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BACKGROUND: Frailty is a physiologic state that affects perioperative outcomes. Studies evaluating the impact of frailty on long-term oncologic outcomes are limited. This study evaluated perioperative and long-term oncologic outcomes for elderly patients undergoing colorectal surgery. METHODS: Patients older than 65 years at the time of colorectal resection between July 2011 and September 2020 at Roswell Park Comprehensive Cancer Center were identified. Variables from the National Surgical Quality Improvement Program (NSQIP), the tumor registry, and electronic medical records (EMRs) were used to identify frail patients using the revised Risk Analysis Index (RAI-A) score. A score of 38 or higher defined a patient as "frail." Perioperative outcomes were evaluated using logistic regression and chi-square, and oncologic outcomes were evaluated using Kaplan-Meier analysis. RESULTS: The study analyzed 411 patients. The mean age at surgery was 75.1 years. The median RAI-A score was 37, and 29.9 % of the patients were frail. The frail patients had significantly higher rates of overall complications (30.1 % vs 14.6 %; p < 0.001). They also had significantly higher rates of postoperative hospitalization longer than 30 days, postoperative delirium, and discharge to rehabilitation. No mortality differences were observed. The 318 patients with colorectal adenocarcinoma undergoing curative-intent resection were evaluated for oncologic outcomes. No differences with frailty in terms of overall survival, disease-specific survival, or progression-free survival were observed except for frail patients with stage 0 or 1 adenocarcinoma, who had worse overall survival than non-frail patients but equivalent other outcomes. CONCLUSIONS: For elderly patients undergoing colorectal surgery, frailty is associated with higher postoperative complications, discharge to rehabitation, and prolonged hospitalization rates. Frailty does not affect long-term oncologic outcomes, so frail elderly patients gain the same oncologic benefit with surgery as non-frail patients.
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Adenocarcinoma , Neoplasias Colorretais , Fragilidade , Humanos , Idoso , Fragilidade/complicações , Idoso Fragilizado , Hospitalização , Complicações Pós-Operatórias/etiologia , Adenocarcinoma/complicações , Fatores de Risco , Estudos RetrospectivosAssuntos
Neoplasias , Medicina de Precisão , Humanos , Neoplasias/terapia , Genômica/métodos , Proteômica , Biomarcadores Tumorais , MultiômicaRESUMO
BACKGROUND: Positron emission tomography/computed tomography (PET/CT) scanning is commonly used for the preoperative staging of patients with at least intermediate thickness (>1 mm) melanomas. Its role in staging at initial diagnosis for clinically asymptomatic patients is not yet established. METHODS: We examined records of all patients receiving an operation for at least an intermediate thickness melanoma from June 2005 to June 2011. Results of preoperative PET/CT scans were evaluated in asymptomatic patients with a negative physical exam. Outcome measures included changes in clinical management, as well as incidence of true- and false-positives. RESULTS: PET/CT scans were performed for 149 patients with at least an intermediate thickness melanoma. Positive scans were identified in 28% (41/149) of patients. An invasive procedure to further aid in diagnosis was performed in 44% (18), yet only 6 (15%) patients were diagnosed with metastatic cancer (85% false positive rate). Each of these patients had regional disease subsequently diagnosed by a sentinel lymph node biopsy. No distant metastatic disease was identified. CONCLUSIONS: Preoperative PET/CT in asymptomatic patients is of limited benefit in staging asymptomatic melanoma patients with at least an intermediate thickness melanoma and may lead to unnecessary invasive procedures.
