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1.
Recent Results Cancer Res ; 214: 71-91, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473849

RESUMO

Bispecific T cell engagers are antibody constructs directed to a tumor-specific target on the one hand and to CD3-positive T cells on the other hand. Blinatumomab is a compound with specificity for the pan-B cell marker CD19. Clinical activity was tested in relapsed and refractory (R/R) non-Hodgkin's Lymphoma (NHL), R/R acute lymphoblastic leukemia (ALL), and ALL patients with minimal residual disease. Trials have already been started in de novo ALL. The most clinically relevant toxicities are neurologic events and cytokine release syndrome as with other T cell-activating therapies. The mechanisms of resistance are not fully understood. Higher leukemia load and later stage disease represent unfavorable factors. Besides, an upregulation of regulatory T cells and inhibitory molecules like PD-1/PD-L1 may have a role as the loss of target by several mechanisms. The future will show whether the use of bispecifics in ALL can change the standard treatment algorithms and whether bispecific T cell engagers will also be successfully used in other malignant entities.


Assuntos
Anticorpos Biespecíficos/farmacologia , Linfoma não Hodgkin/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfócitos T/citologia , Antígenos CD19 , Ensaios Clínicos como Assunto , Humanos , Neoplasia Residual/terapia
2.
Recent Results Cancer Res ; 214: 93-128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473850

RESUMO

As a specifically programmable, living immunotherapeutic drug, chimeric antigen receptor (CAR)-modified T cells are providing an alternative treatment option for a broad variety of diseases including so far refractory cancer. By recognizing a tumor-associated antigen, the CAR triggers an anti-tumor response of engineered patient's T cells achieving lasting remissions in the treatment of leukemia and lymphoma. During the last years, significant progress was made in optimizing the CAR design, in manufacturing CAR-engineered T cells, and in the clinical management of patients showing promise to establish adoptive CAR T cell therapy as an effective treatment option in the forefront.


Assuntos
Imunoterapia Adotiva , Neoplasias/terapia , Receptores de Antígenos Quiméricos , Antígenos de Neoplasias/imunologia , Ensaios Clínicos como Assunto , Humanos , Receptores de Antígenos de Linfócitos T , Linfócitos T/imunologia
3.
Recent Results Cancer Res ; 214: 129-151, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473851

RESUMO

The adoptive cell transfer (ACT) of genetically engineered T cell receptor (TCR) T cells is one of the burgeoning fields of immunotherapy, with promising results in current clinical trials. Presently, clinicaltrials.gov has over 200 active trials involving adoptive cell therapy. The ACT of genetically engineered T cells not only allows the ability to select for TCRs with desired properties such as high-affinity receptors and tumor reactivity but to further enhance those receptors allowing for better targeting and killing of cancer cells in patients. Moreover, the addition of genetic material, including cytokines and cytokine receptors, can increase the survival and persistence of the T cell allowing for complete and sustained remission of cancer targets. The potential for improvement in adoptive cell therapy is limitless, with genetic modifications targeting to improve weaknesses of ACT and to thus enhance receptor affinity and functional avidity of the genetically engineered T cells.


Assuntos
Engenharia Genética , Imunoterapia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T , Linfócitos T/citologia , Humanos
4.
Adv Exp Med Biol ; 1172: 21-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628650

RESUMO

Molecules encoded by the Major Histocompatibility Complex (MHC) bind self or foreign peptides and display these at the cell surface for recognition by receptors on T lymphocytes (designated T cell receptors-TCR) or on natural killer (NK) cells. These ligand/receptor interactions govern T cell and NK cell development as well as activation of T memory and effector cells. Such cells participate in immunological processes that regulate immunity to various pathogens, resistance and susceptibility to cancer, and autoimmunity. The past few decades have witnessed the accumulation of a huge knowledge base of the molecular structures of MHC molecules bound to numerous peptides, of TCRs with specificity for many different peptide/MHC (pMHC) complexes, of NK cell receptors (NKR), of MHC-like viral immunoevasins, and of pMHC/TCR and pMHC/NKR complexes. This chapter reviews the structural principles that govern peptide/MHC (pMHC), pMHC/TCR, and pMHC/NKR interactions, for both MHC class I (MHC-I) and MHC class II (MHC-II) molecules. In addition, we discuss the structures of several representative MHC-like molecules. These include host molecules that have distinct biological functions, as well as virus-encoded molecules that contribute to the evasion of the immune response.


