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1.
Nat Immunol ; 25(5): 755-763, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38641718

RESUMO

T cell infiltration into tumors is a favorable prognostic feature, but most solid tumors lack productive T cell responses. Mechanisms that coordinate T cell exclusion are incompletely understood. Here we identify hepatocyte activation via interleukin-6/STAT3 and secretion of serum amyloid A (SAA) proteins 1 and 2 as important regulators of T cell surveillance of extrahepatic tumors. Loss of STAT3 in hepatocytes or SAA remodeled the tumor microenvironment with infiltration by CD8+ T cells, while interleukin-6 overexpression in hepatocytes and SAA signaling via Toll-like receptor 2 reduced the number of intratumoral dendritic cells and, in doing so, inhibited T cell tumor infiltration. Genetic ablation of SAA enhanced survival after tumor resection in a T cell-dependent manner. Likewise, in individuals with pancreatic ductal adenocarcinoma, long-term survivors after surgery demonstrated lower serum SAA levels than short-term survivors. Taken together, these data define a fundamental link between liver and tumor immunobiology wherein hepatocytes govern productive T cell surveillance in cancer.


Assuntos
Linfócitos T CD8-Positivos , Hepatócitos , Interleucina-6 , Fator de Transcrição STAT3 , Proteína Amiloide A Sérica , Proteína Amiloide A Sérica/metabolismo , Proteína Amiloide A Sérica/genética , Hepatócitos/metabolismo , Hepatócitos/imunologia , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Evasão Tumoral , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linhagem Celular Tumoral
2.
Gastroenterology ; 166(6): 1114-1129, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38244727

RESUMO

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease characterized by a spatially heterogeneous tumor microenvironment. Within the PDA microenvironment, cells organize into communities where cell fate is influenced by neighboring cells of diverse ontogeny and function. However, it remains unclear how cell neighborhoods in the tumor microenvironment evolve with treatment and impact clinical outcomes. METHODS: Here, using automated chromogenic multiplex immunohistochemistry and unsupervised computational image analysis of human PDA tumors, we investigated cell neighborhoods in surgically resected tumors from patients with chemotherapy-naïve PDA (n = 59) and neoadjuvant chemotherapy-treated PDA (n = 57). Single cells were defined by lineage markers (CD3, CD8, Foxp3, CD68, CK19), proliferation (Ki67), and neighboring cells. RESULTS: Distinct intratumoral immune and tumor cell subsets were defined by neighboring cells. Higher content of stromal-associated macrophages was seen in chemotherapy-naïve tumors from long-term survivors (overall survival >3 years) compared with short-term survivors (overall survival <1 year), whereas immune-excluded tumor cells were higher in short-term survivors. Chemotherapy-treated vs -naïve tumors showed lower content of tumor-associated T cells and macrophages but similar densities of stromal-associated immune cells. However, proliferating tumor cell subsets with immune-rich neighborhoods were higher in chemotherapy-treated tumors. In a blinded analysis of tumors from patients treated with neoadjuvant chemotherapy, a composite index comprising lower quantities of immune-excluded tumor cells and higher spatially distinct immune cell subsets was associated with prolonged survival. CONCLUSIONS: Together, these data provide new insights into discrete cell communities in PDA and show their clinical relevance.


Assuntos
Carcinoma Ductal Pancreático , Terapia Neoadjuvante , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/cirurgia , Microambiente Tumoral/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamento farmacológico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Quimioterapia Adjuvante , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Resultado do Tratamento , Linfócitos do Interstício Tumoral/imunologia , Proliferação de Células , Imuno-Histoquímica
3.
Semin Cancer Biol ; 65: 38-50, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31954172

RESUMO

Inflammation is a hallmark of cancer and supports tumor growth, proliferation, and metastasis, but also inhibits T cell immunosurveillance and the efficacy of immunotherapy. The biology of cancer inflammation is defined by a cycle of distinct immunological steps that begins during disease conception with the release of inflammatory soluble factors. These factors communicate with host organs to trigger bone marrow mobilization of myeloid cells, trafficking of myeloid cells to the tumor, and differentiation of myeloid cells within the tumor bed. Tumor-infiltrating myeloid cells then orchestrate an immunosuppressive microenvironment and assist in sustaining a vicious cycle of inflammation that co-evolves with tumor cells. This Cancer-Inflammation Cycle acts as a rheostat or "inflammostat" that impinges upon T cell immunosurveillance and prevents the development of productive anti-tumor immunity. Here, we define the major nodes of the Cancer-Inflammation Cycle and describe their impact on T cell immunosurveillance in cancer. Additionally, we discuss emerging pre-clinical and clinical data suggesting that intervening upon the Cancer-Inflammation Cycle will be a necessary step for broadening the potential of immunotherapy in cancer.


