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1.
Cancer Immunol Immunother ; 68(12): 2015-2027, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31705171

RESUMO

The transformation and progression of myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (sAML) involve genetic, epigenetic, and microenvironmental factors. Driver mutations have emerged as valuable markers for defining risk groups and as candidates for targeted treatment approaches in MDS. It is also evident that the risk of transformation to sAML is increased by evasion of adaptive immune surveillance. This study was designed to explore the immune microenvironment, immunogenic tumor-intrinsic mechanisms (HLA and PD-L1 expression), and tumor genetic features (somatic mutations and altered karyotypes) in MDS patients and to determine their influence on the progression of the disease. We detected major alterations of the immune microenvironment in MDS patients, with a reduced count of CD4+ T cells, a more frequent presence of markers related to T cell exhaustion, a more frequent presence of myeloid-derived suppressor cells (MDSCs), and changes in the functional phenotype of NK cells. HLA Class I (HLA-I) expression was normally expressed in CD34+ blasts and during myeloid differentiation. Only two out of thirty-six patients with homozygosity for HLA-C groups acquired complete copy-neutral loss of heterozygosity in the HLA region. PD-L1 expression on the leukemic clone was also increased in MDS patients. Finally, no interplay was observed between the anti-tumor immune microenvironment and mutational genomic features. In summary, extrinsic and intrinsic immunological factors might severely impair immune surveillance and contribute to clonal immune escape. Genomic alterations appear to make an independent contribution to the clonal evolution and progression of MDS.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Células Supressoras Mieloides/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Carcinogênese , Senescência Celular , Progressão da Doença , Feminino , Antígenos HLA-C/genética , Humanos , Vigilância Imunológica , Masculino , Pessoa de Meia-Idade , Mutação/genética , Evasão Tumoral , Microambiente Tumoral/imunologia , Adulto Jovem
2.
Cancer Immunol Immunother ; 68(11): 1901-1907, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31690955

RESUMO

L-arginine depletion by regulatory cells and cancer cells expressing arginase-1 (Arg-1) is a vital contributor to the immunosuppressive tumor microenvironment in patients with cancer. We have recently described the existence of pro-inflammatory effector T cells that recognize Arg-1. Hence, Arg-1-specific self-reactive T cells are a naturally occurring part of the memory T-cell repertoire of the human immune system. Here, we further characterize a highly immunogenic epitope from Arg-1. We describe frequent T-cell-based immune responses against this epitope in patients with cancer, as well as in healthy donors. Furthermore, we show that Arg-1-specific T cells expand in response to the TH2 cytokine interleukin (IL)-4 without any specific stimulation. Arg-1-specific memory TH1 cells that respond to increased IL-4 concentration may, therefore, drive the immune response back into the TH1 pathway. Arg-1-specific T cells thus appear to have an important function in immune regulation. Because Arg-1 plays an important role in the immunosuppressive microenvironment in most cancers, an immune modulatory vaccination approach can readily be employed to tilt the balance away from immune suppression in these settings.


Assuntos
Arginase/imunologia , Vacinas Anticâncer/administração & dosagem , Epitopos de Linfócito T/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Animais , Vacinas Anticâncer/imunologia , Humanos , Vacinação
3.
Rinsho Ketsueki ; 60(9): 1229-1235, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597848

RESUMO

Recent advances in immunotherapy have highlighted the importance of the tumor microenvironment. Lymphomas are a heterogeneous group of malignancies that arise from lymphocytes and typically develop in lymphoid tissues. It has been recognized that the elements of the lymphoma microenvironment are not mere bystanders to a host antitumor inflammatory response but are important components of the tumor that support proliferation, survival, and chemoresistance of lymphoma cells. Lymphoma cells have individual expression patterns of chemokine receptors and adhesion molecules, according to their histological subtypes, and the patterns of surface molecules determine the sites of tumor involvement. Lymphoma cells often depend on the signals provided by non-tumor cells, such as stromal cells and macrophages, through direct cell contact and paracrine factors. On the other hand, there are genetic and non-genetic mechanisms allowing lymphoma cells to escape from anti-tumor immunity, such as downregulation of HLA molecules, B2M, CD58, CD70, and/or upregulation of PD-L1 and PD-L2. Further understanding of the interactions of lymphoma cells and the tumor microenvironment gives an insight into the pathogenesis of lymphomas and supports new approaches to their treatment.