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Melanoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Feminino , Humanos , Excisão de Linfonodo , Masculino , Melanoma/patologia , Estudos Retrospectivos , Biópsia de Linfonodo SentinelaRESUMO
BACKGROUND: Among patients with peripheral arterial disease (PAD), smokers have a higher incidence of life- and limb-threatening complications, including lower extremity ischemic rest pain, myocardial infarction, and cardiac death, highlighting the need for smoking reduction. Several studies have previously investigated the perioperative period as a teachable moment for smoking cessation. The purpose of this study is to determine whether the type of revascularization for PAD (percutaneous versus open) is associated with smoking reduction. METHODS: Study participants included patients seen at a tertiary academic medical center in Providence, RI, between 2005 and 2010 and assigned International Classification of Diseases, Ninth Revision code diagnoses indicative of PAD. This study uses patient-answered surveys and retrospective chart review to assess changes in smoking habits after medical, percutaneous, or open revascularization. Surveys also assessed patient perceptions regarding the influence of intervention on smoking reduction and how strongly patients associate PAD with their smoking habits. RESULTS: Of 54 patients who were active smokers at the time of intervention, 8 (67%) in the medical management group, 12 (50%) in the percutaneous group, and 15 (83%) in the open intervention group reduced smoking by 50% after intervention. After controlling for several confounders, open revascularization was independently associated with smoking reduction when compared with percutaneous intervention (odds ratio, 8.26; 95% confidence interval, 1.18, 76.7; P = 0.043). Surveys revealed that 94% of the patients believed that smoking was a significant contributor to their PAD. CONCLUSIONS: Patients with PAD who undergo open revascularization are more likely to reduce smoking than those who undergo percutaneous revascularization. The perioperative period provides an opportunity to improve rates of smoking reduction.
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Procedimentos Endovasculares , Doença Arterial Periférica/terapia , Abandono do Hábito de Fumar , Prevenção do Hábito de Fumar , Procedimentos Cirúrgicos Vasculares , Centros Médicos Acadêmicos , Idoso , Procedimentos Endovasculares/efeitos adversos , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Educação de Pacientes como Assunto , Percepção , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/etiologia , Doença Arterial Periférica/psicologia , Doença Arterial Periférica/cirurgia , Estudos Retrospectivos , Rhode Island , Fatores de Risco , Fumar/efeitos adversos , Fumar/psicologia , Abandono do Hábito de Fumar/psicologia , Inquéritos e Questionários , Centros de Atenção Terciária , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/efeitos adversosRESUMO
The success of chimeric antigen receptor (CAR) T cell therapy in solid tumors, unlike in hematologic malignancies, is limited by inadequate tumor infiltration and T cell dysfunction and exhaustion. Regional delivery of CAR T cells in patients with solid tumors is safe and feasible; promotes infiltration, proliferation, and trafficking; and ignites functionally persisting systemic immunity.
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Neoplasias , Receptores de Antígenos Quiméricos , Antígenos de Neoplasias , Humanos , Imunoterapia Adotiva , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T , Microambiente TumoralRESUMO
Despite low mutational burden, immune checkpoint inhibitors have demonstrated promising results in a significant minority of hepatocellular carcinoma (HCC) patients with advanced disease. We hypothesized that HCC patients with higher levels of CD8+ T cell infiltration reflect an immune-inflamed cohort which has improved oncologic outcomes. 355 HCC patients with clinical and transcriptome data in the Cancer Genome Atlas (TCGA) and 151 HCC patients from cohort GSE7624 were analyzed. xCell computational algorithm was used to analyze immune cell infiltration in these patients. Each cohort was divided into high and low expression by the highest 2 terciles value. Gene Set Enrichment Analysis was performed to identify enriched gene sets. High CD8 score associated with improved overall survival in both cohorts (both P < 0.05). High score correlates with early BCLC stage (P = 0.035) but not AJCC stage. High CD8 also correlated with increased IFN-γ response (p = 0.038), lymphocyte infiltration (P < 0.001), and leukocyte fraction (P < 0.001). It was associated with increased polyclonality of T cell (P < 0.001) and B cell response (P = 0.017). High CD8 score correlated with increased cytolytic activity score (P < 0.001) and expression of multiple immune checkpoints including PD-1, PD-L1, CTLA-4 and Lag3 (all P < 0.001). There was no correlation to tumor mutational burden and neoantigens. GSEA demonstrated upregulation of several gene sets involved in inflammatory response and IFN-γ response. In conclusion, HCC patients with high CD8 score demonstrated favorable oncologic outcomes, which may be due to immune-mediated tumor cell attack. Furthermore, CD8 score may be a potentially useful biomarker to select patients for immune checkpoint inhibition.
