RESUMO
Worldwide, gastrointestinal (GI) cancer is recognized as one of the leading malignancies diagnosed in both genders, with mortality largely attributed to metastatic dissemination. It has been identified that in GI cancer, a variety of signaling pathways and key molecules are modified, leading to the emergence of an immunotolerance phenotype. Such modifications are pivotal in the malignancy's evasion of immune detection. Thus, a thorough analysis of the pathways and molecules contributing to GI cancer's immunotolerance is vital for advancing our comprehension and propelling the creation of efficacious pharmacological treatments. In response to this necessity, our review illuminates a selection of groundbreaking cellular signaling pathways associated with immunotolerance in GI cancer, including the Phosphoinositide 3-kinases/Akt, Janus kinase/Signal Transducer and Activator of Transcription 3, Nuclear Factor kappa-light-chain-enhancer of activated B cells, Transforming Growth Factor-beta/Smad, Notch, Programmed Death-1/Programmed Death-Ligand 1, and Wingless and INT-1/beta-catenin-Interleukin 10. Additionally, we examine an array of pertinent molecules like Indoleamine-pyrrole 2,3-dioxygenase, Human Leukocyte Antigen G/E, Glycoprotein A Repetitions Predominant, Clever-1, Interferon regulatory factor 8/Osteopontin, T-cell immunoglobulin and mucin-domain containing-3, Carcinoembryonic antigen-related cell adhesion molecule 1, Cell division control protein 42 homolog, and caspases-1 and -12.
Assuntos
Neoplasias Gastrointestinais , Transdução de Sinais , Humanos , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/metabolismo , Animais , Metástase Neoplásica , Tolerância Imunológica , Evasão TumoralAssuntos
Neoplasias Gastrointestinais , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/terapia , Humanos , Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/uso terapêuticoRESUMO
The immune system is capable of remarkably potent and specific efficacy against infectious diseases. For decades, investigators sought to leverage those characteristics to create immune-based therapies (immunotherapy) that might be far more effective and less toxic than conventional chemotherapy and radiation therapy for cancer. Those studies revealed many factors and mechanisms underlying the success or failure of cancer immunotherapy, leading to synthetic biology approaches, including CAR-T cell therapy. In this approach, patient T cells are genetically modified to express a chimeric antigen receptor (CAR) that converts T cells of any specificity into tumor-specific T cells that can be expanded to large numbers and readministered to the patient to eliminate cancer cells, including bulky metastatic disease. This approach has been most successful against hematologic cancers, resulting in five FDA approvals to date. Here, we discuss some of the most promising attempts to apply this technology to cancers of the gastrointestinal tract.
Assuntos
Neoplasias Gastrointestinais , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/terapia , Humanos , Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologiaRESUMO
Immune checkpoint inhibitors target checkpoint proteins with the goal of reinvigorating the host immune system and thus restoring antitumor response. With the dramatic increase in the use of checkpoint inhibitors for cancer treatment, surgical pathologists have assumed a major role in predicting the therapeutic efficacy (score based on programmed cell death ligand 1 immunohistochemistry and mismatch repair protein loss) as well as diagnosing the complications associated with these medications. Immune-related adverse events (irAEs) manifest as histologic changes seen in both the upper and lower gastrointestinal tract, and when viewed in isolation, may be morphologically indistinguishable from a wide range of diseases including infections, celiac disease, and inflammatory bowel disease, among others. Evaluation of biopsies from both the upper and lower gastrointestinal tract can aid in the distinction of gastrointestinal irAEs from their mimics. In the liver, the histologic changes of hepatic irAEs overlap with de novo diseases associated with hepatitic and cholangitic patterns of injury. The diagnosis of irAEs requires communication and collaboration from the pathologist, oncologist, and gastroenterologist. This review provides a background framework and illustrates the histologic features and differential diagnosis of gastrointestinal and hepatic irAEs.
