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1.
PLoS One ; 16(7): e0253864, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34242269

RESUMO

Sarcomas are rare, difficult to treat, mesenchymal lineage tumours that affect children and adults. Immunologically-based therapies have improved outcomes for numerous adult cancers, however, these therapeutic strategies have been minimally effective in sarcoma so far. Clinically relevant, immunologically-competent, and transplantable pre-clinical sarcoma models are essential to advance sarcoma immunology research. Herein we show that Cre-mediated activation of KrasG12D, and deletion of Trp53, in the hindlimb muscles of C57Bl/6 mice results in the highly penetrant, rapid onset undifferentiated pleomorphic sarcomas (UPS), one of the most common human sarcoma subtypes. Cell lines derived from spontaneous UPS tumours can be reproducibly transplanted into the hindlimbs or lungs of naïve, immune competent syngeneic mice. Immunological characterization of both spontaneous and transplanted UPS tumours demonstrates an immunologically-'quiescent' microenvironment, characterized by a paucity of lymphocytes, limited spontaneous adaptive immune pathways, and dense macrophage infiltrates. Macrophages are the dominant immune population in both spontaneous and transplanted UPS tumours, although compared to spontaneous tumours, transplanted tumours demonstrate increased spontaneous lymphocytic infiltrates. The growth of transplanted UPS tumours is unaffected by host lymphocyte deficiency, and despite strong expression of PD-1 on tumour infiltrating lymphocytes, tumours are resistant to immunological checkpoint blockade. This spontaneous and transplantable immune competent UPS model will be an important experimental tool in the pre-clinical development and evaluation of novel immunotherapeutic approaches for immunologically cold soft tissue sarcomas.


Assuntos
Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Musculares/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Sarcoma/genética , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Membro Posterior , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Neoplasias Musculares/imunologia , Neoplasias Musculares/patologia , Músculo Esquelético/patologia , Mutação , Sarcoma/imunologia , Sarcoma/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
2.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299136

RESUMO

Soft tissue sarcomas (STSs) are a family of rare malignant tumors encompassing more than 80 histologies. Current therapies for metastatic STS, a condition that affects roughly half of patients, have limited efficacy, making innovative therapeutic strategies urgently needed. From a molecular point of view, STSs can be classified as translocation-related and those with a heavily rearranged genotype. Although only the latter display an increased mutational burden, molecular profiles suggestive of an "immune hot" tumor microenvironment are observed across STS histologies, and response to immunotherapy has been reported in both translocation-related and genetic complex STSs. These data reinforce the notion that immunity in STSs is multifaceted and influenced by both genetic and epigenetic determinants. Cumulative evidence indicates that a fine characterization of STSs at different levels is required to identify biomarkers predictive of immunotherapy response and to discover targetable pathways to switch on the immune sensitivity of "immune cold" tumors. In this review, we will summarize recent findings on the interplay between genetic landscape, molecular profiling and immunity in STSs. Immunological and molecular features will be discussed for their prognostic value in selected STS histologies. Finally, the local and systemic immunomodulatory effects of the targeted drugs imatinib and sunitinib will be discussed.


Assuntos
Biomarcadores Tumorais/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Terapia de Alvo Molecular , Sarcoma/imunologia , Microambiente Tumoral/imunologia , Animais , Biomarcadores Tumorais/imunologia , Humanos , Sarcoma/tratamento farmacológico , Sarcoma/patologia
3.
Aging (Albany NY) ; 13(11): 15126-15138, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34081621

RESUMO

Sarcomatoid hepatocellular carcinoma (sHCC) is a rare type of liver malignancy. Currently, the tumor immune features of sHCC are poorly understood. We recruited 31 patients with resected sHCC for whom tissue samples and complete clinicopathologic and follow-up data were available. To understand the immune infiltration of sHCC, immunohistochemical staining was performed on the resected sHCC samples to compare the expressions of programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), B7-H3, indoleamine 2,3-dioxygenase (IDO), lymphocyte-activation gene 3 (LAG-3), CD8, FOXP3, and CD68 in tumor and peritumoral tissues. Kaplan-Meier and Cox regression analyses were used to assess the predictive value of immune markers. Sarcomatoid components were characterized with significantly higher expression of PD-L1 and B7-H3 in tumor cells than in conventional HCC components, as well as in peritumoral tissue. Additionally, sarcomatoid components had a higher density of FOXP3+ and LAG-3+ cells and a lower density of CD8+ cells than conventional HCC components or peritumoral tissue. Higher expression of PD-L1 in tumor cells significantly correlated with higher densities of CD8+, PD-1+, and LAG-3+ cells. Increased tumor PD-L1 expression and decreased CD8+ T-cell density were associated with poor overall survival (OS) and disease-free survival (DFS) in patients of sHCC. These findings suggest further characterization on relative mechanism of sHCC immune infiltration may identify therapeutic targets for immunotherapy.


