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1.
Nat Commun ; 12(1): 5195, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465781

RESUMO

Functional tumor-specific cytotoxic T cells elicited by therapeutic cancer vaccination in combination with oncolytic viruses offer opportunities to address resistance to checkpoint blockade therapy. Two cancer vaccines, the self-adjuvanting protein vaccine KISIMA, and the recombinant oncolytic vesicular stomatitis virus pseudotyped with LCMV-GP expressing tumor-associated antigens, termed VSV-GP-TAA, both show promise as a single agent. Here we find that, when given in a heterologous prime-boost regimen with an optimized schedule and route of administration, combining KISIMA and VSV-GP-TAA vaccinations induces better cancer immunity than individually. Using several mouse tumor models with varying degrees of susceptibility for viral replication, we find that priming with KISIMA-TAA followed by VSV-GP-TAA boost causes profound changes in the tumor microenvironment, and induces a large pool of poly-functional and persistent antigen-specific cytotoxic T cells in the periphery. Combining this heterologous vaccination with checkpoint blockade further improves therapeutic efficacy with long-term survival in the spectrum. Overall, heterologous vaccination with KISIMA and VSV-GP-TAA could sensitize non-inflamed tumors to checkpoint blockade therapy.


Assuntos
Vacinas Anticâncer/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Vírus Oncolíticos/imunologia , Vírus da Estomatite Vesicular Indiana/imunologia , Animais , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Terapia Combinada , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Vírus Oncolíticos/fisiologia , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral , Vacinação , Vírus da Estomatite Vesicular Indiana/genética , Vírus da Estomatite Vesicular Indiana/fisiologia , Replicação Viral
2.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445092

RESUMO

Dendritic cells (DCs) are the most effective antigen presenting cells for the development of T cell responses. The only FDA approved DC-based immunotherapy to date is Sipuleucel-T, which utilizes a fusion protein to stimulate DCs ex vivo with GM-CSF and simultaneously deliver the antigen PAP for prostate cancer. This approach is restricted by the breadth of immunity elicited to a single antigen, and to cancers that have a defined tumor associated antigen. Other multi-antigen approaches have been restricted by poor efficacy of vaccine adjuvants. We have developed a vaccine platform that consists of autologous DCs pulsed with cytokine-adjuvanted tumor membrane vesicles (TMVs) made from tumor tissue, that encapsulate the antigenic landscape of individual tumors. Here we test the efficacy of DCs pulsed with TMVs incorporated with glycolipid-anchored immunostimulatory molecules (GPI-ISMs) in HER2-positive and triple negative breast cancer murine models. Pulsing of DCs with TMVs containing GPI-ISMs results in superior uptake of vesicles, DC activation and cytokine production. Adaptive transfer of TMV-pulsed DCs to tumor bearing mice results in the inhibition of tumor growth, reduction in lung metastasis, and an increase in immune cell infiltration into the tumors. These observations suggest that DCs pulsed with TMVs containing GPI-GM-CSF and GPI-IL-12 can be further developed to be used as a personalized immunotherapy platform for cancer treatment.


Assuntos
Antígenos de Neoplasias/imunologia , Citocinas/imunologia , Células Dendríticas/imunologia , Receptor ErbB-2/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Transferência Adotiva , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Receptor ErbB-2/análise , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia
3.
Nat Commun ; 12(1): 4734, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354077

RESUMO

The tumor microenvironment (TME) is a complex amalgam of tumor cells, immune cells, endothelial cells and fibroblastic stromal cells (FSC). Cancer-associated fibroblasts are generally seen as tumor-promoting entity. However, it is conceivable that particular FSC populations within the TME contribute to immune-mediated tumor control. Here, we show that intratumoral treatment of mice with a recombinant lymphocytic choriomeningitis virus-based vaccine vector expressing a melanocyte differentiation antigen resulted in T cell-dependent long-term control of melanomas. Using single-cell RNA-seq analysis, we demonstrate that viral vector-mediated transduction reprogrammed and activated a Cxcl13-expressing FSC subset that show a pronounced immunostimulatory signature and increased expression of the inflammatory cytokine IL-33. Ablation of Il33 gene expression in Cxcl13-Cre-positive FSCs reduces the functionality of intratumoral T cells and unleashes tumor growth. Thus, reprogramming of FSCs by a self-antigen-expressing viral vector in the TME is critical for curative melanoma treatment by locally sustaining the activity of tumor-specific T cells.