Assuntos
Antígeno B7-H1/antagonistas & inibidores , Doenças do Sistema Digestório/induzido quimicamente , Sistema Digestório/efeitos dos fármacos , Neoplasias Gastrointestinais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Patologistas , Antígeno B7-H1/análise , Biópsia , Tomada de Decisão Clínica , Diagnóstico Diferencial , Sistema Digestório/imunologia , Sistema Digestório/patologia , Doenças do Sistema Digestório/imunologia , Doenças do Sistema Digestório/patologia , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/patologia , Humanos , Valor Preditivo dos TestesRESUMO
The devastating complications of coronavirus disease 2019 (COVID19) result from the dysfunctional immune response of an individual following the initial severe acute respiratory syndrome coronavirus 2 (SARSCoV2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARSCoV2 exploits the dysfunctional immune system to trigger a chain of events, ultimately leading to COVID19. The authors have previously identified a number of contributing factors (CFs) common to myriad chronic diseases. Based on these observations, it was hypothesized that there may be a significant overlap between CFs associated with COVID19 and gastrointestinal cancer (GIC). Thus, in the present study, a streamlined dotproduct approach was used initially to identify potential CFs that affect COVID19 and GIC directly (i.e., the simultaneous occurrence of CFs and disease in the same article). The nascent character of the COVID19 core literature (~1yearold) did not allow sufficient time for the direct effects of numerous CFs on COVID19 to emerge from laboratory experiments and epidemiological studies. Therefore, a literaturerelated discovery approach was used to augment the COVID19 core literaturebased 'direct impact' CFs with discoverybased 'indirect impact' CFs [CFs were identified in the nonCOVID19 biomedical literature that had the same biomarker impact pattern (e.g., hyperinflammation, hypercoagulation, hypoxia, etc.) as was shown in the COVID19 literature]. Approximately 2,250 candidate direct impact CFs in common between GIC and COVID19 were identified, albeit some being variants of the same concept. As commonality proof of concept, 75 potential CFs that appeared promising were selected, and 63 overlapping COVID19/GIC potential/candidate CFs were validated with biological plausibility. In total, 42 of the 63 were overlapping direct impact COVID19/GIC CFs, and the remaining 21 were candidate GIC CFs that overlapped with indirect impact COVID19 CFs. On the whole, the present study demonstrates that COVID19 and GIC share a number of common risk/CFs, including behaviors and toxic exposures, that impair immune function. A key component of immune system health is the removal of those factors that contribute to immune system dysfunction in the first place. This requires a paradigm shift from traditional Western medicine, which often focuses on treatment, rather than prevention.
Assuntos
COVID-19/epidemiologia , Neoplasias Gastrointestinais/epidemiologia , COVID-19/etiologia , COVID-19/imunologia , Neoplasias Gastrointestinais/etiologia , Neoplasias Gastrointestinais/imunologia , Humanos , Fatores de Risco , SARS-CoV-2/fisiologia , Fatores SocioeconômicosRESUMO
Objective: To investigate the characteristics of the tumor immune microenvironment in patients with gastrointestinal stromal tumor (GIST) and identify cancer stem-like properties of GIST to screen potential druggable molecular targets. Methods: The gene expression data of 60 patients with GIST was retrieved from the Array Express database. CIBERSORT was applied to calculate the level of immune infiltration. ssGSEA and ESTIMATE were used to calculate the cancer stemness index and tissue purity. The Connectivity Map (CMAP) database was implemented to screen targeted drugs based on cancer stem-like properties of GIST. Result: There was a difference in the level of immune infiltration between the metastasis and non-metastasis GIST groups. The low level of T-cell infiltration was correlated with high tumor purity and tumor stemness index, and the correlation coefficients were -0.87 and -0.61 (p < 0.001), respectively. Furthermore, there was a positive correlation between cancer stemness index and cell purity (p < 0.001). The cancer stemness index in the metastasis group was higher than that in the non-metastasis group (p = 0.0017). After adjusting for tumor purity, there was no significant correlation between T-cell infiltration and cancer stemness index (p = 0.086). Through the pharmacological mechanism of topoisomerase inhibitors, six molecular complexes may be the targets of GIST treatment. Conclusion: Immune infiltration in GIST patients is related to cancer stem-like properties, and the correlation relies on tumor purity. Cancer stemness index can be used as a new predictive biomarker of tumor metastasis and targets of drug therapy for GIST patients.