Assuntos
Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Sarcoma/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Contagem de Células , Intervalo Livre de Doença , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Análise Multivariada , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Sarcoma/patologia
4.
Eur J Cancer ; 152: 165-182, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34107450

RESUMO

BACKGROUND: Soft-tissue sarcomas (STSs) are rare malignancies, accounting for approximately 1% of adult cancer. Metastatic disease carries a poor prognosis, and various efforts have been made to improve the prognosis of advanced STS, to date with little success. Immune checkpoint inhibitors (ICPIs) have substantially improved prognosis for many cancer types. Their role in the treatment of STS, however, remains unravelled. OBJECTIVE: The objective of the study is to assess the activity of ICPIs in the treatment of STS. METHODS: We performed a systematic review using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Furthermore, abstracts from European Society of Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO) and Connective Tissue Society Oncology (CTOS) congress were searched from 2017 until 2020. Prospective clinical trials investigating ICPIs, either monotherapy or combination therapy, in STS were available for inclusion. The outcomes of interest were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and major toxicity. Cut-off for clinical activity was defined as an ORR of ≥0.15. Subgroup analysis was carried out as per treatment category, disease setting and histologic subtype, using a random effects model. RESULTS: We identified 27 studies, including a total of 1012 patients (range 6-85) with more than 25 histologic subtypes. The pooled ORR was 0.14 (95% confidence interval [CI] 0.09-0.18), DCR was 0.55 (95% CI 0.43-0.66), mean PFS range was 1.8-11.5 months and mean OS was 6.1-34.7 months. The pooled ORR as per treatment category was 0.14 for anti-programmed cell death 1 (anti-PD1) monotherapy (95% CI 0.07-0.23), 0.16 for anti-PD1 + anti-cytotoxic T-lymphocyte-associated protein 4 (95% CI 0.06-0.29), 0.20 for anti-PD1 + tyrosine kinase inhibitor (95% CI 0.06-0.38), 0.20 for anti-PD1 + chemo (95% CI 0.06-0.38) and 0.08 for anti-PD1 + immunomodulator (95% CI 0.01-0.19). The pooled ORR as per disease setting was as follows: neoadjuvant treatment, 0.09 (0.00-0.25); advanced disease first line, 0.23 (0.15-0.32) and advanced pretreated, 0.13 (0.09-0.19). High response rates were seen in classic Kaposi sarcoma (CKS), alveolar soft part sarcoma (ASPS) and undifferentiated pleomorphic sarcoma (UPS) with ORR of 0.69 (95% CI 0.51-0.82), 0.35 (95% CI 0.27-0.44) and 0.20 (95% CI 0.15-0.27), respectively. Activity was limited in gastrointestinal stromal tumour (ORR 0.01 [95% CI 0.0-0.08]), uterine leiomyosarcoma (ORR 0.06 [95% CI 0.02-0.18]), leiomyosarcoma (ORR 0.10 [95% CI 0.06-0.17]) and liposarcoma (ORR 0.11 [95% CI 0.07-0.17]). CONCLUSION: Clinical activity of ICPIs in STS is highly variable and depends on histologic subtype, disease setting and concomitant treatment strategy. Activity was high in CKS, ASPS and UPS. Early incorporation of ICPIs in combination with chemotherapy seems a promising strategy that warrants further interest. Translational research integrating molecular profile, biological behaviour and response to ICPIs should determine their role in treatment of STS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Sarcoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Sarcoma/imunologia , Sarcoma/mortalidade
5.
Front Immunol ; 12: 653081, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936075

RESUMO

Soft tissue sarcoma (STS) constitutes a rare group of heterogeneous malignancies. Effective treatment options for most subtypes of STS are still limited. As a result, especially in metastatic disease, prognosis is still dismal. The ligands for the activating immunoreceptor NKG2D (NKG2DL) are commonly expressed in STS, but generally absent in healthy tissues. This provides the rationale for utilization of NKG2DL as targets for immunotherapeutic approaches. We here report on the preclinical characterization of bispecific fusion proteins (BFP) consisting of the extracellular domain of the NKG2D receptor fused to Fab-fragments directed against CD3 (NKG2D-CD3) or CD16 (NKG2D-CD16) for treatment of STS. After characterization of NKG2DL expression patterns on various STS cell lines, we demonstrated that both NKG2D-CD16 and NKG2D-CD3 induce profound T and NK cell reactivity as revealed by analysis of activation, degranulation and secretion of IFNγ as well as granule associated proteins, resulting in potent target cell lysis. In addition, the stimulatory capacity of the constructs to induce T and NK cell activation was analyzed in heavily pretreated STS patients and found to be comparable to healthy donors. Our results emphasize the potential of NKG2D-CD3 and NKG2D-CD16 BFP to target STS even in an advanced disease.