Assuntos
Melanoma Experimental/terapia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Técnicas de Reprogramação Celular/métodos , Quimiocina CXCL13/genética , Quimiocina CXCL13/imunologia , Feminino , Vetores Genéticos , Interleucina-33/deficiência , Interleucina-33/genética , Interleucina-33/imunologia , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/imunologia , Vírus da Coriomeningite Linfocítica/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células Estromais/imunologia , Células Estromais/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Microambiente Tumoral/imunologia
4.
Nat Commun ; 12(1): 4791, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34373452

RESUMO

Classical dendritic cells (cDC) are professional antigen-presenting cells (APC) that regulate immunity and tolerance. Neutrophil-derived cells with properties of DCs (nAPC) are observed in human diseases and after culture of neutrophils with cytokines. Here we show that FcγR-mediated endocytosis of antibody-antigen complexes or an anti-FcγRIIIB-antigen conjugate converts neutrophils into nAPCs that, in contrast to those generated with cytokines alone, activate T cells to levels observed with cDCs and elicit CD8+ T cell-dependent anti-tumor immunity in mice. Single cell transcript analyses and validation studies implicate the transcription factor PU.1 in neutrophil to nAPC conversion. In humans, blood nAPC frequency in lupus patients correlates with disease. Moreover, anti-FcγRIIIB-antigen conjugate treatment induces nAPCs that can activate autologous T cells when using neutrophils from individuals with myeloid neoplasms that harbor neoantigens or those vaccinated against bacterial toxins. Thus, anti-FcγRIIIB-antigen conjugate-induced conversion of neutrophils to immunogenic nAPCs may represent a possible immunotherapy for cancer and infectious diseases.


Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias/imunologia , Neutrófilos/imunologia , Receptores de IgG/genética , Receptores de IgG/imunologia , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Apresentação do Antígeno/imunologia , Complexo Antígeno-Anticorpo , Medula Óssea , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Movimento Celular , Proliferação de Células , Citocinas/imunologia , Células Dendríticas/imunologia , Endocitose , Humanos , Imunidade Inata , Imunoterapia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Espécies Reativas de Oxigênio , Transcriptoma
5.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360800

RESUMO

Therapeutic cancer vaccines have become increasingly qualified for use in personalized cancer immunotherapy. A deeper understanding of tumor immunology and novel antigen delivery technologies has assisted in optimizing vaccine design. Therapeutic cancer vaccines aim to establish long-lasting immunological memory against tumor cells, thereby leading to effective tumor regression and minimizing non-specific or adverse events. However, due to several resistance mechanisms, significant challenges remain to be solved in order to achieve these goals. In this review, we describe our current understanding with respect to the use of the antigen repertoire in vaccine platform development. We also summarize various intrinsic and extrinsic resistance mechanisms behind the failure of cancer vaccine development in the past. Finally, we suggest a strategy that combines immune checkpoint inhibitors to enhance the efficacy of cancer vaccines.


Assuntos
Vacinas Anticâncer/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Neoplasias/terapia , Medicina de Precisão , Animais , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/uso terapêutico , Humanos , Neoplasias/imunologia
6.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207500

RESUMO

The ability of tumor cells to evade the immune system is one of the main challenges we confront in the fight against cancer. Multiple strategies have been developed to counteract this situation, including the use of immunostimulant molecules that play a key role in the anti-tumor immune response. Such a response needs to be tumor-specific to cause as little damage as possible to healthy cells and also to track and eliminate disseminated tumor cells. Therefore, the combination of immunostimulant molecules and tumor-associated antigens has been implemented as an anti-tumor therapy strategy to eliminate the main obstacles confronted in conventional therapies. The immunostimulant 4-1BBL belongs to the tumor necrosis factor (TNF) family and it has been widely reported as the most effective member for activating lymphocytes. Hence, we will review the molecular, pre-clinical, and clinical applications in conjunction with tumor-associated antigens in antitumor immunotherapy, as well as the main molecular pathways involved in this association.