Assuntos
Linfoma/imunologia , Microambiente Tumoral/imunologia , Humanos , Linfócitos , Macrófagos , Células Estromais
4.
Nature ; 574(7779): 565-570, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645726

RESUMO

Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer1,2. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies3. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement.


Assuntos
Antígenos B7/química , Antígenos B7/metabolismo , Glicoproteínas de Membrana/metabolismo , Linfócitos T/metabolismo , Animais , Anticorpos Bloqueadores/imunologia , Anticorpos Bloqueadores/farmacologia , Antígenos B7/antagonistas & inibidores , Antígenos B7/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Cristalografia por Raios X , Epitopos de Linfócito B/química , Epitopos de Linfócito B/imunologia , Feminino , Histidina/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Ligantes , Masculino , Glicoproteínas de Membrana/imunologia , Camundongos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Linfócitos T/citologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
5.
Mol Biol (Mosk) ; 53(5): 774-789, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31661477

RESUMO

Interleukin-33 (IL-33) belongs to the IL-1 cytokine family and acts as a danger signal. IL-33 is released from stressed or necrotic cells. Initially, IL-33 was described as an inducer of the humoral immune response, which activated Th2 cells and mast cells involved in modulating inflammation and allergic reactions. In addition, IL-33 acts as a stimulator of the Th1, NK, and CD8T cells, which induce a cytotoxic immune response against intracellular pathogens. It was recently discovered that this cytokine is involved in the development of cancer by performing both pro- and antitumor functions. IL-33 can directly affect tumor cells and provokes their proliferation, survival, and metastasis. Moreover, IL-33 stimulates carcinogenesis by remodeling the tumor microenvironment and inducing angiogenesis, thus contributing to the generation of immunosuppressive conditions. At the same time, IL-33 causes tumor infiltration with cytotoxic CD8 T lymphocytes and natural killers, which leads to cytolysis-mediated cancer cell death. This review describes the versatile role of the IL-33/ST2 cascade in the development of experimental and clinical tumors. In addition, we discuss the prospects for the application of IL-33 and ST2 as diagnostic biomarkers and targets for cancer immunotherapy.


Assuntos
Imunoterapia/métodos , Interleucina-33/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Evasão Tumoral/imunologia , Humanos , Neoplasias/irrigação sanguínea , Neoplasias/diagnóstico , Neovascularização Patológica , Microambiente Tumoral/imunologia
6.
Cancer Immunol Immunother ; 68(11): 1733-1745, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31598757

RESUMO

Tumors and their surrounding area represent spatially organized "ecosystems", where tumor cells and the immune contextures of the different compartments are in a dynamic interplay, with potential clinical impact. Here, we aimed to investigate the prognostic significance of peritumoral tertiary lymphoid structures (TLS) either alone or jointly with the intratumoral densities and spatial distribution of CD8 + and CD163 + cells in breast cancer (BCa) patients. TLS were identified peritumorally, within the area distancing up to 5 mm from the infiltrative tumor border, counted and further characterized as adjacent or distal, in formalin-fixed, paraffin-embedded tumor tissue samples from a cohort of 167 patients, with histologically confirmed invasive ductal BCa. TLS and tumor-infiltrating immune cells were determined by H&E and immunohistochemistry. Clinical follow-up was available for 112 of these patients. Patients with peritumoral TLS exhibited worse disease-free survival (DFS) and overall survival (OS) as compared to patients lacking TLS. Moreover, the density of peritumoral TLS was found to be crucial for prognosis, since patients with abundant TLS exhibited the worst DFS and OS. By combining the density of adjacent TLS (aTLS) with our recently published intratumoral signatures based on the differential distribution of CD8 + and CD163 + in the tumor center and invasive margin, we created two improved immune signatures with superior prognostic strength and higher patient population coverage. Our observations strengthen the notion for the fundamental role of the dynamic interplay between the immune cells within the tumor microenvironment (center/invasive margin) and the tumor surrounding area (peritumoral TLS) on the clinical outcome of BCa patients.