Assuntos
Imunidade Adaptativa , Imunidade Inata , Complexo Principal de Histocompatibilidade , Receptores de Antígenos de Linfócitos T , Linfócitos T , Imunidade Adaptativa/imunologia , Animais , Humanos , Imunidade Inata/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Células Matadoras Naturais/química , Receptores de Células Matadoras Naturais/imunologia , Linfócitos T/imunologia
5.
Adv Exp Med Biol ; 1172: 63-78, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628651

RESUMO

The co-stimulation and co-inhibition signal pathways, immune checkpoints, are among the central mechanisms to regulate the T-cell immunity. Optimal signals involve intricate interactions of numerous ligands and receptors. Manipulation of these signals offers great clinical opportunities and has revolutionized the cancer treatment therapies. The 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo in recognition of their discovery of cancer immunotherapy by inhibition of immune checkpoint molecules. Despite the landmark discovery in cancer immunotherapy, the efforts to harness immunity against cancer are also restricted by the limited knowledge on the co-stimulation and co-inhibition signaling networks. Understanding the structures of these molecules, in particular, tackling the interaction paradigms from the structural perspective, help to provide more accurate insights into the signaling mechanisms, which may further facilitate the development of novel biologics and improve the efficacy of the existing biologics against these targets. Here we review our current understanding on the structures of these co-stimulatory and co-inhibitory molecules. Specifically, we focus on the structural basis of several checkpoint molecules among the CD28-B7 family and discuss the therapeutic drugs against these targets for the treatment of human cancers, autoimmune disorders, and transplantation.


Assuntos
Antígenos CD28 , Linfócitos T , Doenças Autoimunes , Antígenos CD28/química , Antígenos CD28/imunologia , Humanos , Imunoterapia , Neoplasias/terapia , Transplante de Órgãos , Transdução de Sinais/imunologia , Linfócitos T/imunologia
6.
Anticancer Res ; 39(10): 5531-5539, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570447

RESUMO

BACKGROUND: Possible correlations between the expression of immune checkpoint molecules and prognosis in childhood acute leukemia were investigated. MATERIALS AND METHODS: The expression of programmed-death 1 (PD1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and B- and T-lymphocyte attenuator (BTLA) was determined by flow cytometry on peripheral αß+ and γδ+ T-cells from patients with newly diagnosed acute lymphoblastic leukemia (ALL) (n=9) or acute myeloid leukemia (AML) (n=12), and from healthy volunteers (n=7). The expression of programmed-death ligand 1 (PD-L1), B7-1, B7-2, human leukocyte antigen-ABC (HLA-ABC), and herpesvirus-entry mediator (HVEM) ligands was determined on leukemia blasts. RESULTS: PD1 expression on αß+ and γδ+ T-cells was significantly higher in patients with ALL than in those with AML (p=0.0019 and 0.0239, respectively). CTLA-4 expression was moderately higher on αß+ and γδ+ T-cells in ALL (p=0.077 and 0.077, respectively), whereas HLA-ABC expression was significantly higher in AML blast cells (p=0.0182). The expression of CTLA-4 on γδ+ T-cells and the B7-2 ligand on blasts was higher in patients with high-risk ALL (p=0.02 and 0.02, respectively). In AML, PD1 expression on αß+ T-cells was higher in the intermediate-risk group (p=0.05), whereas HVEM expression was significantly higher in the low-risk group (p=0.02). Expression of CTLA-4 on γδ+ T-cells and PD-L1 on blasts were both associated with poor relapse-free survival outcomes in ALL (p=0.049). CONCLUSION: The higher expression of immune checkpoint molecules, in particular, CTLA-4 and PD-L1 are associated with a poorer prognosis in ALL, suggesting that selective use of the immune checkpoint blockade might improve the clinical outcomes in patients with ALL.