Assuntos
Ligante 4-1BB/imunologia , Antígenos de Neoplasias/imunologia , Imunidade Inata , Ativação Linfocitária , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Animais , Humanos , Neoplasias/patologia , Neoplasias/terapia
7.
Nature ; 596(7870): 126-132, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34290408

RESUMO

PD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a 'barcode' to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein-Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.


Assuntos
Antígenos de Neoplasias/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Regulação da Expressão Gênica , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Antígenos de Neoplasias/genética , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Células Cultivadas , Humanos , Memória Imunológica , Neoplasias Pulmonares/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA-Seq , Receptores de Interleucina-7/imunologia , Análise de Célula Única , Transcriptoma/genética , Microambiente Tumoral
8.
Adv Clin Chem ; 103: 1-45, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34229848

RESUMO

Lung cancer (LC) accounts for the majority of cancer-related deaths worldwide. Although screening the high-risk population by low-dose CT (LDCT) has reduced mortality, the cost and high false positivity rate has prevented its general diagnostic use. As such, better and more specific minimally invasive biomarkers are needed in general and for early LC detection, specifically. Autoantibodies produced by humoral immune response to tumor-associated antigens (TAA) are emerging as a promising noninvasive biomarker for LC. Given the low sensitivity of any one single autoantibody, a panel approach could provide a more robust and promising strategy to detect early stage LC. In this review, we summarize the background of TAA autoantibodies (TAAb) and the techniques currently used for identifying TAA, as well as recent findings of LC specific antigens and TAAb. This review provides guidance toward the development of accurate and reliable TAAb as immunodiagnostic biomarkers in the early detection of LC.


Assuntos
Anticorpos Antineoplásicos/sangue , Antígenos de Neoplasias/imunologia , Autoanticorpos/sangue , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Humanos , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/metabolismo
9.
Anticancer Res ; 41(7): 3371-3387, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230133

RESUMO

BACKGROUND/AIM: We compared the therapeutic efficacy of two recently developed experimental anticancer technologies: 1) in situ vaccination based on local immunotherapy with CpG oligonucleotides and anti-OX40 antibodies to activate antitumor immune response and 2) "Karanahan" technology [from the Sanskrit karana ('source') + han ('to kill')] based on the combined injection of cyclophosphamide and double-stranded DNA to eradicate cancer stem cells. MATERIALS AND METHODS: The anticancer approaches were compared on three types of mouse malignant tumors with different grades of immunogenicity: weakly immunogenic carcinoma Krebs-2, moderately immunogenic Lewis carcinoma, and highly immunogenic A20 В-cellular lymphoma. RESULTS: Our results indicated that in situ vaccination was the most effective against the highly immunogenic tumor А20. In addition, "Karanahan" demonstrated high efficiency in all types of tumors, regardless of their immunogenicity or size. CONCLUSION: "Karanahan" therapy showed higher efficacy relative to in situ vaccination with CpG oligonucleotides and anti-OX40 antibodies.


Assuntos
Antineoplásicos/imunologia , Imunoterapia/métodos , Animais , Anticorpos/imunologia , Antígenos de Diferenciação/imunologia , Antígenos de Neoplasias/imunologia , Carcinoma Pulmonar de Lewis/imunologia , Linhagem Celular Tumoral , Ciclofosfamida/imunologia , DNA/imunologia , Feminino , Linfoma/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Células-Tronco Neoplásicas/imunologia , Oligodesoxirribonucleotídeos/imunologia , Receptores OX40/imunologia , Vacinação/métodos
10.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204326