Assuntos
Resistencia a Medicamentos Antineoplásicos/imunologia , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Linfócitos T/imunologia , Movimento Celular/efeitos dos fármacos , Humanos , Imunoterapia/efeitos adversos , Inflamação/imunologia , Inflamação/patologia , Células Mieloides/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Microambiente Tumoral/imunologia
4.
Br J Cancer ; 122(3): 333-339, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31787751

RESUMO

BACKGROUND: Retrospective studies suggest a survival benefit when platinum-based chemotherapy is administered to patients with pancreatic cancer harbouring a germline mutation in BRCA1, BRCA2 or PALB2 (mut-positive PDAC). However, the objective response rate (ORR) and real-world progression free survival (rwPFS) achieved with such treatment remain ill-defined. METHODS: Twenty-six patients with advanced-stage mut-positive PDAC who had been treated with platinum-based therapy were matched by age, race and sex to 52 platinum-treated control PDAC patients. Responses to therapy were determined by RECIST v1.1, performed by blinded radiology review. Measured outcomes included ORR and rwPFS. RESULTS: The ORR in mut-positive patients was 58% compared to 21% in the control group (p = 0.0022). There was no significant difference in ORR between platinum regimens in mut-positive patients (p = 0.814), whereas in control patients, the only observed responses were to FOLFIRINOX. rwPFS was 10.1 mo. for mut-positive patients and 6.9 mo. for controls (HR 0.43; 95% CI 0.25-0.74; 0.0068). CONCLUSION: Mut-positive PDAC has a high ORR and prolonged rwPFS to platinum-based chemotherapy. These findings may have implications particularly in the neoadjuvant setting, and for future clinical trial design, and highlight the importance of early germline testing in patients with PDAC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Estudos de Casos e Controles , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Fluoruracila/uso terapêutico , Mutação em Linhagem Germinativa , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina/uso terapêutico , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Gencitabina
5.
Curr Opin Urol ; 26(6): 501-7, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27471994

RESUMO

PURPOSE OF REVIEW: Active investigation suggests immune checkpoint inhibitor therapy and therapeutic cancer vaccines provide clinical benefit for genitourinary malignancies including prostate cancer, renal cell carcinoma, and bladder cancer. Recent developments in the utility of immune checkpoint inhibitor and vaccine therapy for the management of genitourinary malignancies are highlighted in this review. RECENT FINDINGS: Dramatic responses to checkpoint inhibitor therapy have been demonstrated in renal cell carcinoma and bladder cancer with recent Food and Drug Administration approvals in both indications. No benefit to checkpoint inhibitor therapy has yet been shown for the management of prostate cancer. Therapeutic cancer vaccines have also shown benefit in the treatment of genitourinary malignancies, specifically in the treatment of prostate cancer. Despite advances in these therapeutic modalities, benefit is limited to a subset of patients. SUMMARY: Current evidence supports the use of immune checkpoint inhibitor therapy and therapeutic cancer vaccines for the management of genitourinary malignancies. Further development of biomarkers for predicting response and study of combination therapy is required to achieve optimal efficacy with these therapeutic interventions.