Assuntos
Autorrenovação Celular , Neoplasias Gastrointestinais/terapia , Tumores do Estroma Gastrointestinal/terapia , Linfócitos do Interstício Tumoral/imunologia , Terapia de Alvo Molecular , Células-Tronco Neoplásicas/patologia , Autorrenovação Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/secundário , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Metástase Neoplásica , Mapas de Interação de Proteínas , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Máquina de Vetores de Suporte , Subpopulações de Linfócitos T/imunologia , Inibidores da Topoisomerase/farmacologia , Inibidores da Topoisomerase/uso terapêutico , Microambiente Tumoral/imunologiaRESUMO
INTRODUCTION: Multiple previous studies have shown the monoclonal antibody Das-1 (formerly called 7E12H12) is specifically reactive towards metaplastic and carcinomatous lesions in multiple organs of the gastrointestinal system (e.g. Barrett's esophagus, intestinal-type metaplasia of the stomach, gastric adenocarcinoma, high-grade pancreatic intraepithelial neoplasm, and pancreatic ductal adenocarcinoma) as well as in other organs (bladder and lung carcinomas). Beyond being a useful biomarker in tissue, mAb Das-1 has recently proven to be more accurate than current paradigms for identifying cysts harboring advanced neoplasia. Though this antibody has been used extensively for clinical, basic science, and translational applications for decades, its epitope has remained elusive. METHODS: In this study, we chemically deglycosylated a standard source of antigen, which resulted in near complete loss of the signal as measured by western blot analysis. The epitope recognized by mAb Das-1 was determined by affinity to a comprehensive glycan array and validated by inhibition of a direct ELISA. RESULTS: The epitope recognized by mAb Das-1 is 3'-Sulfo-Lewis A/C (3'-Sulfo-LeA/C). 3'-Sulfo-LeA/C is broadly reexpressed across numerous GI epithelia and elsewhere during metaplastic and carcinomatous transformation. DISCUSSION: 3'-Sulfo-LeA/C is a clinically important antigen that can be detected both intracellularly in tissue using immunohistochemistry and extracellularly in cyst fluid and serum by ELISA. The results open new avenues for tumorigenic risk stratification of various gastrointestinal lesions.
Assuntos
Anticorpos Monoclonais/imunologia , Transformação Celular Neoplásica/imunologia , Epitopos de Linfócito B/imunologia , Neoplasias Gastrointestinais/imunologia , Mucosa Intestinal/imunologia , Antígenos do Grupo Sanguíneo de Lewis/imunologia , Oligossacarídeos/imunologia , Especificidade de Anticorpos , Biomarcadores Tumorais/imunologia , Linhagem Celular Tumoral , Humanos , Imuno-HistoquímicaRESUMO
BACKGROUND: Atypical tumor response patterns during immune checkpoint inhibitor therapy pose a challenge to clinicians and investigators in immuno-oncology practice. This study evaluated tumor burden dynamics to identify imaging biomarkers for treatment response and overall survival (OS) in advanced gastrointestinal malignancies treated with PD-1/PD-L1 inhibitors. METHODS: This retrospective study enrolled a total of 198 target lesions in 75 patients with advanced gastrointestinal malignancies treated with PD-1/PD-L1 inhibitors between January 2017 and March 2021. Tumor diameter changes as defined by immunotherapy Response Evaluation Criteria in Solid Tumors (iRECIST) were studied to determine treatment response and association with OS. RESULTS: Based on the best overall response, the tumor diameter ranged from - 100 to + 135.3% (median: - 9.6%). The overall response rate was 32.0% (24/75), and the rate of durable disease control for at least 6 months was 30.7% (23/75, one (iCR, immune complete response) or 20 iPR (immune partial response), or 2iSD (immune stable disease). Using univariate analysis, patients with a tumor diameter maintaining a < 20% increase (48/75, 64.0%) from baseline had longer OS than those with ≥20% increase (27/75, 36.0%) and, a reduced risk of death (median OS: 80 months vs. 48 months, HR = 0.22, P = 0.034). The differences in age (HR = 1.09, P = 0.01), combined surgery (HR = 0.15, P = 0.01) and cancer type (HR = 0.23, P = 0.001) were significant. In multivariable analysis, patients with a tumor diameter with a < 20% increase had notably reduced hazards of death (HR = 0.15, P = 0.01) after adjusting for age, combined surgery, KRAS status, cancer type, mismatch repair (MMR) status, treatment course and cancer differentiation. Two patients (2.7%) showed pseudoprogression. CONCLUSIONS: Tumor diameter with a < 20% increase from baseline during therapy in gastrointestinal malignancies was associated with therapeutic benefit and longer OS and may serve as a practical imaging marker for treatment response, clinical outcome and treatment decision making.