Assuntos
Biomarcadores/análise , Neoplasias da Mama/imunologia , Linfócitos do Interstício Tumoral/imunologia , Estruturas Linfoides Terciárias/imunologia , Microambiente Tumoral/imunologia , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida , Estruturas Linfoides Terciárias/patologia
7.
Cancer Immunol Immunother ; 68(11): 1769-1778, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31616964

RESUMO

Various immune cells are recruited in the tumor microenvironment. It is well established that cellular immune responses, such as cytotoxic or suppressive activities, play an important role in regulating tumor growth and metastasis. However, the contribution of humoral immune responses against tumors is poorly understood. Fc receptors constitute critical elements for the up- or downregulation of immune responses through immune complexes. Here, we examined the potential role of the inhibitory Fc receptor, Fcγ receptor IIB (FcγRIIB), in tumor immunity using a mouse model. Our findings indicated that tumor-specific antibodies are induced in tumor-bearing mice and control tumor immunity. FcγRIIB deletion significantly improved both cellular and humoral immunity against tumors and delayed tumor growth. These findings indicated that spontaneous antibodies against tumors create a suppressive tumor microenvironment through FcγRIIB signaling, thus suggesting an attractive therapeutic target for cancer immunotherapy.


Assuntos
Anticorpos/imunologia , Carcinoma Pulmonar de Lewis/terapia , Imunoterapia , Receptores de IgG/fisiologia , Timoma/terapia , Neoplasias do Timo/terapia , Microambiente Tumoral/imunologia , Animais , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de IgG/imunologia , Timoma/imunologia , Timoma/metabolismo , Timoma/patologia , Neoplasias do Timo/imunologia , Neoplasias do Timo/metabolismo , Neoplasias do Timo/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cancer Immunol Immunother ; 68(11): 1779-1790, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31620857

RESUMO

Human leukocyte antigen class I (HLA I) molecules composed of alpha (heavy) chain, including HLA-A, -B, or -C encoded by HLA genes, and beta-2-microglobulin (ß2M) are membrane proteins on all nucleated cells that display peptide antigens for recognition by CD8-positive cytotoxic T cells. Here, we examined the clinicopathologic signification of HLA I expression in patients with gastric cancer (GC). Immunohistochemistry was performed to detect HLA A/B/C, ß2M, CD8, p53, and programmed death-ligand 1 (PD-L1) in the center and invasive margin of the tumor in 395 stage II and III GCs using tissue array method. Additionally, Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status were investigated. Negative expression of HLA A/B/C and ß2M was observed in 258 (65.3%) and 235 (59.5%) of 395 stage II and III GCs, respectively. Negative HLA I expression was significantly associated with aggressive clinicopathologic features. Furthermore, negative expression of HLA A/B/C and ß2M was inversely correlated with CD8-positive cytotoxic T cell infiltration, EBV-positivity, and PD-L1 expression (all p < 0.001). Patients with HLA A/B/C-negative GC had worse overall survival (OS) (p = 0.019) and combined analysis with both HLA A/B/C and ß2M expression status significantly predicted OS in univariate (p = 0.004) and multivariate survival analysis (p = 0.016). Negative expression of HLA A/B/C and ß2M was frequently observed in stage II and III GCs, particularly with the aggressive clinicopathologic features, and correlated with an unfavorable prognosis and host immune response status. These findings contribute to further development of immunotherapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Antígenos HLA/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Gástricas/patologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/imunologia , Feminino , Seguimentos , Antígenos HLA/imunologia , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/cirurgia , Adulto Jovem , Microglobulina beta-2/imunologia , Microglobulina beta-2/metabolismo
9.
Nat Med ; 25(9): 1341-1355, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501612