RESUMO

Immunotherapy is now considered an innovative and strong strategy to beat metastatic, drug-resistant, or relapsing tumours. It is based on the manipulation of several mechanisms involved in the complex interplay between cancer cells and immune system that culminates in a form of immune-tolerance of tumour cells, favouring their expansion. Current immunotherapies are devoted enforcing the immune response against cancer cells and are represented by approaches employing vaccines, monoclonal antibodies, interleukins, checkpoint inhibitors, and chimeric antigen receptor (CAR)-T cells. Despite the undoubted potency of these treatments in some malignancies, many issues are being investigated to amplify the potential of application and to avoid side effects. In this review, we discuss how sphingolipids are involved in interactions between cancer cells and the immune system and how knowledge in this topic could be employed to enhance the efficacy of different immunotherapy approaches. In particular, we explore the following aspects: how sphingolipids are pivotal components of plasma membranes and could modulate the functionality of surface receptors expressed also by immune cells and thus their functionality; how sphingolipids are related to the release of bioactive mediators, sphingosine 1-phosphate, and ceramide that could significantly affect lymphocyte egress and migration toward the tumour milieu, in addition regulating key pathways needed to activate immune cells; given the renowned capability of altering sphingolipid expression and metabolism shown by cancer cells, how it is possible to employ sphingolipids as antigen targets.


Assuntos
Imunomodulação , Neoplasias/imunologia , Neoplasias/metabolismo , Esfingolipídeos/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Comunicação Celular , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Lisofosfolipídeos/metabolismo , Neoplasias/terapia , Transdução de Sinais , Esfingolipídeos/química , Esfingolipídeos/imunologia , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Resultado do Tratamento
11.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207103

RESUMO

Ovarian cancer response to immunotherapy is limited; however, the evaluation of sensitive/resistant target treatment subpopulations based on stratification by tumor biomarkers may improve the predictiveness of response to immunotherapy. These markers include tumor mutation burden, PD-L1, tumor-infiltrating lymphocytes, homologous recombination deficiency, and neoantigen intratumoral heterogeneity. Future directions in the treatment of ovarian cancer include the utilization of these biomarkers to select ideal candidates. This paper reviews the role of immunotherapy in ovarian cancer as well as novel therapeutics and study designs involving tumor biomarkers that increase the likelihood of success with immunotherapy in ovarian cancer.


Assuntos
Imunoterapia , Neoplasias Ovarianas/terapia , Medicina de Precisão , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Terapia de Alvo Molecular , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/mortalidade , Medicina de Precisão/efeitos adversos , Medicina de Precisão/métodos , Resultado do Tratamento
12.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201655

RESUMO

It is now well accepted that the immune system can control cancer growth. However, tumors escape immune-mediated control through multiple mechanisms and the downregulation or loss of major histocompatibility class (MHC)-I molecules is a common immune escape mechanism in many cancers. MHC-I molecules present antigenic peptides to cytotoxic T cells, and MHC-I loss can render tumor cells invisible to the immune system. In this review, we examine the dysregulation of MHC-I expression in cancer, explore the nature of MHC-I-bound antigenic peptides recognized by immune cells, and discuss therapeutic strategies that can be used to overcome MHC-I deficiency in solid tumors, with a focus on the role of natural killer (NK) cells and CD4 T cells.


Assuntos
Antígenos de Neoplasias/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias/terapia , Evasão Tumoral/fisiologia , Animais , Linfócitos T CD4-Positivos/imunologia , Regulação para Baixo , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Mutação , Neoplasias/imunologia
13.
Theranostics ; 11(14): 6800-6817, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093854

RESUMO

Chimeric antigen receptor T cell (CAR-T) therapy is a new and effective form of adoptive cell therapy that is rapidly entering the mainstream for the treatment of CD19-positive hematological cancers because of its impressive effect and durable responses. Huge challenges remain in achieving similar success in patients with solid tumors. The current methods of monitoring CAR-T, including morphological imaging (CT and MRI), blood tests, and biopsy, have limitations to assess whether CAR-T cells are homing to tumor sites and infiltrating into tumor bed, or to assess the survival, proliferation, and persistence of CAR-T cells in solid tumors associated with an immunosuppressive microenvironment. Radionuclide-based molecular imaging affords improved CAR-T cellular visualization and therapeutic monitoring through either a direct cellular radiolabeling approach or a reporter gene imaging strategy, and endogenous cell imaging is beneficial to reflect functional information and immune status of T cells. Focusing on the dynamic monitoring and precise assessment of CAR-T therapy, this review summarizes the current applications of radionuclide-based noninvasive imaging in CAR-T cells visualization and monitoring and presents current challenges and strategic choices.