Assuntos
Neoplasias Gastrointestinais , Inibidores de Checkpoint Imunológico/uso terapêutico , Critérios de Avaliação de Resposta em Tumores Sólidos , Carga Tumoral , Adulto , Fatores Etários , Análise de Variância , Reparo de Erro de Pareamento de DNA , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Genes ras , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacosRESUMO
Over the past decades, a large amount of data has been accumulated in various subfields of glycobiology. However, much clinically relevant data and many tools are still not widely used in medicine. Synthetic glycoconjugates with the known structure of glycans are an accurate tool for the study of glycan-binding proteins. We used polyacrylamide glycoconjugates (PGs) including PGs with tumour-associated glycans (TAGs) in immunoassays to assess the prognostic potential of the serum level of anti-glycan antibodies (AG Abs) in gastrointestinal cancer patients and found an association of AG Abs with survival. The specificity of affinity-isolated AG Abs was investigated using synthetic and natural glycoconjugates. AG Abs showed mainly a low specificity to tumour-associated and tumour-derived mucins; therefore, the protective role of the examined circulating AG Abs against cancer remains a challenge. In this review, our findings are analysed and discussed in the context of the contribution of bacteria to the AG Abs stimulus and cancer progression. Examples of the influence of pathogenic bacteria colonising tumours on cancer progression and patient survival through mechanisms of interaction with tumours and dysregulated immune response are considered. The possibilities and problems of the integrative study of AG Abs and the microbiome using high-performance technologies are discussed.
Assuntos
Anticorpos/imunologia , Neoplasias Gastrointestinais/imunologia , Microbiota/imunologia , Polissacarídeos/imunologia , Animais , Bactérias/imunologia , Neoplasias Gastrointestinais/microbiologia , Glicoconjugados/imunologia , HumanosRESUMO
Chronic inflammation is a known risk factor for gastrointestinal cancer. The evidence that nonsteroidal anti-inflammatory drugs suppress the incidence, growth, and metastasis of gastrointestinal cancer supports the concept that a nonsteroidal anti-inflammatory drug target, cyclooxygenase, and its downstream bioactive lipid products may provide one of the links between inflammation and cancer. Preclinical studies have demonstrated that the cyclooxygenase-2-prostaglandin E2 pathway can promote gastrointestinal cancer development. Although the role of this pathway in cancer has been investigated extensively for 2 decades, only recent studies have described its effects on host defenses against transformed epithelial cells. Overcoming tumor-immune evasion remains one of the major challenges in cancer immunotherapy. This review summarizes the impacts of the cyclooxygenase-2-prostaglandin E2 pathway on gastrointestinal cancer development. Our focus was to highlight recent advances in our understanding of how this pathway induces tumor immune evasion.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Neoplasias Gastrointestinais/enzimologia , Mediadores da Inflamação/metabolismo , Evasão Tumoral , Microambiente Tumoral/imunologia , Animais , Antineoplásicos/uso terapêutico , Fibroblastos Associados a Câncer/enzimologia , Fibroblastos Associados a Câncer/imunologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Células Epiteliais/enzimologia , Células Epiteliais/imunologia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/patologia , Humanos , Imunoterapia , Linfócitos do Interstício Tumoral/enzimologia , Linfócitos do Interstício Tumoral/imunologia , Transdução de Sinais , Evasão Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/enzimologia , Macrófagos Associados a Tumor/imunologiaRESUMO
Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status of tumors is a distinct predictive biomarker of immune checkpoint inhibitors (ICIs) for colorectal and non-colorectal cancer populations. The overall response rate (ORR) varies from approximately 40% to 60%, indicating that nearly half of MSI-H tumors do not respond to ICIs. The mechanism of response heterogeneity in MSI-H/dMMR cancers is unclear. Some patients who have been treated with ICIs have developed a novel pattern of progression called hyperprogression, which is defined as unexpected accelerated tumor growth. No case of MSI-H/dMMR immunotherapy-associated hyperprogression has been reported in the literature. Here, we present the case of a patient with dMMR gastrointestinal cancer who suffered hyperprogressive disease (HPD) after treatment with nivolumab. We explored the potential mechanisms of HPD by clinical, immune, and genomic characteristics. Extremely high levels of serum LDH, low TMB and TILs, and the disruption of TGFß signaling, may be related to hyperprogression.