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Biliary tract cancers (BTCs) have limited response to systemic therapy and poor prognosis. Immunotherapy in BTCs has been investigated in recent years. Here, we report a case of locally advanced, unresectable gallbladder adenocarcinoma that progressed on chemotherapy. The patient was then treated with ipilimumab and nivolumab, which resulted in tumor shrinkage and autoimmune hepatitis, but established technical resectability. He underwent complete resection through extended right hepatectomy with en bloc cholecystectomy bile duct resection, hepatic and portal lymphadenectomy and Roux-Y hepaticojejunostomy reconstruction. The final pathology revealed a pathologic complete response. The scope of operative intervention after immunotherapy is still evolving for BTCs. Establishing resectability in tumors not susceptible to cytotoxic agents but responding to immunotherapy not only facilitates curative intent resection but also enhances the importance of infection prevention through operative stent-free long-term biliary decompression. Immunotherapy may also carry a unique risk profile for post-operative morbidity potential as in this case with autoimmune hepatitis.
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Hepatocellular carcinoma (HCC) is one of the most common malignancies and a leading cause of cancer-related deaths worldwide. In this study, a total of 749 HCC patients from 5 cohorts were studied to examine the relationships between enhancement of DNA repair and cancer aggressiveness, tumor immune microenvironment, and patient survival in HCC, utilizing a DNA repair pathway score. Our findings suggest that the DNA repair pathway was not only enhanced by the stepwise carcinogenic process of HCC, but also significantly enhanced in grade 3 HCC compared with grade 1 and 2 tumors. DNA repair high HCC was associated with worse survival, elevated intratumor heterogeneity, and mutation load, but not with the fraction of immune cell infiltration nor immune response. HCC tumors with a DNA repair high score enriched the cell proliferation- and other cancer aggressiveness-related gene sets. Interestingly, these features were more pronounced in grade 1 and 2 HCC compared to grade 3 HCC. To our knowledge, this is the first study to use DNA repair pathway-related gene set expression data to examine and validate the clinical relevance of DNA repair pathway activity in HCC. The DNA repair score may be used to better understand and predict prognosis in HCC.
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Managing patients with incidental gallbladder cancer requires stratifying patients risk for recurrence and an appreciation for the recurrence patterns characterizing this malignancy. Although standard management includes reresection to remove sites at risk of harboring residual disease and to achieve negative resection margin status, the decision to perform surgery is tempered by an early and frequent distant recurrence, the most common cause of surgical failure. High-risk patients may benefit from neoadjuvant chemotherapy before reresection. The goal of curative-intent reresection is achieving R0 margin status and optimal staging while limiting morbidity and mortality.
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Neoplasias da Vesícula Biliar/terapia , Achados Incidentais , Terapia Combinada , Gerenciamento Clínico , Neoplasias da Vesícula Biliar/diagnóstico , Humanos , PrognósticoRESUMO
At MSKCC, over 50% of the patients presenting with gallbladder cancer have been diagnosed incidentally following elective cholecystectomy for presumed benign disease. While traditional management of incidental gallbladder cancer (IGBC) dictates re-resection with the ultimate goal of achieving cure, surgical decision-making must take into account that this malignancy is characterized by poor tumor biology with frequent distant recurrence. Since early and frequent distant recurrence is the most common cause of surgical failure, the surgical oncologist's goal should be to selectively re-resect only those patients most likely to benefit from an operation. The astute surgeon recognizes the high-risk patients who likely have micrometastatic disease at the time of diagnosis and alters the treatment sequence, delivering neoadjuvant chemotherapy. This strategy acts as a selection tool, as those progressing at distant sites during therapy are spared the morbidity and mortality of surgery and furthermore has the potential to treat micrometastatic disease. However, a chemotherapy first approach must be applied selectively since a poor response risks local progression to unresectability and a decrease in functional status that comes from the toxicities of dual agent chemotherapy that can impair surgical candidacy. To balance these risks and benefits, two other criteria for a neoadjuvant approach must be met: i) reliable identification of those patients who are at high risk of distant recurrence and who are, therefore, most likely to benefit from a systemic therapy first approach and ii) availability of effective chemotherapy options. In this review, we will outline the data and judgement we use to select a treatment sequence at our institution.