Assuntos
Antígenos de Neoplasias/imunologia , Imunoterapia Adotiva/métodos , Imagem Molecular/métodos , Neoplasias/diagnóstico por imagem , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/imunologia , Microambiente Tumoral , Animais , Genes Reporter , Humanos , Camundongos , Radioisótopos , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Tomografia Computadorizada por Raios X , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Nat Commun ; 12(1): 3615, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127674

RESUMO

Glioblastoma is considered one of the most aggressive malignancies in adult and pediatric patients. Despite decades of research no curative treatment is available and it thus remains associated with a very dismal prognosis. Although recent pre-clinical and clinical studies have demonstrated the feasibility of chimeric antigen receptors (CAR) T cell immunotherapeutic approach in glioblastoma, tumor heterogeneity and antigen loss remain among one of the most important challenges to be addressed. In this study, we identify p32/gC1qR/HABP/C1qBP to be specifically expressed on the surface of glioma cells, making it a suitable tumor associated antigen for redirected CAR T cell therapy. We generate p32 CAR T cells and find them to recognize and specifically eliminate p32 expressing glioma cells and tumor derived endothelial cells in vitro and to control tumor growth in orthotopic syngeneic and xenograft mouse models. Thus, p32 CAR T cells may serve as a therapeutic option for glioblastoma patients.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/farmacologia , Glioma/imunologia , Glioma/terapia , Linfócitos T/imunologia , Idoso , Animais , Antígenos de Neoplasias/imunologia , Neoplasias Encefálicas , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Feminino , Glioblastoma/genética , Glioblastoma/patologia , Glioma/genética , Glioma/metabolismo , Humanos , Imunoterapia Adotiva , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Proteínas Mitocondriais/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Serina Endopeptidases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cancer Sci ; 112(8): 3388-3400, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34115421

RESUMO

Tumor-associated autoantibodies (TAAb) could be serological tumor markers. This study aims to discover novel TAAb signatures for breast cancer (BC) detection. The protein microarray was used to identify candidate TAAb, which were further validated in 1197 sera from BC, benign breast diseases (BD), and healthy controls (HC) by enzyme-linked immunosorbent assay. In addition, 319 preoperative and postoperative sera were evaluated. A panel was determined using four different classifiers. Twelve TAAb were identified with frequencies of 15.8%-59.2%; their levels were significantly decreased in postoperative sera compared to those in preoperative sera (P < .05). A panel with six TAAb was developed and evaluated. The area under the curve (AUC) was 0.879 (74.3% sensitivity, 91.9% specificity) and 0.865 (69.7% sensitivity, 91.7% specificity) for distinguishing BC from HC in the training set and test set, respectively. The panel had an AUC of .884 (71.2% sensitivity, 90.5% specificity) for discriminating BC from BD. For identifying BC from all controls (HC+BD), the AUC was .916 (78.9% sensitivity, 90.2% specificity). The AUC of the panel was .920 and .934 for distinguishing stage I-II and age < 50 BC from HC, respectively. These identified TAAb have the potential to provide a non-invasive approach to detect BC.


Assuntos
Antígenos de Neoplasias/imunologia , Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Neoplasias da Mama/imunologia , Adulto , Área Sob a Curva , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Estudos de Casos e Controles , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Análise Serial de Proteínas
16.
Theranostics ; 11(15): 7425-7438, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34158858

RESUMO

The lack of tumor specific antigens (TSA) and the immune tolerance are two major obstacles for the immunotherapy of cancer. Current immune checkpoint inhibitors (ICIs) show clinical responses in only limited subsets of cancer patients, which, to some extent, depends on the mutation load of tumor cells that may generate neoantigens. Here, we aimed to generate a neoantigen MDP to exhibit stronger anti-tumor efficacy. Methods: In this study, we utilized chemically modified sialic acid precursor tetra acetyl-N-azidoacetyl-mannosamine (AC4ManNAZ) to engineer the glycoproteins on the membranes of tumor cells for the covalent ligation of hapten adjuvant Pam3CSK4 in vivo, which eventually generated a neoantigen, i.e., ManNAZ-DBCO-Pam3CSK4 (MDP), on tumor cells. The high labeling efficiency, relatively specific biodistribution in tumor tissues and the anti-tumor efficacy were confirmed in the syngeneic murine models of the breast cancer and the lung cancer. Results: The generation of MDP neoantigen in tumor-bearing mice significantly evoked both the humoral and the T-cell-dependent antitumor immune responses, resulting in a strong inhibition on the growth of the breast cancer and the lung cancer allografts and significantly prolonged survival of tumor-bearing mice. Interestingly, MDP neoantigen was able to dramatically increase the sensitivity of cancer cells to ICIs and greatly enhance the anti-tumor efficacy in the murine models of both breast cancer and the lung cancer, which showed no or low responses to the immunotherapy with anti-PD1 antibody alone. Conclusions: We developed a simple metabolic glycoengineering method to artificially generate neoantigens on tumor cells to enhance tumor cell immunogenicity, which is able to significantly improve the response and the clinical outcome of ICIs.