Assuntos
Leucemia/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Linfócitos T/imunologia , Doença Aguda , Adolescente , Adulto , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/metabolismo , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Ligantes , Masculino , Pessoa de Meia-Idade , Recidiva , Adulto Jovem
7.
Science ; 366(6462): 188-189, 2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31601759
8.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(9): 1133-1136, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31657339

RESUMO

OBJECTIVE: To investigate the expressions of CD4+CD45RA+T cells and CD4+CD45RO+T cells in peripheral blood of patients with acute coronary syndrome (ACS) and their significance. METHODS: A case-control study was conducted. Ninety-four patients receiving coronary angiography (CAG) admitted to Tianjin Chest Hospital from March 5th to April 27th in 2018 were enrolled. They were divided into non-coronary heart disease (CHD) group (n = 12), unstable angina pectoris (UAP) group (n = 27), acute non-ST elevation myocardial infarction (NSTEMI) group (n = 27) and acute ST elevation myocardial infarction (STEMI) group (n = 28) according to the patients' symptoms, electrocardiogram, troponin test and angiographic results. General data, blood routine parameters, and biochemical indicators were collected. The ratios of CD4+CD45RA+T cells and CD4+CD45RO+T cells were determined by flow cytometry. Multivariate Logistic regression was used to evaluate whether CD4+CD45RA+T cells and CD4+CD45RO+T cells were associated with STEMI. RESULTS: Ninety-four patients were included initially. After excluding the patients who died during the intervention, 93 patients were enrolled in the data analysis finally, with 12 patients in the non-CHD group, 27 patients in the UAP group, and the same as the NSTEMI group and the STEMI group. Compared with the non-CHD group, white blood cell count (WBC) was decreased (×109/L: 6.03±1.30 vs. 6.60±1.30, P < 0.05), and lymphocyte ratio was increased (0.273±0.059 vs. 0.269±0.070, P > 0.05) in patients of the UAP group; however, in the NSTEMI group and STEMI group, WBC was increased (×109/L: 8.29±2.28, 9.86±2.76 vs. 6.60±1.30, both P < 0.05), and lymphocyte ratio was decreased (0.236±0.076, 0.173±0.094 vs. 0.269±0.070, P > 0.05 and P < 0.05), especially in the STEMI group [WBC (×109/L): 9.86±2.76 vs. 6.60±1.30, lymphocyte ratio: 0.173±0.094 vs. 0.269±0.070, both P < 0.05]. There was no significant difference in biochemical indicators among all of the groups. Flow cytometry results showed that the ratios of CD4+CD45RO+T cells in the UAP group and NSTEMI group were higher than those in the non-CHD group (0.323±0.074, 0.319±0.078 vs. 0.314±0.058, both P > 0.05); however, the ratio of CD4+CD45RO+T cells in the STEMI group showed a decreased tendency (0.270±0.057 vs. 0.314±0.058, P > 0.05), and it was significantly lower than that in the UAP group and the NSTEMI group (0.270±0.057 vs. 0.323±0.074, 0.319±0.078, both P < 0.05). There was no significant difference in the ratio of CD4+CD45RA+T cells among all of the groups. Multivariate Logistic regression analysis showed that CD4+CD45RA+T cells ratio was not significantly correlated with the occurrence of STEMI [odds ratio (OR) = 0.976, 95% confidence interval (95%CI) was 0.907-1.050, P = 0.518], but CD4+CD45RO+T cells ratio was significantly correlated with the occurrence of STEMI (OR = 0.888, 95%CI was 0.821-0.961, P = 0.003). CONCLUSIONS: There was no significant difference in the ratio of CD4+CD45RA+T cells among UAP, NSTEMI and STEMI patients, and CD4+CD45RO+T cells ratio in the STEMI group was significantly lower than that in the UAP group and NSTEMI group. CD4+CD45RO+T cells ratio may be risk factor of STEMI.