Assuntos
Neoplasias Gastrointestinais , Inibidores de Checkpoint Imunológico/uso terapêutico , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Reparo de Erro de Pareamento de DNA , Progressão da Doença , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Accumulating evidence has revealed the critical roles of commensal microbes in cancer progression and recently several investigators have evaluated the therapeutic effectiveness of targeting the microbiota. This gut microbiota-related approach is especially attractive in the treatment of gastrointestinal cancers. Probiotics supplementation is a microbiota-targeted strategy that appears to improve treatment efficacy; Lactobacillus spp. and Bifidobacterium spp. are among the most commonly used probiotic agents. These bacteria seem to exert immunomodulatory effects, impacting on the immune system both locally and systemically. The gut microbiota are able to affect the efficiency of immunotherapy, mainly acting as inhibitors at immune checkpoints. The effects of immunotherapy may be modulated using traditional probiotic strains and/or next generation probiotics, such as Akkermansia municiphila. It is possible that probiotics might enhance the efficiency of immunotherapy based on PD-1/PD-L1 and CTLA-4 but more data are needed to confirm this speculation. Indeed, although there is experimental evidence for the efficacy of several strains, the health-promoting effects of numerous probiotics have not been demonstrated in human patients and furthermore the potential risks of these products, particularly in oncologic patients, are rarely mentioned.
Assuntos
Bifidobacterium , Microbioma Gastrointestinal/imunologia , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/microbiologia , Lactobacillus , Akkermansia , Animais , Bactérias , Humanos , Sistema Imunitário , Imunomodulação , Probióticos/administração & dosagemRESUMO
Gastrointestinal cancer is a leading cause of cancer-related mortality and remains a major challenge for cancer treatment. Despite the combined administration of modern surgical techniques and chemoradiotherapy (CRT), the overall 5-year survival rate of gastrointestinal cancer patients in advanced stage disease is less than 15%, due to rapid disease progression, metastasis, and CRT resistance. A better understanding of the mechanisms underlying cancer progression and optimized treatment strategies for gastrointestinal cancer are urgently needed. With increasing evidence highlighting the protective role of immune responses in cancer initiation and progression, immunotherapy has become a hot research topic in the integrative management of gastrointestinal cancer. Here, an overview of the molecular understanding of colorectal cancer, esophageal cancer and gastric cancer is provided. Subsequently, recently developed immunotherapy strategies, including immune checkpoint inhibitors, chimeric antigen receptor T cell therapies, tumor vaccines and therapies targeting other immune cells, have been described. Finally, the underlying mechanisms, fundamental research and clinical trials of each agent are discussed. Overall, this review summarizes recent advances and future directions for immunotherapy for patients with gastrointestinal malignancies.