Assuntos
Complexo CD3/antagonistas & inibidores , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Receptores de IgG/antagonistas & inibidores , Proteínas Recombinantes de Fusão/uso terapêutico , Sarcoma/tratamento farmacológico , Adulto , Idoso , Anticorpos Biespecíficos/genética , Anticorpos Biespecíficos/farmacologia , Complexo CD3/metabolismo , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Linhagem Celular Tumoral , Feminino , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Cultura Primária de Células , Domínios Proteicos/genética , Receptores de IgG/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/farmacologia , Sarcoma/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto Jovem
6.
Aging (Albany NY) ; 13(10): 13708-13725, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33946044

RESUMO

BACKGROUND: Immune infiltration is a prognostic marker to clinical outcomes in various solid tumors. However, reports that focus on bone and soft tissue sarcoma are rare. The study aimed to analyze and identify how immune components influence prognosis and develop a novel prognostic system for sarcomas. METHODS: We retrieved the gene expression data from 3 online databases (GEO, TCGA, and TARGET). The immune fraction was estimated using the CIBERSORT algorithm. After that, we re-clustered samples by K-means and constructed immunoscore by the least absolute shrinkage and selection operator (LASSO) Cox regression model. Next, to confirm the prognostic value, nomograms were constructed. RESULTS: 334 samples diagnosed with 8 tumor types (including osteosarcoma) were involved in our analysis. Patients were next re-clustered into three subgroups (OS, SAR1, and SAR2) through immune composition. Survival analysis showed a significant difference between the two soft tissue groups: patients with a higher proportion of CD8+ T cells, macrophages M1, and mast cells had favorable outcomes (p=0.0018). Immunoscore models were successfully established in OS and SAR2 groups consisting of 12 and 9 cell fractions, respectively. We found immunosocre was an independent factor for overall survival time. Patients with higher immunoscore had poor prognosis (p<0.0001). Patients with metastatic lesions scored higher than those counterparts with localized tumors (p<0.05). CONCLUSIONS: Immune fractions could be a useful tool for the classification and prognosis of bone and soft tissue sarcoma patients. This proposed immunoscore showed a promising impact on survival prediction.


Assuntos
Neoplasias Ósseas/genética , Neoplasias Ósseas/imunologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Sarcoma/genética , Sarcoma/imunologia , Adolescente , Adulto , Neoplasias Ósseas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Metástase Neoplásica , Nomogramas , Análise de Regressão , Sarcoma/tratamento farmacológico , Fatores de Tempo
7.
Curr Opin Oncol ; 33(4): 315-322, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33927108

RESUMO

PURPOSE OF REVIEW: Next-generation sequencing (NGS) has enabled fast, high-throughput nucleotide sequencing and has begun to be implemented into clinical practice for genomic-guided precision medicine in various cancer types. This review will discuss recent evidence that highlights opportunities for NGS to improve outcomes in sarcomas that have complex genomic profiles with no known driver mutations. RECENT FINDINGS: Global genomic signatures detectable by NGS including tumour mutational burden and microsatellite instability have potential as biomarkers for response to immunotherapy in certain sarcoma subtypes including angiosarcomas. Identification of hallmarks associated with 'BRCAness' and homologous recombination repair defects in leiomyosarcomas and osteosarcomas may predict sensitivity to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. Lastly, the use of NGS for evaluating cancer predisposition in sarcomas may be useful for early detection, screening and surveillance. SUMMARY: Currently, the implementation of NGS for every sarcoma patient is not practical or useful. However, adopting NGS as a complementary approach in sarcomas with complex genomics and those with limited treatment options has the potential to deliver precision medicine to a subgroup of patients, with novel therapies such as immune checkpoint and PARP inhibitors. Moving forward, molecular tumour boards incorporating multidisciplinary teams of pathologists, oncologists and genomic specialists to interpret NGS data will complement existing tools in diagnosis and treatment decision making in sarcoma patients.


Assuntos
Sarcoma/genética , Sarcoma/terapia , Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia , Instabilidade de Microssatélites , Mutação , Medicina de Precisão , Sarcoma/tratamento farmacológico , Sarcoma/imunologia
8.
Eur J Cancer ; 150: 143-154, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33901793