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Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/cirurgia , Terapia Neoadjuvante , Antineoplásicos/administração & dosagem , Capecitabina/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/patologia , Humanos , Achados Incidentais , Estadiamento de Neoplasias , Neoplasia Residual , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Risco , Medição de RiscoRESUMO
Checkpoint blockade (CPB) therapy can elicit durable clinical responses by reactivating an exhausted immune response. However, response rates remain limited, likely secondary to a lack of a tumor-reactive immune infiltrate. Chimeric antigen receptor (CAR) T cells may provide the necessary tumor-targeting immune infiltrate and a highly specific antitumor immune response. This can be further amplified by the addition of CPB agents, which serve to counteract the immune inhibitory environment undermining optimal CAR T cell efficacy. Herein, we review preclinical and clinical combination therapy with CAR T cells and CPB agents, with a focus on solid tumor malignancies.
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Antineoplásicos Imunológicos/uso terapêutico , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Animais , Antineoplásicos Imunológicos/farmacologia , Terapia Combinada/métodos , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Modelos Animais de Doenças , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
Resistance of human renal cell carcinoma (RCC) and melanoma to the apoptosis-inducing effects of IFNs was postulated to result from epigenetic silencing of genes by DNA methylation, a common feature of human cancers. To reverse silencing, 5-AZA-deoxycytidine (5-AZA-dC) or selective depletion of DNA methyltransferase 1 (DNMT1) by phosphorothioate oligonucleotide antisense (DNMT1 AS) were employed in cells resistant (<5% terminal deoxynucleotidyl transferase-mediated nick-end labeling positive) to apoptosis induction by IFN-alpha2 and IFN-beta (ACHN, SK-RC-45, and A375). 5-AZA-dC and DNMT1 AS similarly depleted available DNMT1 protein and, at doses that did not cause apoptosis alone, resulted in apoptotic response to IFNs. The proapoptotic tumor suppressor RASSF1A was reactivated by DNMT1 inhibitors in all three cell lines. This was associated with demethylation of its promoter region. IFNs augmented RASSF1A protein expression after reactivation by DNMT1 inhibition. In IFN-sensitive WM9 melanoma cells, expression of RASSF1A was constitutive but also augmented by IFNs. RASSF1A small interfering RNA reduced IFN-induced apoptosis in WM9 cells and in DNMT1-depleted ACHN cells. Conversely, lentiviral expression of RASSF1A but not transduction with empty virus enabled IFN-induced apoptosis. IFN induced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL-neutralizing antibody inhibited apoptotic response to IFN in RASSF1A-expressing ACHN cells. Accordingly, RASSF1A markedly sensitized to recombinant TRAIL. Normal kidney epithelial cells, although expressing RASSF1A, did not undergo apoptosis in response to IFN or TRAIL but had >400-fold higher TRAIL decoy receptor 1 expression than transduced ACHN cells (real-time reverse transcription-PCR). Results identified RASSF1A as regulated by IFNs and participating in IFN-induced apoptosis at least in part by sensitization to TRAIL.