Assuntos
Vacinas Anticâncer/uso terapêutico , Carcinoma de Células Renais/terapia , Imunoterapia/tendências , Neoplasias da Próstata/terapia , Neoplasias Urogenitais/terapia , Carcinoma de Células Renais/imunologia , Humanos , Masculino , Neoplasias da Próstata/imunologia , Neoplasias da Bexiga Urinária/imunologia , Neoplasias Urogenitais/imunologia
6.
Biochem Biophys Res Commun ; 437(1): 29-34, 2013 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-23792098

RESUMO

Shwachman Diamond syndrome (SDS) is an inherited bone marrow failure syndrome typically characterized by neutropenia, exocrine pancreas dysfunction, metaphyseal chondrodysplasia, and predisposition to myelodysplastic syndrome and leukemia. SBDS, the gene affected in most cases of SDS, encodes a protein known to influence many cellular processes including ribosome biogenesis, mitotic spindle assembly, chemotaxis, and the regulation of reactive oxygen species production. The best characterized role for the SBDS protein is in the production of functional 60S ribosomal subunits. Given that a reduction in functional 60S subunits could impact on the translational output of cells depleted of SBDS we analyzed protein synthesis in yeast cells lacking SDO1, the ortholog of SBDS. Cells lacking SDO1 selectively increased the synthesis of POR1, the ortholog of mammalian VDAC1 a major anion channel of the mitochondrial outer membrane. Further studies revealed the cells lacking SDO1 were compromised in growth on non-fermentable carbon sources suggesting mitochondrial function was impaired. These observations prompted us to examine mitochondrial function in human cells where SBDS expression was reduced. Our studies indicate that reduced expression of SBDS decreases mitochondrial membrane potential and oxygen consumption and increases the production of reactive oxygen species. These studies indicate that mitochondrial function is also perturbed in cells expressing reduced amounts of SBDS and indicate that disruption of mitochondrial function may also contribute to SDS pathophysiology.


Assuntos
Doenças da Medula Óssea/metabolismo , Doenças da Medula Óssea/patologia , Insuficiência Pancreática Exócrina/metabolismo , Insuficiência Pancreática Exócrina/patologia , Lipomatose/metabolismo , Lipomatose/patologia , Mitocôndrias/metabolismo , Modelos Biológicos , Saccharomyces cerevisiae/metabolismo , Carbono/farmacologia , Linhagem Celular , Fermentação/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Proteínas/metabolismo , Proteômica , Espécies Reativas de Oxigênio/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/crescimento & desenvolvimento , Proteínas de Saccharomyces cerevisiae/metabolismo , Síndrome de Shwachman-Diamond
7.
Nat Commun ; 14(1): 6330, 2023 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-37816712

RESUMO

Although macrophages contribute to cancer cell dissemination, immune evasion, and metastatic outgrowth, they have also been reported to coordinate tumor-specific immune responses. We therefore hypothesized that macrophage polarization could be modulated therapeutically to prevent metastasis. Here, we show that macrophages respond to ß-glucan (odetiglucan) treatment by inhibiting liver metastasis. ß-glucan activated liver-resident macrophages (Kupffer cells), suppressed cancer cell proliferation, and invoked productive T cell-mediated responses against liver metastasis in pancreatic cancer mouse models. Although excluded from metastatic lesions, Kupffer cells were critical for the anti-metastatic activity of ß-glucan, which also required T cells. Furthermore, ß-glucan drove T cell activation and macrophage re-polarization in liver metastases in mice and humans and sensitized metastatic lesions to anti-PD1 therapy. These findings demonstrate the significance of macrophage function in metastasis and identify Kupffer cells as a potential therapeutic target against pancreatic cancer metastasis to the liver.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Hepáticas , Neoplasias Pancreáticas , beta-Glucanas , Humanos , Animais , Camundongos , Células de Kupffer/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/prevenção & controle , Neoplasias Hepáticas/patologia
8.
Sci Immunol ; 8(89): eadj5097, 2023 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-37976347

RESUMO

Myeloid cells facilitate T cell immune evasion in cancer yet are pliable and have antitumor potential. Here, by cotargeting myeloid activation molecules, we leveraged the myeloid compartment as a therapeutic vulnerability in mouse models of pancreatic cancer. Myeloid cells in solid tumors expressed activation receptors including the pattern recognition receptor Dectin-1 and the TNF receptor superfamily member CD40. In mouse models of checkpoint inhibitor-resistant pancreatic cancer, coactivation of Dectin-1, via systemic ß-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors and induced immunological memory. Antitumor activity was dependent on cDC1s and T cells but did not require classical T cell-mediated cytotoxicity or blockade of checkpoint molecules. Rather, targeting CD40 drove T cell-mediated IFN-γ signaling, which converged with Dectin-1 activation to program distinct macrophage subsets to facilitate tumor responses. Thus, productive cancer immune surveillance in pancreatic tumors resistant to checkpoint inhibition can be invoked by coactivation of complementary myeloid signaling pathways.