RESUMO

BACKGROUND: L19TNF is a recombinant fusion protein composed of a human antibody fragment and human tumour necrosis factor. L19TNF targets the EDB domain of oncofetal fibronectin highly expressed in tumour vasculature and induces tumour remission in mouse tumours. We summarise two phase I trials testing a combination of L19TNF with doxorubicin in patients with solid tumours, particularly soft tissue sarcomas (STS). PATIENTS AND METHODS: The first study, an open-label, dose-escalation and expansion phase I study of L19TNF plus doxorubicin, enrolled 27 patients. Three cohorts (10.4-17 µg/kg L19TNF) of patients received L19TNF intravenously at days 1, 3, and 5 and doxorubicin (75 mg/m2, then 60 mg/m2) on day 1 every 3 weeks. The expansion cohort enrolled patients with STS. The second study tried to re-escalate the doxorubicin dose to 75 mg/m2 with 13 µg/kg L19TNF. Among primary objectives was the establishment of a recommended dose (RD). RESULTS: The combination was safely applicable. Dose-limiting toxicity occurred either at 17 µg/kg L19TNF or at 75 mg/m2 doxorubicin. RD is 13 µg/kg L19TNF plus 60 mg/m2 doxorubicin. In 15 STS patients of the extension cohort evaluable for efficacy, antitumour activity was observed with complete remission in 1, partial remission in 1 and minor tumour shrinkage in 7 patients. The median overall survival for this heavily pretreated cohort was 14.9 months. CONCLUSION: L19TNF can be safely applied in combination with doxorubicin and induces encouraging tumour remissions in patients with soft tissue sarcomas.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doxorrubicina/administração & dosagem , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Adulto , Idoso , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/farmacocinética , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sarcoma/imunologia , Sarcoma/mortalidade , Sarcoma/patologia , Neoplasias de Tecidos Moles/imunologia , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/patologia , Fatores de Tempo , Resultado do Tratamento
9.
Sci Rep ; 11(1): 8321, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859303

RESUMO

Interleukin-12 (IL-12) is an inflammatory cytokine that has demonstrated efficacy for cancer immunotherapy, but systemic administration has detrimental toxicities. Lentiviral transduction eliciting IL-12-producing human sarcoma for autologous reintroduction provides localized delivery for both innate and adaptive immune response augmentation. Sarcoma cell lines and primary human sarcoma samples were transduced with recombinant lentivirus engineering expression of human IL-12 (hu-IL-12). IL-12 expressing sarcomas were assessed in vitro and in vivo following implantation into humanized NSG and transgenic human IL-15 expressing (NSG.Tg(Hu-IL-15)) murine models. Lentiviral transduction (LV/hu-IL-12) of human osteosarcoma, Ewing sarcoma and rhabdomyosarcoma cell lines, as well as low-passage primary human sarcomas, engendered high-level expression of hu-IL-12. Hu-IL-12 demonstrated functional viability, eliciting specific NK cell-mediated interferon-γ (IFN-γ) release and cytotoxic growth restriction of spheroids in vitro. In orthotopic xenograft murine models, the LV/hu-IL-12 transduced human sarcoma produced detectable IL-12 and elicited an IFN-γ inflammatory immune response specific to mature human NK reconstitution in the NSG.Tg(Hu-IL-15) model while restricting tumor growth. We conclude that LV/hu-IL-12 transduction of sarcoma elicits a specific immune reaction and the humanized NSG.Tg(Hu-IL-15) xenograft, with mature human NK cells, can define in vivo anti-tumor effects and systemic toxicities. IL-12 immunomodulation through autologous tumor transduction and reintroduction merits exploration for sarcoma treatment.


Assuntos
Expressão Gênica/genética , Imunidade , Imunomodulação , Interleucina-12/genética , Interleucina-12/metabolismo , Células Matadoras Naturais/imunologia , Sarcoma/genética , Sarcoma/imunologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Imunoterapia , Interferon gama/metabolismo , Interleucina-12/imunologia , Interleucina-15 , Lentivirus , Camundongos , Sarcoma/terapia
10.
Int J Cancer ; 149(3): 546-560, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33662146

RESUMO

Sarcomatoid hepatocellular carcinoma (SHCC), which was a rare histological subtype of hepatocellular carcinoma (HCC), is currently subclassified as poorly differentiated HCC because of insufficient evidence to define SHCC as a subtype of HCC. We aimed to assess the feasibility of classifying SHCC as a histological subtype of HCC by comprehensively identifying novel and distinct characteristics of SHCC compared to ordinary HCC (OHCC). Fifteen SHCCs (1.4%) defined as HCC with at least a 10% sarcomatous component, 15 randomly disease-stage-matched OHCCs and 163 consecutive OHCCs were extracted from 1106 HCCs in the Pathology Database (1997-2019) of our hospital. SHCC patients showed poor prognosis, and the tumors could be histologically subclassified into the pleomorphic, spindle and giant cell types according to the subtype of carcinomas with sarcomatoid or undifferentiated morphology in other organs. The transcriptomic analysis revealed distinct characteristics of SHCC featuring the upregulation of genes associated with epithelial-to-mesenchymal transition and inflammatory responses. The fluorescent multiplex immunohistochemistry results revealed prominent programmed death-ligand 1 (PD-L1) expression on sarcomatoid tumor cells and higher infiltration of CD4+ and CD8+ T cells in SHCCs compared to OHCCs. The density of CD8+ T cells in the nonsarcomatous component of SHCCs was also higher than that in OHCCs. In conclusion, the comprehensive analyses in our study demonstrated that SHCC is distinct from OHCC in terms of clinicopathologic, transcriptomic and immunologic characteristics. Therefore, it is reasonable to consider SHCC as a histological subtype of HCC.