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Apoptose/efeitos dos fármacos , Interferon-alfa/farmacologia , Interferon beta/farmacologia , Proteínas Supressoras de Tumor/biossíntese , Apoptose/genética , Proteínas Reguladoras de Apoptose/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferases/deficiência , Resistencia a Medicamentos Antineoplásicos , Epigênese Genética , Inativação Gênica , Células HeLa , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Lentivirus/genética , Lentivirus/metabolismo , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Glicoproteínas de Membrana/farmacologia , Regiões Promotoras Genéticas , RNA Interferente Pequeno/genética , Ligante Indutor de Apoptose Relacionado a TNF , Transfecção , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genéticaRESUMO
Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies.
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Mesotelioma/metabolismo , Neoplasias Pleurais/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Células 3T3 , Animais , Antígenos CD28/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Citocinas/metabolismo , Feminino , Genes Dominantes , Humanos , Mesotelina , Camundongos , Camundongos Nus , Camundongos SCID , Recidiva Local de Neoplasia , Neoplasias Pleurais/imunologiaRESUMO
BACKGROUND: Immune cell infiltration associated with tumor capsule disruption and tumor budding has been shown to reflect invasiveness, metastasis, and unfavorable prognosis in colorectal cancer. We investigated the influence of tumor budding on prognosis and its association with the immune microenvironment in lung adenocarcinoma. METHODS: Tumor slides from resected stage I lung adenocarcinomas were reviewed (n = 524 and n = 514, for training and validation cohorts, respectively) for assessment of tumor budding. CD3+ and forkhead box P3+ (FoxP3+) lymphocytes, CD68+ macrophages, IL-7 receptor, and IL-12 receptor ß2 were analyzed using tissue microarrays constructed from tumor and stroma. Probability of recurrence was calculated using the competing risks method. RESULTS: In the training cohort, risk of recurrence for high-grade tumor budding was higher than it was for low-grade tumor budding (32% vs 12%, P < .001), which was confirmed in the validation cohort (P = .005). Tumor budding stratified the risk of recurrence for acinar-predominant (22% vs 9%, P < .001), papillary-predominant (22% vs 13%, P = .045), and solid-predominant (39% vs 19%, P = .022) tumors. Tumor budding was associated with higher stromal FoxP3+ lymphocyte infiltration, higher stromal FoxP3/CD3 risk index, higher tumoral and stromal CD68+ macrophage infiltration, and IL-7 receptor overexpression (P < .001, all associations). Tumor budding remained independently associated with recurrence on multivariate analysis (hazard ratio, 1.61; P = .008). CONCLUSIONS: Tumor budding is an independent prognostic factor of stage I lung adenocarcinoma and correlates with the protumor immune microenvironment. Our findings advocate investigating tumor-immune cell interactions at the invading edge as a biologic driver of tumor aggressiveness.
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Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Biomarcadores Tumorais/análise , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Complexo CD3/análise , Feminino , Fatores de Transcrição Forkhead/análise , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Receptores de Interleucina-12/análise , Receptores de Interleucina-7/análise , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taxa de Sobrevida , Análise Serial de Tecidos , Microambiente TumoralRESUMO
Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intrapleurally administered CAR T cells vastly outperformed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. After intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced antitumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4(+) T cell activation associated with a higher intratumoral CD4/CD8 cell ratios and CD28-dependent CD4(+) T cell-mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor, did not achieve comparable activation, tumor eradication, or persistence. The ability of intrapleurally administered T cells to circulate and persist supports the concept of delivering optimal CAR T cell therapy through "regional distribution centers." On the basis of these results, we are opening a phase 1 clinical trial to evaluate the safety of intrapleural administration of mesothelin-targeted CAR T cells in patients with primary or secondary pleural malignancies.