Assuntos
Neoplasias Pancreáticas , Camundongos , Animais , Antígenos CD40 , Imunoterapia
9.
Cancers (Basel) ; 13(18)2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34572943

RESUMO

Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients.

10.
JCI Insight ; 6(5)2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33497362

RESUMO

Agonistic anti-CD40 monoclonal antibody (mAb) therapy in combination with chemotherapy (chemoimmunotherapy) shows promise for the treatment of pancreatic ductal adenocarcinoma (PDA). To gain insight into immunological mechanisms of response and resistance to chemoimmunotherapy, we analyzed blood samples from patients (n = 22) with advanced PDA treated with an anti-CD40 mAb (CP-870,893) in combination with gemcitabine. We found a stereotyped cellular response to chemoimmunotherapy characterized by transient B cell, CD56+CD11c+HLA-DR+CD141+ cell, and monocyte depletion and CD4+ T cell activation. However, these cellular pharmacodynamics did not associate with outcomes. In contrast, we identified an inflammatory network in the peripheral blood consisting of neutrophils, cytokines (IL-6 and IL-8), and acute phase reactants (C-reactive protein and serum amyloid A) that was associated with outcomes. Furthermore, monocytes from patients with elevated plasma IL-6 and IL-8 showed distinct transcriptional profiles, including upregulation of CCR2 and GAS6, genes associated with regulation of leukocyte chemotaxis and response to inflammation. Patients with systemic inflammation, defined by neutrophil/lymphocyte ratio (NLR) greater than 3.1, had a shorter median overall survival (5.8 vs. 12.3 months) as compared with patients with NLR less than 3.1. Taken together, our findings identify systemic inflammation as a potential resistance mechanism to a CD40-based chemoimmunotherapy and suggest biomarkers for future studies.


Assuntos
Antígenos CD40/antagonistas & inibidores , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Quimioterapia Combinada/métodos , Imunoterapia/métodos , Neoplasias Pancreáticas/tratamento farmacológico , Desoxicitidina/farmacologia , Humanos , Gencitabina
11.
J Clin Oncol ; 39(22): 2497-2505, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33970687

RESUMO

PURPOSE: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved as maintenance therapy for patients with advanced pancreatic cancer (PC) and a germline BRCA1 or BRCA2 pathogenic variant (PV). This investigator-initiated, single-arm phase II study assessed the role of the PARPi rucaparib as maintenance therapy in advanced PC with germline or somatic PV in BRCA1, BRCA2, or PALB2. PATIENTS AND METHODS: Eligible patients had advanced PC; germline (g) or somatic (s) PVs in BRCA1, BRCA2, or PALB2, and received at least 16 weeks of platinum-based chemotherapy without evidence of platinum resistance. Chemotherapy was discontinued and patients received rucaparib 600 mg orally twice a day until progression. The primary end point was the progression-free survival (PFS) rate at 6 months (PFS6). Secondary end points included safety, ORR, disease control rate, duration of response, and overall survival. RESULTS: Of 46 enrolled patients, 42 were evaluable (27 gBRCA2, seven gBRCA1, six gPALB2, and two sBRCA2). PFS6 was 59.5% (95% CI, 44.6 to 74.4), median PFS was 13.1 months (95% CI, 4.4 to 21.8), and median overall survival was 23.5 months (95% CI, 20 to 27). The PFS at 12 months was 54.8%. ORR of the 36 patients with measurable disease was 41.7% (3 complete responses; 12 partial responses; 95% CI, 25.5 to 59.2), and disease control rate was 66.7% (95% CI, 49.0 to 81.4). Median duration of response was 17.3 months (95% CI, 8.8 to 25.8). Responses occurred in patients with gBRCA2 (41%, 11 out of 27), gPALB2 (50%, 3 out of 6), and sBRCA2 (50%, 1 out of 2). No new safety signals were noted. CONCLUSION: Maintenance rucaparib is a safe and effective therapy for platinum-sensitive, advanced PC with a PV in BRCA1, BRCA2, or PALB2. The finding of efficacy in patients with gPALB2 and sBRCA2 PVs expands the population likely to benefit from PARPi beyond gBRCA1/2 PV carriers.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Indóis/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Mutação em Linhagem Germinativa , Humanos , Indóis/efeitos adversos , Estimativa de Kaplan-Meier , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico
12.
Mol Cancer Ther ; 20(2): 389-397, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33268571