Assuntos
Biomarcadores Tumorais/genética , Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Sarcoma/patologia , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Sarcoma/genética , Sarcoma/imunologia , Taxa de Sobrevida
11.
Eur J Immunol ; 51(6): 1473-1481, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33684223

RESUMO

Therapeutic antibodies blocking PD-1-/PD-L1 interaction have achieved remarkable clinical success in cancer. In addition to blocking a target molecule, some isotypes of antibodies can activate complement, NK cells or phagocytes, resulting in death of the cell expressing the antibody's target. Human anti-PD-1 therapeutics use antibody isotypes designed to minimize such antibody-dependent lysis. In contrast, anti-PD-1 reagents used in mice are derived from multiple species, with different isotypes, and are not engineered to reduce target cell death: few studies analyze or discuss how antibody species and isotype may impact data interpretation. We demonstrate here that anti-PD-1 therapy to promote activation and proliferation of murine PD-1-expressing CD8 T cells sometimes led instead to a loss of antigen specific cells. This phenomenon was seen in two tumor models and a model of virus infection, and varied with the clone of anti-PD-1 antibody. Additionally, we compared competition among anti-PD-1 clones to find a combination that allows detection of PD-1-expressing cells despite the presence of blocking anti-PD1 antibodies in vivo. These data bring attention to the possibility of unintended target cell depletion with some commonly used anti-mouse PD-1 clones, and should provide a valuable resource for the design and interpretation of anti-PD-1 studies in mice.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Herpesviridae/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Muromegalovirus/fisiologia , Sarcoma/imunologia , Neoplasias Cutâneas/imunologia , Animais , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/transplante , Morte Celular , Linhagem Celular Tumoral , Cricetinae , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Infecções por Herpesviridae/terapia , Humanos , Imunoglobulina G/metabolismo , Isotipos de Imunoglobulinas/metabolismo , Metilcolantreno , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ratos , Sarcoma/terapia , Neoplasias Cutâneas/terapia
12.
Eur J Cancer ; 147: 164-169, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33684876

RESUMO

A group of patients with adult-type soft tissue sarcoma is at high risk of local recurrence and distant metastases. Age, tumour site, histological subtype, tumour size and grade have been identified as the most important independent adverse prognostic factors. Macroscopically complete tumour resection is considered as the mainstay of treatment with the addition of preoperative or postoperative radiotherapy for extremity or trunk localisation. Retroperitoneal localisation requires compartmental resection and is associated with a worse prognosis. Here, radiotherapy is of no proven value. Perioperative chemotherapy is considered to treat micrometastatic disease not detectable at the time of diagnosis. The neoadjuvant application gives the risk of distant metastasis the greatest importance as therapy is carried out at the earliest possible time, whereas adjuvant chemotherapy is delayed by surgery and the necessary wound healing. With reported response rates up to 30%, both the operability may be improved and the risk of intraoperative tumour cell dissemination may be reduced, resulting also in reduced local relapse rates. However, the potential risk of early tumour progression may counteract this benefit. Optimised strategies with multimodality approaches including chemotherapy, regional hyperthermia (RHT) and immunotherapeutic agents have been shown to improve survival in high-risk patients. Here, we focus on the data from available randomised studies investigating the use of perioperative chemotherapy in patients with high-risk adult-type soft tissue sarcoma, including the use of RHT for local enhancement of chemotherapy effect and immune induction.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hipertermia Induzida , Terapia Neoadjuvante , Sarcoma/terapia , Neoplasias de Tecidos Moles/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Ensaios Clínicos Fase III como Assunto , Progressão da Doença , Humanos , Hipertermia Induzida/efeitos adversos , Terapia Neoadjuvante/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sarcoma/imunologia , Sarcoma/mortalidade , Sarcoma/patologia , Neoplasias de Tecidos Moles/imunologia , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/patologia , Fatores de Tempo , Resultado do Tratamento
13.
BMC Cancer ; 21(1): 108, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33530966