Assuntos
Vacinas Anticâncer/uso terapêutico , Imunoterapia Adotiva , Vacinas Anticâncer/imunologia , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/terapia , HumanosRESUMO
Gastrointestinal cancer is one of the most common cancers globally. Melatonin, a natural endogenous body hormone, has been of interest for years, due to its anti-cancer characteristics, such as antiproliferative, antimetastatic, and cytotoxic as well as apoptotic induction. Through regulating several proteins such as melatonin upregulated mRNAs and proteins of downregulated Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2), as well as cytoplasmic protein such as calcium-binding proteins calmodulin or tubulin, and nuclear receptors, including RORα/RZR, and acts by non-receptor-regulated mechanisms, melatonin can exert anti-cancer efficacy. Moreover, melatonin modulates angiogenesis by targeting mRNA and protein expression of endothelin-converting enzyme (ECE-1) protein. In the present review, we address in vivo, in vitro and clinical reports on its anti-cancer efficacies, and the molecular mechanisms of action responsible for these effects. We advance the possibility of therapeutic melatonin administration for cancer therapy.
Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Melatonina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Humanos , Melatonina/farmacologia , Receptores de Melatonina/metabolismoRESUMO
OBJECTIVES: The aim of this study was to characterize the tumor microenvironment of patients with gastroenteropancreatic neuroendocrine tumors relative to progression-free survival (PFS). METHODS: Immune profiling for CD3, CD8, programmed death-1/programmed death-ligand 1, and indoleamine 2,3-dioxygenase expression in 2 cohorts of gastroenteropancreatic neuroendocrine tumors: patients with short PFS (<4 years, n = 12) versus long PFS (≥4 years, n = 14) after surgery. Immune infiltrates in the tumor and interface were quantified. Programmed death-ligand 1 expression was determined within the tumor, stroma, and interface. RESULTS: Patients with shorter PFS had larger tumors (P = 0.02), mostly in the pancreas (P = 0.04). We observed a higher mean expression of CD3+, CD8+, programmed death-1+ cells, and indoleamine 2,3-dioxygenase at the interface compared with the tumor: log 10 mean differences 0.56 (95% confidence interval [CI], 0.43-0.68; P < 0.0001), 0.45 (95% CI, 0.32-0.59; P = 0.0002), 0.50 (95% CI, 0.40-0.61; P < 0.0001), and 0.24 (95% CI, 0.03-0.46; P = 0.046), respectively. Patients with longer PFS had higher intratumoral CD3+ T cells, log 10 mean difference 0.38 (95% CI, 0.19-0.57; P = 0.004). Programmed death-ligand 1 expression tended to be higher among patients with shortened PFS (odds ratio, 2.00; 95% CI, 0.68-5.91). CONCLUSIONS: Higher intratumoral CD3+ T-cell infiltrate was associated with longer PFS after resection.
Assuntos
Neoplasias Gastrointestinais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Tumores Neuroendócrinos/imunologia , Neoplasias Pancreáticas/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Adolescente , Adulto , Idoso , Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Complexo CD3/análise , Feminino , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Receptor de Morte Celular Programada 1/análise , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: This communication reports the identification of a new panel of transcriptional changes in inflammation-associated genes observed in response to ionising radiation received by radiotherapy patients. METHODS: Peripheral blood samples were taken with ethical approval and informed consent from a total of 20 patients undergoing external beam radiotherapy for breast, lung, gastrointestinal or genitourinary tumours. Nanostring nCounter analysis of transcriptional changes was carried out in samples prior and 24 h post-delivery of the 1st radiotherapy fraction, just prior to the 5th or 6th fraction, and just before the last fraction. RESULTS: Statistical analysis with BRB-ArrayTools, GLM MANOVA and nSolver, revealed a radiation responsive panel of genes which varied by patient group (type of cancer) and with time since exposure (as an analogue for dose received), which may be useful as a biomarker of radiation response. CONCLUSION: Further validation in a wider group of patients is ongoing, together with work towards a full understanding of patient specific responses in support of personalised approaches to radiation medicine.