RESUMO

TGFß is a pleiotropic cytokine with immunosuppressive activity. In preclinical models, blockade of TGFß enhances the activity of radiation and invokes T-cell antitumor immunity. Here, we combined galunisertib, an oral TGFß inhibitor, with stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC) and assessed safety, efficacy, and immunologic correlatives. Patients (n = 15) with advanced HCC who progressed on, were intolerant of, or refused sorafenib were treated with galunisertib (150 mg orally twice a day) on days 1 to 14 of each 28-day cycle. A single dose of SBRT (18-Gy) was delivered between days 15 to 28 of cycle 1. Site of index lesions treated with SBRT included liver (9 patients), lymph node (4 patients), and lung (2 patients). Blood for high-dimensional single cell profiling was collected. The most common treatment-related adverse events were fatigue (53%), abdominal pain (46.6%), nausea (40%), and increased alkaline phosphatase (40%). There were two instances of grade 2 alkaline phosphatase increase and two instances of grade 2 bilirubin increase. One patient developed grade 3 achalasia, possibly related to treatment. Two patients achieved a partial response. Treatment with galunisertib was associated with a decrease in the frequency of activated T regulatory cells in the blood. Distinct peripheral blood leukocyte populations detected at baseline distinguished progressors from nonprogressors. Nonprogressors also had increased CD8+PD-1+TIGIT+ T cells in the blood after treatment. We found galunisertib combined with SBRT to be well tolerated and associated with antitumor activity in patients with HCC. Pre- and posttreatment immune profiling of the blood was able to distinguish patients with progression versus nonprogression.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Pirazóis/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Pirazóis/farmacologia , Quinolinas/farmacologia , Radiocirurgia
13.
J Exp Med ; 217(8)2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32453421

RESUMO

Type 1 conventional dendritic cells (cDC1s) are typically thought to be dysregulated secondarily to invasive cancer. Here, we report that cDC1 dysfunction instead develops in the earliest stages of preinvasive pancreatic intraepithelial neoplasia (PanIN) in the KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-Cre-driven (KPC) mouse model of pancreatic cancer. cDC1 dysfunction is systemic and progressive, driven by increased apoptosis, and results in suboptimal up-regulation of T cell-polarizing cytokines during cDC1 maturation. The underlying mechanism is linked to elevated IL-6 concomitant with neoplasia. Neutralization of IL-6 in vivo ameliorates cDC1 apoptosis, rescuing cDC1 abundance in tumor-bearing mice. CD8+ T cell response to vaccination is impaired as a result of cDC1 dysregulation. Yet, combination therapy with CD40 agonist and Flt3 ligand restores cDC1 abundance to normal levels, decreases cDC1 apoptosis, and repairs cDC1 maturation to drive superior control of tumor outgrowth. Our study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation during pancreatic carcinogenesis and suggests therapeutically tractable strategies toward cDC1 repair.


Assuntos
Carcinogênese/imunologia , Células Dendríticas/imunologia , Neoplasias Experimentais/imunologia , Neoplasias Pancreáticas/imunologia , Idoso , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinogênese/genética , Carcinogênese/patologia , Células Dendríticas/patologia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia
14.
Cancer Med ; 8(4): 1442-1446, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30790466

RESUMO

Hepatocellular carcinoma (HCC) is a challenging to treat malignancy with few available systemic therapies. Angiogenesis has been implicated in the pathogenesis of HCC and prior studies have suggested a role for anti-VEGF therapy. Prior to FDA approval of second-line therapy for advanced HCC, from 2008 until 2017, we initiated bevacizumab monotherapy (5-10 mg/kg every 2-3 weeks) in 12 patients with intolerance of or progression during sorafenib therapy. Bevacizumab therapy was well tolerated with only 1/12 patients experiencing a grade 3-4 treatment-related adverse event (transient ischemic attack) and only 2/12 patients discontinued the therapy due to adverse events. Median overall survival was 20.2 months (IQR, 7.0-43.5), with a median time to radiologic progression of 10.4 months (IQR, 2.8-16.1) and a disease control rate of 54%. Taken together, our experience provides rationale for further prospective investigation of bevacizumab for the treatment of advanced HCC.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Idoso , Inibidores da Angiogênese/efeitos adversos , Bevacizumab/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Uso Off-Label , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Veteranos
15.
Radiat Res ; 182(2): 126-38, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24960415