RESUMO

BACKGROUND: Currently, the choice of treatment for individuals with metastatic soft tissue sarcomas (MSTS) presents a significant challenge to clinicians. The aim of this retrospective study was to assess the efficacy and safety of nivolumab plus ipilimumab (NPI) versus nivolumab alone (NIV) in individuals with treatment-naive programmed death-ligand 1 (PD-L1) positive MSTS. METHODS: Prospectively maintained databases were reviewed from 2013 to 2018 to assess individuals with treatment-naive PD-L1 MSTS who received NPI (nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by nivolumab 3 mg/kg every 2 weeks) or NIV (3 mg/kg every 2 weeks) until disease progression, withdrawal, unendurable [AEs], or death. The co-primary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: The median follow-up was 16.0 months (IQR 14.4-18.5) after targeted intervention. The median OS was 12.2 months (95% confidence interval [CI], 6.1-13.7) and 9.2 months (95% CI, 4.2-11.5) for the NPI and NIV groups, respectively (hazard ratio [HR] 0.49, 95% CI, 0.33-0.73; p=0.0002); the median PFS was 4.1 months (95% CI, 3.2-4.5) and 2.2 months (95% CI, 1.1-3.4) for the NPI and NIV groups, respectively (HR 0.51, 95% CI, 0.36-0.71; p< 0.0001). Key grade 3-5 AEs occurred more frequently in the NPI group than in the NIV group (94 [72.9%] for NPI vs. 35 [27.1%], p< 0.001). CONCLUSIONS: For treatment-naive PD-L1 positive MSTS, NPI seems to be less tolerated but has a greater survival advantage than NIV as the primary therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/metabolismo , Sarcoma/tratamento farmacológico , Adulto , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Feminino , Seguimentos , Humanos , Ipilimumab/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Nivolumabe/administração & dosagem , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Sarcoma/imunologia , Sarcoma/patologia , Taxa de Sobrevida
14.
Jpn J Clin Oncol ; 51(4): 523-537, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33611603

RESUMO

Sarcomas are a heterogeneous group of malignancies of mesenchymal origin; their molecular and genomic mechanisms differ with regard to histology. These characteristics lead to the presentation of varied immunological profiles based on the tumor microenvironment. Various immunotherapies are considered for the treatment of sarcoma. These treatments are performed either in isolation or in combination with other methods such as cytotoxic chemotherapy or the use of molecular target agents. Among these, two recently emerging immunotherapies include T-cell receptor gene therapy and immune checkpoint inhibitor therapy, which are expected to be effective for many types of sarcoma. A sarcoma with a disease-specific translocation and a limited number of mutations, such as synovial sarcoma, expresses high levels of self-antigens, like the New York esophageal squamous cell carcinoma 1, which has been targeted in T-cell receptor gene therapy. On the other hand, sarcomas with a greater number of mutations, such as undifferentiated pleomorphic sarcomas, myxofibrosarcoma and dedifferentiated liposarcomas, can be good candidates for immune checkpoint inhibitors. Among immune checkpoint inhibitor therapies, programmed cell death-1 blockade (nivolumab and pembrolizumab) and cytotoxic T-lymphocyte-associated antigen 4 blockade (ipilimumab) have been investigated most often in sarcoma. Although the sole use of immune checkpoint inhibitors provides limited efficacy, combined immunotherapy with immune checkpoint inhibitors or molecular target agents, especially antiangiogenic agents, has shown moderate results against some types of sarcoma, such as the alveolar soft part sarcoma. Several clinical trials utilizing immunotherapy, including T-cell receptor gene therapy and immune checkpoint inhibitors, in sarcomas are under progress. By clarifying the tumor microenvironment and biomarker-predictive capacity of immunotherapy in sarcomas, better clinical trials can be designed; this could lead to improved outcomes for immunotherapy in sarcoma.


Assuntos
Imunoterapia , Sarcoma/imunologia , Sarcoma/terapia , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Vacinas Anticâncer/imunologia , Humanos , Sarcoma/patologia , Microambiente Tumoral
15.
Clin Transl Oncol ; 23(8): 1620-1629, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33635466

RESUMO

BACKGROUND: Although immunotherapy is thought to be a promising cancer treatment, most patients do not respond to immunotherapy. In this post hoc analysis of a phase 1/2 study, associations of programmed death ligand 1 (PD-L1), PD-L2, and HLA class I expressions with responses to dendritic cells (DCs)-based immunotherapy were investigated in patients with advanced sarcoma. METHODS: This study enrolled 35 patients with metastatic and/or recurrent sarcomas who underwent DC-based immunotherapy. The associations of PD-L1, PD-L2, and HLA class I expressions in tumor specimens, which were resected before immunotherapy, with immune responses (increases of IFN-γ and IL-12) and oncological outcomes were evaluated. RESULTS: Patients who were PD-L2 (+) showed lower increases of IFN-γ and IL-12 after DC-based immunotherapy than patients who were PD-L2 (-). The disease control (partial response or stable disease) rates of patients who were PD-L1 (+) and PD-L1 (-) were 0% and 22%, respectively. Disease control rates of patients who were PD-L2 (+) and PD-L2 (-) were 13% and 22%, respectively. Patients who were PD-L1 (+) tumors had significantly poorer overall survival compared with patients who were PD-L1 (-). No associations of HLA class I expression with the immune response or oncological outcomes were observed. CONCLUSIONS: This study suggests that PD-L1 and PD-L2 are promising biomarkers of DC-based immunotherapy, and that addition of immune checkpoint inhibitors to DC-based immunotherapy may improve the outcomes of DC-based immunotherapy.