RESUMO

Chimeric antigen receptor (CAR) T cell therapy for B cell malignancies has surpassed expectations, driving an ever-expanding number of clinical trials and the first US Food and Drug Administration approvals of cell therapies for the treatment of cancer. This experience has illuminated some generalizable requirements for CAR T cell efficacy as well as the interplay between disease biology and clinical outcomes. Major CAR intrinsic variables affecting T cell behavior have been defined, and mechanisms of tumor resistance are increasingly understood. Here, we review the clinical experience with CAR T cells amassed to date, including but not limited to B cell malignancies, emphasizing factors associated with efficacy, resistance and major barriers to success. We also discuss how these insights are driving next-generation clinical trials, including those in solid tumors.


Assuntos
Antígenos de Neoplasias/uso terapêutico , Imunoterapia Adotiva/tendências , Neoplasias/terapia , Antígenos de Neoplasias/imunologia , Humanos , Neoplasias/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Estados Unidos , United States Food and Drug Administration
10.
Magy Onkol ; 63(3): 209-216, 2019 Sep 18.
Artigo em Húngaro | MEDLINE | ID: mdl-31533141

RESUMO

Immunotherapy is getting more and more successful therapeutic option in case of many cancer types. Despite the clinical effectiveness of checkpoint inhibitor antibodies, long-lasting advantages can only be seen in a part of the patients, which makes necessary to examine immunotherapy more thoroughly. Immunity is influenced by the tumor, its microenvironment, and patient's characteristic and environmental factors. These elements control the strength and duration of antitumor response. Immunotherapeutic response may be more significant and may even last for years in case of hot tumors, while in most of the cases immunotherapy is not so effective in poorly immunogenic cold tumors. Combined therapies potentially increase efficiency. In our article T-cell activation phases of antitumor immune response, possible defects, their consequences and the potentially effective therapeutic opportunities are summarized shortly. Combined immunotherapy is a novel, promising possibility for modern oncology.


Assuntos
Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Neoplasias/imunologia , Neoplasias/terapia , Humanos , Imunoterapia/normas , Microambiente Tumoral/imunologia
11.
Magy Onkol ; 63(3): 217-223, 2019 Sep 18.
Artigo em Húngaro | MEDLINE | ID: mdl-31533142

RESUMO

Despite the spectacular development of clinical immunotherapy (IT) in the last decade, the regular treatment approaches for the most common central nervous system (CNS) tumors, the malignant gliomas (MGs) has not changed yet. The most important pitfalls of the routine application of immunotherapy can be imputed to the special and originally immunosuppressed microenvironment and the extreme heterogeneity of MGs, however the defensive role of the blood-brain barrier, the general usage of steroids and the difficulties in the evaluation of brain images can also play a role in these types of difficulties. Additionally, in the case of MGs, well-accepted IT biomarker assays (PDL1 positivity, mismatch repair deficiencies, tumor mutation burden, etc.) generally reveal only minimal levels of immunogen activities. Nevertheless, there are some promising results with the utilization of checkpoint inhibitors and other IT modalities (such as virus-based therapies, tumor vaccines, adoptive T cell therapies) and with the combination of conventional oncotherapy methods in case of CNS malignancies, as well. In conclusion, although the CNS is not any more considered as an "immunological sanctuary" and despite some encouraging experimental and clinical results in CNS oncotherapy, the routine application of IT in case of MGs is still awaited.