Assuntos
Síndrome Coronariana Aguda , Infarto do Miocárdio , Angina Instável , Estudos de Casos e Controles , Humanos , Linfócitos T
9.
Adv Exp Med Biol ; 1164: 225-233, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576552

RESUMO

Immune checkpoint blockade (ICB) has proved successful in the immunotherapeutic treatment of various human cancers. Despite its success, most patients are still not cured while immunogenic cold cancers are still poorly responsive. There is a need for novel clinical interventions in immunotherapy, either alone or in conjunction with ICB. Here, we outline our recent discovery that the intracellular signaling kinase glycogen synthase kinase-3 (GSK-3) is a central regulator of PD-1 in T-cells. We demonstrate the application of small molecule inhibitor (SMI) approaches to down-regulate PD-1 in tumor immunotherapy. GSK-3 SMIs were found as effective as anti-PD-1 in the elimination of melanoma in mouse models. We propose the development of novel SMIs to target co-receptors for the future of immunotherapy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase , Imunoterapia , Melanoma , Animais , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Melanoma/terapia , Camundongos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/fisiologia
10.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3448-3453, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602908

RESUMO

The aim of this paper was to study the influence of triptolide in the immune response pathways of acquired immune deficiency syndrome( AIDS). Target proteins of triptolide and related genes of AIDS were searched in PubChem and Gene databases on line. Molecular networks and canonical pathways comparison analyses were performed by bioinformatics software( IPA). There were 15 targets proteins of triptolide and 258 related genes of AIDS. Close biological relationships of molecules of triptolide and AIDS were established by networks analysis. There were 21 common immune response pathways of triptolide and AIDS,including neuroinflammation signaling pathway,Th1 and Th2 activation pathway and role of pattern recognition receptors in recognition of bacteria and viruses. Triptolide stimulated immune response pathways by the main molecules of IFNγ,JAK2,NOD1,PTGS2,RORC. IFNγ is the focus nodes of triptolide and AIDS,and regulates genes of AIDS directly or indirectly. Triptolide may against AIDS by regulating molecules IFNγ in immune response pathways.


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Diterpenos/farmacologia , Interferon gama/genética , Fenantrenos/farmacologia , Síndrome de Imunodeficiência Adquirida/imunologia , Biologia Computacional , Compostos de Epóxi/farmacologia , Redes Reguladoras de Genes , Humanos , Receptores de Reconhecimento de Padrão/imunologia , Transdução de Sinais , Linfócitos T/imunologia
11.
Rinsho Ketsueki ; 60(9): 1046-1055, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597826

RESUMO

Human iPS cells are somatic cells reprogrammed to the pluripotent state. Because of their pluripotent nature, iPS cells are now commonly used to model several developmental processes including hematopoiesis in vitro. The in vitro models can be used to study the mechanisms regulating not only normal hematopoiesis but also hematological diseases ranging from monogenic congenital disorders to genetically multifactorial malignancies. Those disease models can also be used to investigate novel treatments through procedures including high throughput drug screening. The possible clinical applications of iPS cell-derived hematopoietic cells include immunotherapy with T lymphocytes, NK cells and macrophages, and transfusion therapy with platelets and red blood cells. Platelets have now been produced from iPS cells in quantities sufficient for clinical use. By developing expandable immortalized megakaryocyte cell lines (imMKCLs), several novel drugs and turbulence-incorporated bioreactors, efficient and scalable generation of platelets was achieved. This review summarizes the current status of iPS cell research in hematopoiesis with details on iPS cell-derived platelets.


Assuntos
Plaquetas/citologia , Terapia Baseada em Transplante de Células e Tecidos , Células-Tronco Pluripotentes Induzidas/citologia , Diferenciação Celular , Eritrócitos , Hematopoese , Humanos , Imunoterapia , Células Matadoras Naturais , Macrófagos , Megacariócitos , Linfócitos T
12.
Genes Dev ; 33(17-18): 1117-1135, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31481536

RESUMO

T-cell development in mammals is a model for lineage choice and differentiation from multipotent stem cells. Although T-cell fate choice is promoted by signaling in the thymus through one dominant pathway, the Notch pathway, it entails a complex set of gene regulatory network and chromatin state changes even before the cells begin to express their signature feature, the clonal-specific T-cell receptors (TCRs) for antigen. This review distinguishes three developmental modules for T-cell development, which correspond to cell type specification, TCR expression and selection, and the assignment of cells to different effector types. The first is based on transcriptional regulatory network events, the second is dominated by somatic gene rearrangement and mutation and cell selection, and the third corresponds to establishing a poised state of latent regulator priming through an unknown mechanism. Interestingly, in different lineages, the third module can be deployed at variable times relative to the completion of the first two modules. This review focuses on the gene regulatory network and chromatin-based kinetic constraints that determine activities of transcription factors TCF1, GATA3, PU.1, Bcl11b, Runx1, and E proteins in the primary establishment of T-cell identity.


