotes immunogenicity and immune infiltration. This research provides crucial support for the development of prognostic biomarkers and treatment strategies for ccRCC.
RESUMEN
Background: Immune checkpoint blockade (ICB) is rapidly becoming a standard of care in the treatment of many cancer types. However, the subset of patients who respond to this type of therapy is limited. Another way to promote antitumoral immunity is the use of immunostimulatory molecules, such as cytokines or T cell co-stimulators. The systemic administration of immunotherapeutics leads to significant immune-related adverse events (irAEs), therefore, the localized antitumoral action is needed. One way to achieve this is intratumoral non-viral gene-immune therapy, which allows for prolonged and localized gene expression, and multiple drug administration. In this study, we combined the previously described non-viral gene delivery system, PEG-PEI-TAT copolymer, PPT, with murine OX40L-encoding plasmid DNA. Methods: The resulting OX40L/PPT nanoparticles were characterized via gel mobility assay, dynamic light scattering analysis and in vitro transfection efficiency evaluation. The antitumoral efficacy of intratumorally (i.t.) administered nanoparticles was estimated using subcutaneously (s.c.) implanted CT26 (colon cancer), B16F0 (melanoma) and 4T1 (breast cancer) tumor models. The dynamics of stromal immune cell populations was analyzed using flow cytometry. Weight loss and cachexia were used as irAE indicators. The effect of combination of i.t. OX40L/PPT with intraperitoneal PD-1 ICB was estimated in s.c. CT26 tumor model. Results: The obtained OX40L/PPT nanoparticles had properties applicable for cell transfection and provided OX40L protein expression in vitro in all three investigated cancer models. We observed that OX40L/PPT treatment successfully inhibited tumor growth in B16F0 and CT26 tumor models and showed a tendency to inhibit 4T1 tumor growth. In B16F0 tumor model, OX40L/PPT treatment led to the increase in antitumoral effector NK and T killer cells and to the decrease in pro-tumoral myeloid cells populations within tumor stroma. No irAE signs were observed in all 3 tumor models, which indicates good treatment tolerability in mice. Combining OX40L/PPT with PD-1 ICB significantly improved treatment efficacy in the CT26 subcutaneous colon cancer model, providing protective immunity against CT26 colon cancer cells. Conclusion: Overall, the anti-tumor efficacy observed with OX40L non-viral gene therapy, whether administered alone or in combination with ICB, highlights its potential to revolutionize cancer gene therapy, thus paving the way for unprecedented advancements in the cancer therapy field.
Asunto(s)
Inmunoterapia , Ligando OX40 , Animales , Ligando OX40/genética , Ratones , Inmunoterapia/métodos , Línea Celular Tumoral , Femenino , Terapia Genética/métodos , Nanopartículas , Técnicas de Transferencia de Gen , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Microambiente Tumoral/inmunología , Polietileneimina/química , Humanos , Melanoma Experimental/terapia , Melanoma Experimental/inmunología , Polietilenglicoles/químicaRESUMEN
Interleukin-2 (IL-2) holds promise for the treatment of cancer and autoimmune diseases, but its high-dose usage is associated with systemic immunotoxicity. Differential IL-2 receptor (IL-2R) regulation might impact function of cells upon IL-2 stimulation, possibly inducing cellular changes similar to patients with hypomorphic IL2RB mutations, presenting with multiorgan autoimmunity. Here, we show that sustained high-dose IL-2 stimulation of human lymphocytes drastically reduces IL-2Rß surface expression especially on T cells, resulting in impaired IL-2R signaling which correlates with high IL-2Rα baseline expression. IL-2R signaling in NK cells is maintained. CD4+ T cells, especially regulatory T cells are more broadly affected than CD8+ T cells, consistent with lineage-specific differences in IL-2 responsiveness. Given the resemblance of cellular characteristics of high-dose IL-2-stimulated cells and cells from patients with IL-2Rß defects, impact of continuous IL-2 stimulation on IL-2R signaling should be considered in the onset of clinical adverse events during IL-2 therapy.
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Interleucina-2 , Células Asesinas Naturales , Humanos , Interleucina-2/inmunología , Interleucina-2/genética , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Transducción de Señal , Fenotipo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Subunidad beta del Receptor de Interleucina-2/genética , Subunidad beta del Receptor de Interleucina-2/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
A series of novel 2-arylmethoxy-4-(2-fluoromethyl-biphenyl-3-ylmethoxy) benzylamine derivatives was designed, synthesized, and evaluated for their antitumor effects as PD-1/PD-L1 inhibitors both in vitro and in vivo. Firstly, the ability of these compounds to block the PD-1/PD-L1 immune checkpoint was assessed using the homogeneous time-resolved fluorescence (HTRF) assay. Two of the compounds can strongly block the PD-1/PD-L1 interaction, with IC50 values of less than 10 nM, notably, compound HD10 exhibited significant clinical potential by inhibiting the PD-1/PD-L1 interaction with an IC50 value of 3.1 nM. Further microscale thermophoresis (MST) analysis demonstrated that HD10 had strong interaction with PD-L1 protein. Co-crystal structure (2.7 Å) analysis of HD10 in complex with the PD-L1 protein revealed a strong affinity between the compound and the target PD-L1 dimer. This provides a solid theoretical basis for further in vitro and in vivo studies. Next, a typical cell-based experiment demonstrated that HD10 could remarkably prevent the interaction of hPD-1 293 T cells from human recombinant PD-L1 protein, effectively restoring T cell function, and promoting IFN-γ secretion in a dose-dependent manner. Moreover, HD10 was effective in suppressing tumor growth (TGI = 57.31 %) in a PD-1/PD-L1 humanized mouse model without obvious toxicity. Flow cytometry, qPCR, and immunohistochemistry data suggested that HD10 inhibits tumor growth by activating the immune system in vivo. Based on these results, it seems likely that HD10 is a promising clinical candidate that should be further investigated.