Assuntos
Neoplasias Encefálicas/terapia , Glioma/terapia , Imunoterapia , Neoplasias Encefálicas/imunologia , Glioma/imunologia , Humanos , Fatores Imunológicos/imunologia , Microambiente Tumoral/imunologia
12.
Anticancer Res ; 39(9): 4699-4709, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519569

RESUMO

BACKGROUND/AIM: Metformin, a drug for type 2 diabetes, also exerts anticancer effects. This study addressed the immunological effects of metformin on peritoneal dissemination. MATERIALS AND METHODS: We developed a mouse model of peritoneal dissemination via intraperitoneal injection of RLmale1, an X-ray-induced leukemia cell line, into BALB/c mice. Cell-surface markers, cytokine production, and myeloid-derived suppressor cells (MDSCs) were examined in cells from spleen and peritoneal lavage fluid. RESULTS: Metformin-treated mice exhibited suppressed intraperitoneal tumor growth and extended survival, and these effects were lost in mice with severe combined immunodeficiency. MDSCs induction was inhibited in metformin-treated mice. Although MDSC mobilization into the peritoneal cavity was correlated with suppression of interferon-γ production by tumor-infiltrating lymphocytes, the T-helper 1 ability of these lymphocytes was preserved in metformin-treated mice. CONCLUSION: Our findings demonstrate the action of metformin on both intraperitoneal tumors and immune-suppressive cells and might contribute to the development of immunotherapy against peritoneal dissemination.


Assuntos
Imunomodulação/efeitos dos fármacos , Metformina/farmacologia , Neoplasias Peritoneais/imunologia , Neoplasias Peritoneais/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Biomarcadores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Imunofenotipagem , Masculino , Camundongos , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Metástase Neoplásica , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/mortalidade , Modelos de Riscos Proporcionais , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Nat Cell Biol ; 21(9): 1113-1126, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31451770

RESUMO

Cancer-induced immune responses affect tumour progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages that define 'immune subtypes' of triple-negative breast cancer (TNBC), including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumour-intrinsic pathways and mutual regulation between macrophages (or monocytes) and neutrophils contribute to the development of a dichotomous myeloid compartment. MES contains predominantly macrophages that are CCR2-dependent and exhibit variable responses to immune checkpoint blockade (ICB). NES exhibits systemic and local accumulation of immunosuppressive neutrophils (or granulocytic myeloid-derived suppressor cells), is resistant to ICB, and contains a minority of macrophages that seem to be unaffected by CCR2 knockout. A MES-to-NES conversion mediated acquired ICB resistance of initially sensitive MES models. Our results demonstrate diverse myeloid cell frequencies, functionality and potential roles in immunotherapies, and highlight the need to better understand the inter-patient heterogeneity of the myeloid compartment.


Assuntos
Imunoterapia , Células Mieloides/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Microambiente Tumoral/imunologia , Animais , Modelos Animais de Doenças , Feminino , Granulócitos/imunologia , Imunoterapia/métodos , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia , Neutrófilos/imunologia , Neutrófilos/patologia , Neoplasias de Mama Triplo Negativas/patologia
15.
Semin Oncol ; 46(3): 254-260, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31383368

RESUMO

The broad use of radiotherapy (RT) in the management of solid human tumors is based on its ability to damage cellular macromolecules, particularly the DNA, effectively inducing growth arrest and cell death locally in irradiated tumor cells. However, bystander effects, such as the transmission of lethal signals between cells via gap junctions or the production of diffusible cytotoxic mediators, can also contribute to the local antineoplastic action of RT. Traditionally, RT has been considered to exert immunosuppressive effects on the host. This idea largely stems from the radiosensitivity of quiescent lymphocytes and on the use of total body irradiation as part of myeloablative conditioning regimens preceding hematopoietic stem cell transplantation. Additionally, the occurrence of the so-called "abscopal effect," where nonirradiated distant lesions display effects of RT response, suggests that RT may also induce tumor immunization. Several RT-induced effects on cancer, immune and stromal cells, contribute to the abscopal effect: (1) induction of "immunogenic cell death", with release of tumor-associated antigens, (2) alterations of cancer cell immunophenotype, and (3) modulation of the tumor microenvironment. Damage and death of cancer cells leads to the surface exposure of immunogenic molecules as well as the release of damage associated molecular patterns such as adenosine triphosphate or High-Mobility-Group-Protein B1, and potentially tumor antigens that activate the innate and adaptive immune systems. Moreover, nuclear release and cytoplasmic sensing of altered nucleic acids via cyclic GMP-AMP Synthase/Stimulator of Interferon Genes is connected to the secretion of cytokines that support innate and adaptive antitumor immunity. As a result of the above, irradiated tumor cells may potentially act as an "in situ vaccine."