Assuntos
Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Linfócitos T/citologia , Animais , Diferenciação Celular/genética , Linhagem da Célula , Cromatina/metabolismo , Redes Reguladoras de Genes , Hematopoese , Linfócitos T/metabolismo , Timo/citologia , Timo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Cancer Discov ; 9(9): 1164-1166, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31481406

RESUMO

Unlike conventional MHC-reactive T cells, unconventional T cells have emerged as an abundant component of the human immune system because of their role in tumor immunology. In this issue of Cancer Discovery, Hundeyin and colleagues have identified a population of unconventional T cells in pancreatic tumors that can reprogram the immune evasive components of the tumor to promote immunogenicity and thus are critical for the development of novel cell-based therapy in pancreatic cancer.See related article by Hundeyin et al., p. 1288.


Assuntos
Neoplasias Pancreáticas , Linfócitos T , Humanos , Macrófagos
14.
Tumour Biol ; 41(9): 1010428319873749, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31496424

RESUMO

Differentiation therapy is directed to the self-renewing cancer stem cells, as well as their progeny transit amplifying cells, to force them to mature to terminal differentiation. Differentiation therapy is effective in treatment of neuroblastomas and myeloid leukemias. Checkpoint inhibition therapy removes blocks to cancer reactive T-killer cells and allows them to react to malignant cells and limit the growth of cancer. The percentage of patients with a given cancer that responds to either therapy is less than hoped for, and the duration of response is variable. Multiplying the response rate (percentage of patients responding to therapy) by the duration of response may be used to derive a survival score for patients treated with differentiation therapy or checkpoint inhibition. By this criterion, differentiation therapy gives better survival scores than checkpoint inhibition. Yet, checkpoint inhibition is considered a great success, mostly because it may be applied to many different types of cancer, and differentiation therapy is considered relatively ineffective because it is limited to a few specific cancers. On the other hand, the cost of checkpoint inhibition treatment is 10-20 times more per patient than that of differentiation therapy. Hopefully, future combined treatments and advances in both approaches will increase the effectiveness of these cancer treatments.


Assuntos
Antineoplásicos/uso terapêutico , Sobreviventes de Câncer/estatística & dados numéricos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Neoplasias/mortalidade , Células-Tronco Neoplásicas/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Prognóstico , Taxa de Sobrevida
15.
Anticancer Res ; 39(9): 4957-4963, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519601

RESUMO

BACKGROUND/AIM: Adjuvant radiotherapy (RT) damages multiple layers of skin, muscle, blood vessels and blood cells that are included within the RT area. Indirect, bystander systemic effects could also develop in cells not directly hit by radiation. MATERIALS AND METHODS: Ninety-three female patients recovering from breast cancer surgery and 82 female healthy blood donors were analyzed. For identification of systemic adaptive and innate immune response, rapid and low-cost blood-based biomarkers were assayed. RESULTS: Post-operated breast cancer patients had a decreased number of circulating adaptive immune response cells but increased number of circulating immunosuppressive myeloid subpopulations. RT decreased the number of T-cells and platelets without influencing the number of immunosuppressive myeloid subpopulations. Alterations in the number and phenotypes of T-cell subpopulations were associated with SNPs. CONCLUSION: The combination of RT and immunotherapy might provide optimal treatment for cancer patients.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Imunidade Celular/genética , Imunidade Celular/efeitos da radiação , Contagem de Leucócitos , Fenótipo , Polimorfismo de Nucleotídeo Único , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Estudos de Casos e Controles , Feminino , Humanos , Imunidade Inata , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Radioterapia Adjuvante , Linfócitos T/imunologia , Linfócitos T/metabolismo
16.
Gan To Kagaku Ryoho ; 46(9): 1372-1376, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31530773