RESUMO

There is increasing evidence of the potential for radiation therapy to generate antitumor immune responses. The mechanisms of this immune-activating potential include actions on tumor cells such as immunogenic cell death and phenotypic change. Radiation modulates tumor cell surface expression of cell death receptors, tumor-associated antigens and adhesion molecules. This process of immunomodulation sensitizes tumor cells to immune-mediated killing. Radiation also affects immune compartments, including antigen-presenting cells, cytotoxic T lymphocytes and humoral immunity, leading to specific antitumor immune responses. Recognizing the importance of immunity as a potentiator of response to radiation leads to rational augmentation of antitumor immunity by combining radiation and immunotherapy. Targeted immunotherapy manipulates the immune system in a way that best synergizes with radiation. This article discusses the ability of radiation monotherapy to induce antitumor immunity, with a focus on the effect of radiation on antigen-presenting cells and cytotoxic T lymphocytes. We define two important responses generated by tumor cells, immunogenic cell death and immunomodulation, both of which are radiation dose-dependent. In conclusion, we describe the translation of several combination therapies from the preclinical to the clinical setting and identify opportunities for further exploration.


Assuntos
Imunoterapia/métodos , Neoplasias/terapia , Radioterapia/métodos , Morte Celular/imunologia , Morte Celular/efeitos da radiação , Terapia Combinada , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/radioterapia
16.
Oncotarget ; 5(2): 403-16, 2014 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-24480782

RESUMO

Radiation therapy (RT) is used for local tumor control through direct killing of tumor cells. Radiation-induced cell death can trigger tumor antigen-specific immune responses, but these are often noncurative. Radiation has been demonstrated to induce immunogenic modulation (IM) in various tumor types by altering the biology of surviving cells to render them more susceptible to T cell-mediated killing. Little is known about the mechanism(s) underlying IM elicited by sub-lethal radiation dosing. We have examined the molecular and immunogenic consequences of radiation exposure in breast, lung, and prostate human carcinoma cells. Radiation induced secretion of ATP and HMGB1 in both dying and surviving tumor cells. In vitro and in vivo tumor irradiation induced significant upregulation of multiple components of the antigen-processing machinery and calreticulin cell-surface expression. Augmented CTL lysis specific for several tumor-associated antigens was largely dictated by the presence of calreticulin on the surface of tumor cells and constituted an adaptive response to endoplasmic reticulum stress, mediated by activation of the unfolded protein response. This study provides evidence that radiation induces a continuum of immunogenic alterations in tumor biology, from immunogenic modulation to immunogenic cell death. We also expand the concept of immunogenic modulation, where surviving tumor cells recovering from radiation-induced endoplasmic reticulum stress become more sensitive to CTL killing. These observations offer a rationale for the combined use of radiation with immunotherapy, including for patients failing RT alone.


Assuntos
Apresentação de Antígeno/efeitos da radiação , Calreticulina/farmacologia , Neoplasias/imunologia , Neoplasias/radioterapia , Linfócitos T Citotóxicos/efeitos da radiação , Sequência de Aminoácidos , Apresentação de Antígeno/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Neoplasias da Mama/radioterapia , Linhagem Celular Tumoral , Relação Dose-Resposta à Radiação , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/imunologia , Estresse do Retículo Endoplasmático/efeitos da radiação , Feminino , Humanos , Imunogenética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/radioterapia , Masculino , Dados de Sequência Molecular , Neoplasias/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/radioterapia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia
17.
Radiat Res ; 182(2): 149-62, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25036982