Assuntos
Antígenos de Neoplasias , Vacinas Anticâncer , Glicoproteínas , Lipopeptídeos , Neoplasias Mamárias Experimentais , Animais , Antígenos de Neoplasias/química , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/farmacologia , Vacinas Anticâncer/química , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/farmacologia , Linhagem Celular Tumoral , Feminino , Glicoproteínas/química , Glicoproteínas/imunologia , Glicoproteínas/farmacologia , Lipopeptídeos/química , Lipopeptídeos/imunologia , Lipopeptídeos/farmacologia , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/terapia , Camundongos
17.
Nat Commun ; 12(1): 3862, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162858

RESUMO

Memory CD8+ T cells populate non-lymphoid tissues (NLTs) following pathogen infection, but little is known about the establishment of endogenous tumor-specific tissue-resident memory T cells (TRM) during cancer immunotherapy. Using a transplantable mouse model of prostate carcinoma, here we report that tumor challenge leads to expansion of naïve neoantigen-specific CD8+ T cells and formation of a small population of non-recirculating TRM in several NLTs. Primary tumor destruction by irreversible electroporation (IRE), followed by anti-CTLA-4 immune checkpoint inhibitor (ICI), promotes robust expansion of tumor-specific CD8+ T cells in blood, tumor, and NLTs. Parabiosis studies confirm that TRM establishment following dual therapy is associated with tumor remission in a subset of cases and protection from subsequent tumor challenge. Addition of anti-PD-1 following dual IRE + anti-CTLA-4 treatment blocks tumor growth in non-responsive cases. This work indicates that focal tumor destruction using IRE combined with ICI is a potent in situ tumor vaccination strategy that generates protective tumor-specific TRM.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Eletroporação/métodos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Neoplasias da Próstata/terapia , Animais , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Memória Imunológica/imunologia , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias da Próstata/imunologia , Microambiente Tumoral/imunologia
18.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072732

RESUMO

CAR-T (chimeric antigen receptor T) cells have emerged as a milestone in the treatment of patients with refractory B-cell neoplasms. However, despite having unprecedented efficacy against hematological malignancies, the treatment is far from flawless. Its greatest drawbacks arise from a challenging and expensive production process, strict patient eligibility criteria and serious toxicity profile. One possible solution, supported by robust research, is the replacement of T lymphocytes with NK cells for CAR expression. NK cells seem to be an attractive vehicle for CAR expression as they can be derived from multiple sources and safely infused regardless of donor-patient matching, which greatly reduces the cost of the treatment. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have activity against non-hematological neoplasms. Here, we present a thorough overview of the current state of knowledge regarding the use of CAR-NK cells in treating various solid tumors.


Assuntos
Imunoterapia Adotiva , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/imunologia , Técnicas de Cultura de Células , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Engenharia Genética , Humanos , Células Matadoras Naturais/metabolismo , Neoplasias/diagnóstico , Neoplasias/etiologia , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Resultado do Tratamento
19.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071152