RESUMO

T cells are critical effector immune cells, and mutation-derived neoantigens are critical tumor-specific antigens in natural immune responses to cancer(cancer immunosurveillance). However, the underlying mechanisms are poorly understood, particularly in the human clinical setting, such as how many tumor antigens are related to cancer elimination and whether immunodominance of antigens exist in humans. Furthermore, it is unclear whether specific T cells recognizing neoantigens can control cancer for a long time in an equilibrium state. Cancer immunotherapy including immune checkpoint inhibitors (ICIs)such as PD-1 and CTLA-4 blockades has attracted much attention for cancer treatment, but they remain effective only in a minority of patients. However, the efficacy of ICIs, which is characterized by long term durable responses has suggested that host immunity, if re-activated, can eliminate cancer cells or maintain cancer for a long time(therapeutically induced cancer immune elimination or equilibrium). Recent reports show that the loss of neoantigens has occurred at the DNA and RNA level as results of both naturally and therapeutically induced tumor-specific immune responses, leading to tumor immune escape(re-escape). Here we focus on the role of neoantigens in naturally and therapeutically induced immunoediting revealed by cancer immunogenomics approaches utilizing clinical samples to develop effective neoantigen-based cancer immunotherapies.


Assuntos
Neoplasias , Antígenos de Neoplasias , Humanos , Imunoterapia , Mutação , Linfócitos T
17.
Cancer Immunol Immunother ; 68(10): 1621-1633, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31549213

RESUMO

Defects in DNA damage repair caused by mutations in BRCA1/2, ATM or other genes have been shown to play an important role in the development and progression of prostate cancer. The influence of such mutations on anti-tumor immunity in prostate cancer, however, is largely unknown. To better understand the correlation between BRCA1/2 mutations and the immune phenotype in prostate cancer, we characterized the immune infiltrate of eight BRCA2-mutated tumors in comparison with eight BRCA1/2 wild-type patients by T-cell receptor sequencing and immunohistochemistry for CD45, CD4, CD8, FOXP3, and CD163. In addition, we analyzed seven prostate cancer biopsies that were either BRCA2 or ATM-mutated in comparison with wild-type tumors. Whereas in BRCA1/2 wild-type tumors, immune cells were found predominantly extratumorally, most BRCA2-mutated tumors including one biopsy showed a significantly increased intratumoral immune cell infiltration. The ratio of intratumoral to extratumoral immune cells was considerably higher in BRCA2-mutated tumors for all markers and reached statistical significance for CD4 (p = 0.007), CD8 (p = 0.006), and FOXP3 (p = 0.001). However, the intratumoral CD8 to FOXP3 ratio showed a trend to be lower in BRCA2-mutated tumors suggesting a more suppressed tumor immune microenvironment. Our findings provide a rationale for the future use of immune oncological approaches in BRCA2-mutated prostate cancer and may encourage efforts to target immunosuppressive T-cell populations to prime tumors for immunotherapy.


Assuntos
Genes BRCA2 , Mutação , Neoplasias da Próstata/imunologia , Antígenos CD8/análise , Fatores de Transcrição Forkhead/análise , Humanos , Masculino , Fenótipo , Neoplasias da Próstata/genética , Linfócitos T/imunologia , Microambiente Tumoral
18.
Cancer Immunol Immunother ; 68(10): 1635-1648, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31549214

RESUMO

Pancreatic cancer has been termed a 'recalcitrant cancer' due to its relative resistance to chemotherapy and immunotherapy. This resistance is thought to be due in part to the dense fibrotic tumor microenvironment and lack of tumor infiltrating CD8 + T cells. The gastrointestinal peptide, gastrin, has been shown to stimulate growth of pancreatic cancer by both a paracrine and autocrine mechanism. Interruption of gastrin at the CCK receptor may reduce tumor-associated fibrosis and alter tumor immune cells. Polyclonal Ab Stimulator (PAS) is a vaccine that targets gastrin and has been shown to prolong survival of patients with pancreatic cancer. Here, we report that PAS vaccination monotherapy elicits both a humoral and cellular immune response when used in immune competent mice-bearing pancreatic tumors and that PAS monotherapy produced a marked T-cell activation and influx of CD8 + lymphocytes into pancreatic tumors. Isolated peripheral lymphocytes elicited cytokine release upon re-stimulation with gastrin in vitro demonstrating specificity of immune activation for the target peptide. Combination therapy with PAS and PD-1 Ab activated CD4 -/CD8 - TEMRA cells important in T-cell-mediated tumor death and memory. Tumors of mice treated with PAS (250 µg) or PAS (100 and 250 µg) in combination with a PD-1 Ab were significantly smaller compared to tumors from PBS or PD-1 Ab-treated mice. When PAS was given in combination with PD-1 Ab, tumors had less fibrosis, fewer inhibitory Treg lymphocytes, and fewer tumor-associated macrophages. These findings reveal a novel approach to improve treatment strategies for pancreatic cancer.