Assuntos
Antígeno B7-H1/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunoterapia , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Sarcoma/terapia , Adulto , Biomarcadores Tumorais/metabolismo , Células Dendríticas , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-12/metabolismo , Masculino , Sarcoma/imunologia , Sarcoma/mortalidade , Sarcoma/patologia , Resultado do Tratamento
16.
BMC Cancer ; 21(1): 144, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33557781

RESUMO

BACKGROUND: Sarcomas is a group of heterogeneous malignant tumors originated from mesenchymal tissue and different types of sarcomas have disparate outcomes. The present study aims to identify the prognostic value of immune-related genes (IRGs) in sarcoma and establish a prognostic signature based on IRGs. METHODS: We collected the expression profile and clinical information of 255 soft tissue sarcoma samples from The Cancer Genome Atlas (TCGA) database and 2498 IRGs from the ImmPort database. The LASSO algorithm and Cox regression analysis were used to identify the best candidate genes and construct a signature. The prognostic ability of the signature was evaluated by ROC curves and Kaplan-Meier survival curves and validated in an independent cohort. Besides, a nomogram based on the IRGs and independent prognostic clinical variables was developed. RESULTS: A total of 19 IRGs were incorporated into the signature. In the training cohort, the AUC values of signature at 1-, 2-, and 3-years were 0.938, 0.937 and 0.935, respectively. The Kaplan-Meier survival curve indicated that high-risk patients were significantly worse prognosis (P < 0.001). In the validation cohort, the AUC values of signature at 1-, 2-, and 3-years were 0.730, 0.717 and 0.647, respectively. The Kaplan-Meier survival curve also showed significant distinct survival outcome between two risk groups. Furthermore, a nomogram based on the signature and four prognostic variables showed great accuracy in whole sarcoma patients and subgroup analyses. More importantly, the results of the TF regulatory network and immune infiltration analysis revealed the potential molecular mechanism of IRGs. CONCLUSIONS: In general, we identified and validated an IRG-based signature, which can be used as an independent prognostic signature in evaluating the prognosis of sarcoma patients and provide potential novel immunotherapy targets.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Regulação Neoplásica da Expressão Gênica , Nomogramas , Sarcoma/patologia , Transcriptoma , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Sarcoma/genética , Sarcoma/imunologia
17.
Cells ; 10(1)2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466646

RESUMO

NY-ESO-1-specific T cells have shown promising activity in the treatment of soft tissue sarcoma (STS). However, standardized protocols for their generation are limited. Particularly, cost-effectiveness considerations of cell production protocols are of importance for conducting clinical studies. In this study, two different NY-ESO-1-specific T cell production protocols were compared. Major differences between protocols 1 and 2 include culture medium, interleukin-2 and retronectin concentrations, T cell activation strategy, and the transduction process. NY-ESO-1-specific T cells generated according to the two protocols were investigated for differences in cell viability, transduction efficiency, T cell expansion, immunophenotype as well as functionality. NY-ESO-1-specific T cells showed similar viability and transduction efficiency between both protocols. Protocol 1 generated higher absolute numbers of NY-ESO-1-specific T cells. However, there was no difference in absolute numbers of NY-ESO-1-specific T cell subsets with less-differentiated phenotypes accounting for efficient in vivo expansion and engraftment. Furthermore, cells generated according to protocol 1 displayed higher capacity of TNF-α generation, but lower cytotoxic capacities. Overall, both protocols provided functional NY-ESO-1-specific T cells. However, compared to protocol 1, protocol 2 is advantageous in terms of cost-effectiveness. Cell production protocols should be designed diligently to achieve a cost-effective cellular product for further clinical evaluation.


Assuntos
Antígenos de Neoplasias/imunologia , Proteínas de Membrana/imunologia , Sarcoma/imunologia , Linfócitos T Citotóxicos/imunologia , Transferência Adotiva , Técnicas de Cultura de Células , Linhagem Celular , Humanos , Sarcoma/terapia , Linfócitos T Citotóxicos/transplante
18.
Pediatr Blood Cancer ; 68 Suppl 2: e28439, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32827353