RESUMO

Radiation is a potent immune-modulator that elicits cell death upon tumor, stromal and angiogenic compartments of tumor microenvironment. Here, we test a novel approach of high-dose radiation delivery using three dimensional volume based lattice radiation therapy (LRT) to understand the impact of different volume irradiation in eliciting both local and metastatic/distant tumor control through modulation of tumor immune micro-environment. To study such effects of LRT, tumors were implanted in both hind legs of C57BL/6 mice using Lewis lung carcinoma 1 (LLC1) cells. Mice were divided into five groups: untreated; partial tumor volume groups included two 10% vertices, one 20% vertex and one 50% vertex of the total tumor volume; and 100% open-field irradiation. Tumors implanted in the left flank were irradiated with a single dose of 20 Gy while the tumors in the right flank were unirradiated. Tumor growth and regression as well as immune responses (such as Th1 and Th2; T-cell infiltration) were determined after radiation treatment. Results demonstrated that both 100% open-field irradiation and 20% volume irradiation (in two 10% volumes) resulted in significant growth delay in the irradiated tumor. Further, all types of radiation exposures, partial or 100% volume, demonstrated distal effectiveness, however, 20% volume irradiation (in two 10% volumes) and 50% tumor volume irradiation led to maximum growth delay. Mice treated with partial tumor volume radiation induced a robust IFN-γ and Th1 response when compared to whole-tumor irradiation and down-modulated Th2 functions. The presence of increased CD3+ cells and TRAIL in partially irradiated tumor volumes correlated well with tumor growth delay. Further, serum obtained from any of the LRT treated mice caused growth inhibition of endothelial cells when compared to serum obtained from either untreated or open-field irradiated groups. These results indicate that high-dose partial volume irradiation can cause an improved distant effect than the total tumor volume irradiation through activating the host immune system.


Assuntos
Imunomodulação/efeitos da radiação , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/radioterapia , Animais , Proliferação de Células/efeitos da radiação , Fatores Quimiotáticos/metabolismo , Citocinas/metabolismo , Fracionamento da Dose de Radiação , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Queratinócitos/imunologia , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Esfingomielina Fosfodiesterase/metabolismo , Baço/imunologia , Baço/efeitos da radiação , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação
18.
Cancer Biother Radiopharm ; 29(4): 153-61, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24693958

RESUMO

We sought to determine if single-dose external beam radiation therapy (EBRT) could modulate the expression signature of T-cell costimulatory and coinhibitory molecules in human prostate cancer (PCa) cell lines in vitro. We investigated the functional impact of irradiated PCa cells with a modulated costimulatory profile on responder T-cell activity. We used three PCa cell lines (DU145, PC3, and LNCaP) and two epithelial cell lines from noncancerous prostate and lung tissue. After 72 hours of EBRT, surface expression of four immunostimulatory molecules (CD70, CD275/ICOSL, CD134L/OX40L, and CD137L/41BBL) and two immunosuppressive markers (CTLA-4/CD152 and PD-L1/CD274) were evaluated by flow cytometry. We evaluated the impact of several radiation doses and the longevity of modulated expression. We examined the functional impact of radiation-induced modulation of cancer cells by cytotoxic T cells (CTL) cytotoxicity and ELISPOT assay for interferon-gamma (IFN-γ) production. Last, we evaluated whether IFN-γ-induced PD-L1 expression could be reversed by EBRT. After 10 Gy EBRT, expression of OX40L and 41BBL increased in all three PCa cell lines; expression of CD70 and ICOSL increased in PC3 cells. Conversely, a decrease in PD-L1 expression in DU145 and PC3 cells was detectable up to 144 hours after EBRT. No PD-L1 was detected in LNCaP. Epithelial cells from normal prostate were not modulated by radiation. CTL cytolytic activity and IFN-γ production were enhanced by interaction with irradiated PCa cells. Finally, EBRT failed to prevent IFN-γ-induced upregulation of PD-L1. We demonstrate that a single dose of EBRT increased surface expression of costimulatory molecules and decreased the expression of coinhibitory molecules in human PCa cell lines. Changes in irradiated tumor cells led to functional enhancement of T-cell activity, despite EBRT failing to reduce IFN-γ-induced expression of PD-L1. These data suggest that combining radiotherapy with T-cell stimulating immunotherapy may be an attractive strategy for cancer treatment.


Assuntos
Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/radioterapia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/efeitos da radiação , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos Endogâmicos C57BL , Neoplasias da Próstata/patologia , Transdução de Sinais
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