Assuntos
Vacinas Anticâncer/imunologia , Gastrinas/imunologia , Neoplasias Pancreáticas/terapia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral , Vacinação , Animais , Linhagem Celular Tumoral , Memória Imunológica , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Linfócitos T/imunologia
19.
Isr Med Assoc J ; 21(7): 454-459, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31507120

RESUMO

BACKGROUND: Platelets have the ability to influence the immune system and the inflammatory process and may be strongly involved in the whole pathogenic process of chronic inflammatory joint diseases, such as rheumatoid arthritis. They may play a significant role even before the clinical onset of the disease, contributing to the loss of tolerance of the immune system and the induction of autoimmunity. Subsequently, they can interact with the most important cellular players involved in autoimmunity and inflammation, namely innate immunity cells and T cells and eventually contribute to the building of inflammation in the synovium, thus inducing the activation, migration, and proliferation of fibroblasts that eventually lead to joint damage. Due to their peculiar features, studying the behavior of platelets is a challenging task; however, platelets may prove to be valuable therapeutic targets in the future.


Assuntos
Artrite Reumatoide/imunologia , Plaquetas/imunologia , Sinovite/imunologia , Artrite Reumatoide/patologia , Autoimunidade/imunologia , Fibroblastos/imunologia , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Inflamação/patologia , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Sinovite/patologia , Linfócitos T/imunologia
20.
Isr Med Assoc J ; 21(7): 503, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31507132

RESUMO

BACKGROUND: Tumor treating fields (TTFields) are low-intensity, intermediate frequency electric fields that affect proliferating cells. TTFields are FDA approved for treatment of newly diagnosed and recurrent glioblastoma. Combining TTFields with immunotherapy is a rational approach due to their different mechanisms of action (MOA) and to the ability of TTFields to induce immunogenic cell death. Conversely, TTFields may interfere with immune functions critical for effective T-cell responses. OBJECTIVES: To evaluate the effects of TTFields on pivotal antitumoral T-cell functions. METHODS: T-cells from healthy donor peripheral blood (PB) or from viably dissociated human glioblastoma samples were cultured under normal or TTFields conditions, with or without superantigen stimulation. Multiparametric flow cytometry (8-color) was used to assess T-cell responses by monitoring select pivotal functions: proliferation (CFSE), IFNγ secretion, cytotoxic degranulation (CD107a), and activation/exhaustion (PD-1). Cellular viability was assessed in a dedicated assay. A chimeric antigen receptor (CAR) T-cell-based assay directly evaluated cellular cytotoxicity. RESULTS: Activated PB T-cells and tumor-infiltrating T-cells (TILs) preserved all monitored anti- tumoral functions under TTFields, apart from proliferation. This finding also applied specifically to PD-1 + TILs, comprised predominantly of tumor antigen-specific cells. Activated T-cells that attempted to proliferate under TTFields demonstrated decreased viability, in line with TTField MOA. Small or no reduction in viability was found in T-cells that did not attempt to proliferate, whether activated or resting. CONCLUSIONS: All monitored anti-tumoral T cell functions, except for proliferation, were unhindered by TTFields. Our results support further investigation into combinations of TTFields with T-cell based immunotherapeutic approaches.


Assuntos
Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Terapia por Estimulação Elétrica/métodos , Glioblastoma/terapia , Citometria de Fluxo/métodos , Glioblastoma/patologia , Humanos , Recidiva Local de Neoplasia , Linfócitos T/citologia
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