Assuntos
Morte Celular/efeitos da radiação , Neoplasias/radioterapia , Tolerância a Radiação/imunologia , Células Estromais/efeitos da radiação , Antígenos de Neoplasias/imunologia , Morte Celular/imunologia , Proteína HMGB1/genética , Proteína HMGB1/imunologia , Humanos , Imunofenotipagem , Imunossupressão , Linfócitos/imunologia , Linfócitos/efeitos da radiação , Neoplasias/imunologia , Células Estromais/imunologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação , Irradiação Corporal Total/efeitos adversos
16.
Vet Immunol Immunopathol ; 214: 109891, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31378219

RESUMO

Animal models are invaluable tools in cancer research. In this context, salmon is a promising candidate. Intestinal adenocarcinoma with metastases may be induced as a consequence of a plant-based diet triggering the inflammation - dysplasia- carcinogenesis pathway. Here, we investigate the stroma and the presence and nature of immune cells in such tumors by staining for mast cells, immunohistochemistry for T cells and antigen-presenting cells and in situ hybridization for B cells. In intestinal tumors, substantial amounts of T cells were detected in the stroma, whilst MHC class II+ cells were mainly among the cancerous cells. Ig+ cells were observed primarily in the tumor periphery. Mast cells showed a strong association with stroma. In metastases, scarce amounts of T cells were detected, whilst MHC I and II-reactivity varied, some tumors being completely negative. Ig+ cells were scattered around the metastatic tissue in no particular pattern, but were occasionally observed within clusters of tumor cells. Small numbers of mast cells were detected in the stroma. To the best of our knowledge, this is the first report addressing immune cells in fish tumors. The teleost tumor microenvironment seems comparable to that of mammals, making fish interesting model animals in oncoimmunology research.


Assuntos
Adenocarcinoma/veterinária , Doenças dos Peixes/patologia , Neoplasias Intestinais/veterinária , Metástase Neoplásica , Salmo salar/imunologia , Microambiente Tumoral/imunologia , Adenocarcinoma/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Modelos Animais de Doenças , Doenças dos Peixes/imunologia , Inflamação , Neoplasias Intestinais/imunologia , Mastócitos/imunologia , Linfócitos T/imunologia
17.
Int J Mol Sci ; 20(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261963

RESUMO

Radiotherapy (RT), besides cancer cells, also affects the tumor microenvironment (TME): tumor blood vessels and cells of the immune system. It damages endothelial cells and causes radiation-induced inflammation. Damaged vessels inhibit the infiltration of CD8+ T lymphocytes into tumors, and immunosuppressive pathways are activated. They lead to the accumulation of radioresistant suppressor cells, including tumor-associated macrophages (TAMs) with the M2 phenotype, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). The area of tumor hypoxia increases. Hypoxia reduces oxygen-dependent DNA damage and weakens the anti-cancer RT effect. It activates the formation of new blood vessels and leads to cancer relapse after irradiation. Irradiation may also activate the immune response through immunogenic cell death induction. This leads to the "in situ" vaccination effect. In this article, we review how changes in the TME affect radiation-induced anticancer efficacy. There is a very delicate balance between the activation of the immune system and the immunosuppression induced by RT. The effects of RT doses on immune system reactions and also on tumor vascularization remain unclear. A better understanding of these interactions will contribute to the optimization of RT treatment, which may prevent the recurrence of cancer.