Assuntos
Biomarcadores Tumorais/sangue , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Inflamação/genética , Neoplasias/sangue , Radiação Ionizante , Transcriptoma/efeitos da radiação , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/radioterapia , Feminino , Neoplasias Gastrointestinais/sangue , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/radioterapia , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/radioterapia , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/radioterapia , Projetos Piloto , Prognóstico , Neoplasias Urogenitais/sangue , Neoplasias Urogenitais/genética , Neoplasias Urogenitais/imunologia , Neoplasias Urogenitais/radioterapiaRESUMO
Antibody-mediated transient depletion of CD4+ cells enhances the expansion of tumor-reactive CD8+ T cells and exhibits robust antitumor effects in preclinical and clinical studies. To investigate the clonal T-cell responses following transient CD4+ cell depletion in patients with cancer, we conducted a temporal analysis of the T-cell receptor (TCR) repertoire in the first-in-human clinical trial of IT1208, a defucosylated humanized monoclonal anti-CD4. Transient depletion of CD4+ cells promoted replacement of T-cell clones among CD4+ and CD8+ T cells in the blood. This replacement of the TCR repertoire was associated with the extent of CD4+ T-cell depletion and an increase in CD8+ T-cell count in the blood. Next, we focused on T-cell clones overlapping between the blood and tumor in order to track tumor-associated T-cell clones in the blood. The total frequency of blood-tumor overlapping clones tended to increase in patients receiving a depleting dose of anti-CD4, which was accompanied by the replacement of overlapping clones. The greater expansion of CD8+ overlapping clones was commonly observed in the patients who achieved tumor shrinkage. These results suggested that the clonal replacement of the TCR repertoire induced by transient CD4+ cell depletion was accompanied by the expansion of tumor-reactive T-cell clones that mediated antitumor responses. Our findings propose beneficial remodeling of the TCR repertoire following transient CD4+ cell depletion and provide novel insight into the antitumor effects of monoclonal anti-CD4 treatment in patients with cancer.See related Spotlight on p. 601.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Antígenos CD4/antagonistas & inibidores , Neoplasias Gastrointestinais/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/genética , Adulto , Idoso , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Esquema de Medicação , Feminino , Neoplasias Gastrointestinais/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Chronic inflammation is thought to promote tumorigenesis and metastasis by several mechanisms, such as affecting tumor cells directly, establishing a tumor-supporting microenvironment, enhancing tumor angiogenesis, and suppressing antitumor immunity. In this review, we discuss the recent advances in our understanding of how inflammation induces the immunosuppressive tumor microenvironment, such as increasing the level of pro-inflammatory cytokines, chemokines, and immunosuppressive molecules, inducing immune checkpoint molecules and cytotoxic T-cell exhaustion, and accumulating regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). The suppression of antitumor immunity by inflammation is especially examined in the liver and colorectal cancer. In addition, chronic inflammation is induced during aging and causes age-related diseases, including cancer, by affecting immunity. Therefore, we also discuss the age-related diseases regulated by inflammation, especially in the liver and colon.
Assuntos
Envelhecimento/imunologia , Transformação Celular Neoplásica/imunologia , Neoplasias Gastrointestinais/imunologia , Imunomodulação , Inflamação/imunologia , Neoplasias Hepáticas/imunologia , Envelhecimento/patologia , Animais , Transformação Celular Neoplásica/patologia , Neoplasias Gastrointestinais/patologia , Humanos , Neoplasias Hepáticas/patologiaRESUMO
Gastrointestinal cancers are one of the most common types of cancer that have high annual mortality; therefore, identification and introduction of safe drugs in the control and prevention of these cancers are of particular importance. Metformin, a lipophilic biguanide, is the most commonly prescribed agent for type 2 diabetes management. In addition to its great effects on lowering the blood glucose concentrations, the anti-cancer properties of this drug have been reported in many types of cancers such as gastrointestinal cancers. Hence the effects of this agent as a safe drug on the reduction of gastrointestinal cancer risk and suppression of these types of cancers have been studied in different clinical trials. Furthermore, the proposed mechanisms of metformin in preventing the growth of these cancers have been investigated in several studies. In this review, we discuss recent advances in elucidating the molecular mechanisms that are relevant for metformin use in gastrointestinal cancer treatment.