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Linfócitos T CD4-Positivos/transplante , Proteínas Ligadas por GPI/metabolismo , Terapia Genética/métodos , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral/transplante , Mesotelioma/terapia , Neoplasias Pleurais/terapia , Receptores de Antígenos de Linfócitos T/biossíntese , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Quimerismo , Citotoxicidade Imunológica , Feminino , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Mesotelina , Mesotelioma/genética , Mesotelioma/imunologia , Mesotelioma/metabolismo , Mesotelioma/patologia , Mesotelioma Maligno , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Pleurais/genética , Neoplasias Pleurais/imunologia , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Fatores de Tempo , Transdução Genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Alloreactive T cells and anti-human leukocyte antigen antibodies mediate transplant injury. Environmental exposures, including vaccinations, may activate the alloimmune repertoire leading to accelerated allograft injury. To test whether vaccination impacts human alloimmunity, we analyzed humoral and cellular immune reactivity in subjects undergoing influenza vaccination. METHODS: We serially obtained blood samples from 30 healthy subjects and 8 kidney and 9 lung transplant recipients who received influenza vaccination, and from 20 healthy unvaccinated controls. We measured cellular and humoral anti-influenza responses, anti-human leukocyte antigen antibodies, and alloreactive T-cell immunity (interferon-gamma ELISPOT) at 0, 2, 4, and 12 weeks after vaccination. RESULTS: Vaccination induced influenza-reactive humoral and cellular responses in control subjects and in transplant recipients. Only two of 30 vaccinated volunteers developed new alloantibodies, but none of the transplant patients. Vaccination also specifically and significantly augmented cellular alloimmunity based on reactivity to a panel of stimulators in both healthy subjects and in transplant recipients within 4 weeks of vaccination. The enhanced cellular alloresponse waned toward prevaccine levels by week 12. CONCLUSION: Our findings newly demonstrate that influenza vaccination can have a significant impact on the potency of the alloimmune repertoire. Because the strength of the alloresponse influences long-term graft function, our results suggest that further investigation of alloimmune monitoring after vaccination is needed.
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Antígenos HLA/imunologia , Imunidade Celular , Imunidade Humoral , Imunização , Vacinas contra Influenza/imunologia , Isoanticorpos/sangue , Transplante de Rim/imunologia , Transplante de Pulmão/imunologia , Linfócitos T/imunologia , Adulto , Anticorpos Antivirais/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Imunização/efeitos adversos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza/efeitos adversos , Interferon gama/sangue , Masculino , Pessoa de Meia-Idade , Linfócitos T/virologia , Fatores de TempoRESUMO
Epigenetic editing of gene expression by aberrant methylation of DNA may help tumor cells escape attack from the innate and acquired immune systems. Resistance to antiproliferative effects and apoptosis induction by interferons (IFNs) was postulated to result from silencing of IFN response genes by promoter hypermethylation. Treatment of human ACHN renal cell carcinoma (RCC) and A375 melanoma cells with the DNA demethylating nucleoside analog 5-AZA-2'-deoxycytidine (5-AZA-dC) synergistically augmented antiproliferative effects of IFN- alpha (alpha) 2 and IFN-beta (beta). Either 5-AZA-dC or an antisense to DNA methyltransferase 1 (DNMT1) overcame resistance to apoptosis induction by IFNs with up to 85% apoptotic cells resulting from the combinations. No similar potentiation occurred in normal kidney epithelial cells. IFN response genes were augmented more than 10 times in expression by 5-AZA-dC. Demethylation by 5-AZA-dC of the promoter of the prototypic, apoptosis-associated IFN response gene XAF1 was confirmed by methylation-specific polymerase chain reaction. siRNA to XAF1 inhibited IFN-induced apoptosis; conversely, overexpression of XAF1 overcame resistance to apoptosis induction by IFN-beta. As occurred with apoptosis-resistant melanoma cells in vitro, tumor growth inhibition in the nude mouse of human A375 melanoma xenografts resulted from treatment with 5-AZA-dC in combination with IFN-beta, an effect not resulting from either single agent. The importance of epigenetic remodeling of expression of immune-modifying genes in tumor cells was further suggested by identifying reactivation of the cancer-testis antigens MAGE and RAGE in ACHN cells after DNMT1 depletion. Thus, inhibitors of DNMT1 may have clinical relevance for immune modulation by augmentation of cytokine effects and/or expression of tumor-associated antigens.