RESUMO

Despite radiation therapy (RT) being an integral part of the treatment of most pediatric cancers and the recent discovery of novel molecular-targeted agents (MTAs) in this era of precision medicine with the potential to improve the therapeutic ratio of modern chemoradiotherapy regimens, there are only a few preclinical trials being conducted to discover novel radiosensitizers and radioprotectors. This has resulted in a paucity of translational clinical trials combining RT and novel MTAs. This report describes the opportunities and challenges of investigating RT together with MTAs in preclinical testing for immunotherapy, brain tumors, and sarcomas in pediatric oncology. We discuss the need for improving the collaboration between radiation oncologists, biologists, and physicists to improve the reliability, reproducibility, and translational potential of RT-based preclinical research. Current translational clinical trials using RT and MTAs for immunotherapy, brain tumors, and sarcomas are described. The technologic advances in experimental RT, availability of novel experimental tumor models, advances in immunology and tumor biology, and the discovery of novel MTAs together hold considerable promise for good quality preclinical and clinical multimodality research to improve the current rates of survival and toxicity in children afflicted with cancer.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Imunoterapia/métodos , Terapia de Alvo Molecular , Sarcoma/terapia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Criança , Humanos , Radiossensibilizantes/uso terapêutico , Sarcoma/imunologia , Sarcoma/patologia
19.
Oncol Rep ; 45(1): 379-389, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33155664

RESUMO

The prognosis of undifferentiated pleomorphic sarcoma (UPS) is generally unfavorable. Recently, clinical trials such as SARC028 demonstrated the utility of cancer immunotherapy for soft tissue sarcomas. The aim of the present study was to assess the expression of PD­L1 and IDO­1 as prognostic factors and therapeutic targets. A total of 52 primary UPS cases were retrieved and two UPS cell lines were utilized for supplementary analysis. Immunohistochemical staining of anti­PD­L1 (28­8), IDO­1, CD8, CD4, CD3, HLA class I, MSH2, MSH6, MLH1 and PMS2 was carried out. Immunohistochemically, 19 of 52 (36.5%) cases showed PD­L1 expression at least focally (≥1%) and 5 of 52 (9.62%) showed strong PD­L1 expression (≥50%). Overall, 25 of 52 (48.1%) cases expressed IDO­1 (≥1%). Two tumors were evaluated as having deficient mismatch repair and six tumors as having the loss of HLA class I. PD­L1 expression (≥1%) was significantly related to the infiltration of CD8­ and CD3­positive lymphocytes, but strong PD­L1 expression (≥50%) did not present a significant relationship with tumor­infiltrating lymphocytes. IDO­1 expression was also associated with CD8­, CD4­, and CD3­positive lymphocytes. In vitro, both PD­L1 and IDO­1 were induced by IFN­Î³ stimulation. In survival analysis, strong PD­L1 expression (≥50%) was a significant poor prognostic factor, while IDO­1 expression (≥1%) was a favorable one. In conclusion, UPS was shown to frequently express PD­L1 and IDO­1. It was suggested that PD­L1 expression (≥50%) and IDO­1 expression are poor and favorable prognostic factors of UPS patients, respectively.


Assuntos
Antígeno B7-H1/análise , Neoplasias Encefálicas/etiologia , Neoplasias Colorretais/etiologia , Antígenos de Histocompatibilidade Classe I/análise , Indolamina-Pirrol 2,3,-Dioxigenase/análise , Linfócitos do Interstício Tumoral/patologia , Síndromes Neoplásicas Hereditárias/etiologia , Sarcoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Interferon gama/farmacologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Sarcoma/mortalidade , Sarcoma/patologia
20.
Gene ; 764: 145105, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32882333

RESUMO

Sarcoma (SARC) represents a group of highly histological and molecular heterogeneous rare malignant tumors with poor prognosis. There are few proposed classifiers for predicting patient's outcome. The Cancer Proteome Atlas (TPCA) and The Cancer Genome Atlas (TCGA) databases provide multi-omics datasets that enable a comprehensive investigation for this disease. The proteomic expression profile of SARC patients along with the clinical information was downloaded. 55 proteins were found to be associated with overall survival (OS) of patients using univariate Cox regression analysis. We developed a prognostic risk signature that comprises seven proteins (AMPKALPHA, CHK1, S6, ARID1A, RBM15, ACETYLATUBULINLYS40, and MSH6) with robust predictive performance using multivariate Cox stepwise regression analysis. Additionally, the signature could be an independent prognostic predictor after adjusting for clinicopathological parameters. Patients in high-risk group also have worse progression free intervals (PFI) than that of patients in low-risk group, but not for disease free intervals (DFI). The signature was validated using transcriptomic profile of SARC patients from TCGA. Potential mechanisms between high- and low-risk groups were identified using differentially expressed genes (DEGs) analysis. These DEGs were primarily enriched in RAS and MPAK signaling pathways. The signature protein molecules are candidate biomarkers for SARC, and the analysis of computational biology in tumor infiltrating lymphocytes and immune checkpoint molecules revealed distinctly immune landscapes of high- and low-risk patients. Together, we constructed a prognostic signature for predicting outcomes for SARC integrating proteomic and transcriptomic profiles, this might have value in guiding clinical practice.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Testes Genéticos/métodos , Sarcoma/mortalidade , Microambiente Tumoral/imunologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Mapeamento de Interação de Proteínas , Proteômica , Curva ROC , Sarcoma/tratamento farmacológico , Sarcoma/genética , Sarcoma/imunologia , Transcriptoma/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
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