Assuntos
Sistema Imunitário/efeitos da radiação , Neoplasias/radioterapia , Radioterapia/efeitos adversos , Microambiente Tumoral/efeitos da radiação , Animais , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Radioterapia/métodos , Microambiente Tumoral/imunologia
18.
Nat Commun ; 10(1): 2977, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278255

RESUMO

Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. To define the biological features driving this phenotype, we performed an integrated analysis of whole-exome and RNA sequencing of UTUC. Here we report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-papillary; 2) UTUC has a T-cell depleted immune contexture; 3) High FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immune microenvironment; 4) Sporadic UTUC is characterized by a lower total mutational burden than urothelial carcinoma of the bladder. Our findings lay the foundation for a deeper understanding of UTUC biology and provide a rationale for the development of UTUC-specific treatment strategies.


Assuntos
Carcinoma de Células de Transição/patologia , Neoplasias Renais/patologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Linfócitos T/imunologia , Neoplasias Ureterais/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/imunologia , Análise Mutacional de DNA , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Análise de Sequência de RNA , Transdução de Sinais/genética , Microambiente Tumoral/imunologia , Neoplasias Ureterais/genética , Neoplasias Ureterais/imunologia , Urotélio/patologia , Sequenciamento Completo do Exoma
19.
Crit Rev Oncol Hematol ; 141: 146-152, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301542

RESUMO

Clinical response to checkpoint inhibitors-based (CPIs) therapies can vary among tumor types and between patients. This led to a significant amount of pre-clinical and clinical research into biomarker identification. Biomarkers have been found to cover both the tumor itself and the tumor microenvironment. Entering host-related parameters into the equation should provide a valuable strategy for identifying not only factors predictive of treatment efficacy but also of treatment-related toxicity. It is clear that germline variants can offer efficient and easily-assessable indicators (blood DNA) to enlarge the spectrum of predictive markers for CPI-based treatment. A major issue concerns the real functional significance of the reported single-nucleotide polymorphisms (SNPs) linked to CPI-treatment outcome. Powered calculations should lead to an optimal trade-off between sample size and allele frequency. New molecular technologies and new analytical methods should provide opportunities to bridge the knowledge gap between SNP-CPI treatment associations and the functional impact of these SNPs.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Mutação em Linhagem Germinativa/fisiologia , Imunogenética/métodos , Imunoterapia , Neoplasias/diagnóstico , Neoplasias/terapia , Análise Mutacional de DNA/métodos , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Neoplasias/imunologia , Testes Farmacogenômicos/métodos , Prognóstico , Resultado do Tratamento , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
20.
J Cancer Res Clin Oncol ; 145(8): 2149-2156, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31273513

RESUMO

BACKGROUND: First-line rituximab therapy together with chemotherapy is the standard care for patients with advanced follicular B-cell lymphoma, as rituximab together with chemotherapy prolongs progression-free and overall survival (Herold et al. 2007; Marcus et al. 2005). However, as not all patient subgroups benefit from combined immuno-chemotherapy, we asked whether the microenvironment may predict benefit from rituximab-based therapy. DESIGN: To address this question, we performed a retrospective immunohistochemical analysis on pathological specimens of 18 patients recruited into a randomized clinical trial, where patients with advanced follicular lymphoma were randomized into either chemotherapy or immuno-chemotherapy with rituximab (Herold et al. 2007). RESULTS: We show here that rituximab exerts beneficial effects, especially in the subgroup of follicular lymphoma patients with low intrafollicular CD3, CD5, CD8, and ZAP70 and high CD56 and CD68 expression. CONCLUSION: Rituximab may overcome immune-dormancy in follicular lymphoma in cases with lower intrafollicular T-cell numbers and higher CD56 and CD68 cell counts. As this was a retrospective analysis on a small subgroup of patients, these data need to be corroborated in larger clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos do Interstício Tumoral/patologia , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/imunologia , Rituximab/administração & dosagem , Linfócitos T/patologia , Clorambucila/administração & dosagem , Feminino , Humanos , Imunoterapia , Células Matadoras Naturais/patologia , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Prednisona/administração & dosagem , Prognóstico , Estudos Retrospectivos , Linfócitos T/efeitos dos fármacos , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
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