RESUMO

Prostate cancer (PCa) is the second most common cancer in men, causing more than 300,000 deaths every year worldwide. Due to their superior cell-killing ability and the relative simplicity of their preparation, immunotoxin molecules have great potential in the clinical treatment of cancer, and several such molecules have been approved for clinical application. In this study, we adopted a relatively simple strategy based on a single-domain antibody (sdAb) and an improved Pseudomonas exotoxin A (PE) toxin (PE24X7) to prepare a safer immunotoxin against prostate-specific membrane antigen (PSMA) for PCa treatment. The designed anti-PSMA immunotoxin, JVM-PE24X7, was conveniently prepared in its soluble form in an Escherichia coli (E. coli) system, avoiding the complex renaturation process needed for immunotoxin preparation by the conventional strategy. The product was very stable and showed a very strong ability to bind the PSMA receptor. Cytotoxicity assays showed that this molecule at a very low concentration could kill PSMA-positive PCa cells, with an EC50 value (concentration at which the cell viability decreased by 50%) of 15.3 pM against PSMA-positive LNCaP cells. Moreover, this molecule showed very good killing selectivity between PSMA-positive and PSMA-negative cells, with a selection ratio of more than 300-fold. Animal studies showed that this molecule at a very low dosage (5 × 0.5 mg/kg once every three days) completely inhibited the growth of PCa tumors, and the maximum tolerable dose (MTD) was more than 15 mg/kg, indicating its very potent tumor-treatment ability and a wide therapeutic window. Use of the new PE toxin, PE24X7, as the effector moiety significantly reduced off-target toxicity and improved the therapeutic window of the immunotoxin. The above results demonstrate that the designed anti-PSMA immunotoxin, JVM-PE24X7, has good application value for the treatment of PCa.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Glutamato Carboxipeptidase II/antagonistas & inibidores , Imunotoxinas/uso terapêutico , Terapia de Alvo Molecular , Neoplasias da Próstata/tratamento farmacológico , Anticorpos de Domínio Único/uso terapêutico , Animais , Especificidade de Anticorpos , Reações Antígeno-Anticorpo , Antígenos de Superfície/imunologia , Antineoplásicos Imunológicos/toxicidade , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Glutamato Carboxipeptidase II/imunologia , Humanos , Imunotoxinas/toxicidade , Masculino , Dose Máxima Tolerável , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Moleculares , Conformação Proteica , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/toxicidade , Anticorpos de Domínio Único/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188558, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33933558

RESUMO

Increasing evidence shows that numerous cancer-testis antigens (CTAs) are uniquely overexpressed in various types of cancer and most CTAs are oncogenic. Overexpression of oncogenic CTAs promotes carcinogenesis, cancer metastasis, and drug resistance. Oncogenic CTAs are generally associated with poor prognosis in cancer patients and are an important hallmark of cancer, making them a crucial target for cancer immunotherapy. CTAs-targeted antibodies, vaccines, and chimeric antigen receptor-modified T cells (CAR-T) have recently been used in cancer treatment and achieved promising outcomes in the preclinical and early clinical trials. However, the efficacy of current CTA-targeted therapeutics is either moderate or low in cancer therapy. CTA-targeted cancer immunotherapy is facing enormous challenges. Several critical scientific problems need to be resolved: (1) the antigen presentation function of MHC-I protein is usually deficient in cancer patients, so that very low amounts of intracellular CTA epitopes are presented to tumor cell membrane surface, leading to weak immune response and subsequent immunity to CTAs; (2) various immunosuppressive cells are rich in tumor tissues leading to diminished tumor immunity; (3) the tumor tissue microenvironment markedly reduces the efficacy of cancer immunotherapy. In the current review paper, the authors propose new strategies and approaches to overcome the barriers of CTAs-targeted immunotherapy and to develop novel potent immune therapeutics against cancer. Finally, we highlight that the oncogenic CTAs have high tumor specificity and immunogenicity, and are sensible targets for cancer immunotherapy. We predict that CTAs-targeted immunotherapy will bring about breakthroughs in cancer therapy in the near future.


Assuntos
Antígenos de Neoplasias/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Neoplasias/terapia , Proteínas Oncogênicas/metabolismo , Linfócitos T/transplante , Testículo/metabolismo , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/efeitos adversos , Vacinas Anticâncer/efeitos adversos , Humanos , Imunoterapia Adotiva/efeitos adversos , Masculino , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/imunologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Testículo/imunologia , Resultado do Tratamento , Microambiente Tumoral
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