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1.
Nat Commun ; 11(1): 4740, 2020 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-32958755

RESUMEN

The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptides. This correlation is absent in tumors with Beta-2-microglobulin mutations, and HLA-A*02:01 status is related to cMS mutation patterns. Importantly, certain outlier mutations are common in MSI cancers despite being related to frameshift peptides with functionally confirmed immunogenicity, suggesting a possible driver role during MSI tumor evolution. Neoantigens resulting from shared mutations represent promising vaccine candidates for prevention of MSI cancers.


Asunto(s)
Mutación del Sistema de Lectura , Repeticiones de Microsatélite/genética , Neoplasias/genética , Neoplasias/inmunología , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Antígenos HLA/genética , Humanos , Mutación INDEL , Vigilancia Inmunológica , Inestabilidad de Microsatélites , Tasa de Mutación , Selección Genética , Microglobulina beta-2/genética
2.
Anticancer Res ; 40(10): 5329-5341, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32988851

RESUMEN

Investigation of the efficacy and mechanisms of human immuno-oncology agents has been hampered due to species-specific differences when utilizing preclinical mouse models. Peripheral blood mononuclear cell (PBMC) humanized mice provide a platform for investigating the modulation of the human immune-mediated antitumor response while circumventing the limitations of syngeneic model systems. Use of humanized mice has been stymied by model-specific limitations, some of which include the development of graft versus host disease, technical difficulty and cost associated with each humanized animal, and insufficient engraftment of some human immune subsets. Recent advances have addressed many of these limitations from which have emerged humanized models that are more clinically relevant. This review characterizes the expanded usage, advantages and limitations of humanized mice and provides insights into the development of the next generation of murine humanized models to further inform clinical applications of cancer immunotherapeutic agents.


Asunto(s)
Inmunidad Celular/efectos de los fármacos , Inmunoterapia , Leucocitos Mononucleares/inmunología , Neoplasias/tratamiento farmacológico , Animales , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos/inmunología , Antineoplásicos/farmacología , Modelos Animales de Enfermedad , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Ratones , Neoplasias/inmunología , Neoplasias/patología
3.
Anticancer Res ; 40(10): 5355-5359, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32988854

RESUMEN

BACKGROUND/AIM: Recent studies indicate that chimeric antigen receptor (CAR)-T-cells seem to be superior to CAR modified NK-92 cells. One, at least partial, explanation to this discrepancy has been addressed herein, by having NK-92 cells as target cells in cytotoxicity reactions using peripheral blood mononuclear cells. MATERIALS AND METHODS: A time-resolved fluorometric assay (TDA-labeled NK-92 or K562 as target cells) was used for measuring the cytotoxic activity of blood mononuclear cells (PBMC). RESULTS: The cytotoxic capacity of the NK-92 cells was initially demonstrated by their ability to efficiently kill K562 cells. Interestingly, having PBMC as effector cells rendered the very same NK-92 cells sensitive to NK-cell mediated cytolysis. A 1:100 target:effector ratio gave 34.1% lysis compared to 72.2% lysis for K562 cells. Incubating PBMC for longer times (24 up to 48 h) potentiated their NK-activity against NK-92 cells even more, reaching a level close to that obtained with K562 cells. CONCLUSION: This study pinpoints a severe problem that has to be considered in future immune-based cancer therapies with NK-92 as well as CAR-transduced NK-92 cells.


Asunto(s)
Inmunoterapia Adoptiva , Células Asesinas Naturales/efectos de los fármacos , Leucocitos Mononucleares/efectos de los fármacos , Neoplasias/terapia , Citotoxicidad Inmunológica/efectos de los fármacos , Humanos , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/inmunología , Interleucina-2/genética , Interleucina-2/inmunología , Células K562 , Neoplasias/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología
4.
ESMO Open ; 5(5)2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32958531

RESUMEN

BACKGROUND: Immunosuppression induced by anticancer therapy in a COVID-19-positive asymptomatic patient with cancer may have a devastating effect and, eventually, be lethal. To identify asymptomatic cases among patients receiving active cancer treatment, the Federico II University Hospital in Naples performs rapid serological tests in addition to hospital standard clinical triage for COVID-19 infection. METHODS: From 6 to 17 April 2020, all candidates for chemotherapy, radiotherapy or target/immunotherapy, if negative at the standard clinical triage on the day scheduled for anticancer treatment, received a rapid serological test on peripheral blood for COVID-19 IgM and IgG detection. In case of COVID-19 IgM and/or IgG positivity, patients underwent a real-time PCR (RT-PCR) SARS-CoV-2 test to confirm infection, and active cancer treatment was delayed. RESULTS: Overall 466 patients, negative for COVID-19 symptoms, underwent serological testing in addition to standard clinical triage. The average age was 61 years (range 25-88 years). Most patients (190, 40.8%) had breast cancer, and chemotherapy with or without immunotherapy was administered in 323 (69.3%) patients. Overall 433 (92.9%) patients were IgG-negative and IgM-negative, and 33 (7.1%) were IgM-positive and/or IgG-positive. Among the latter patients, 18 (3.9%), 11 (2.4%) and 4 (0.9%) were IgM-negative/IgG-positive, IgM-positive/IgG-negative and IgM-positive/IgG-positive, respectively. All 33 patients with a positive serological test, tested negative for RT-PCR SARS-CoV-2 test. No patient in our cohort developed symptoms suggestive of active COVID-19 infection. CONCLUSION: Rapid serological testing at hospital admission failed to detect active asymptomatic COVID-19 infection. Moreover, it entailed additional economic and human resources, delayed therapy administrationand increased hospital accesses.


Asunto(s)
Infecciones Asintomáticas , Técnicas de Laboratorio Clínico/métodos , Infecciones por Coronavirus/diagnóstico , Inmunosupresión/efectos adversos , Neoplasias/terapia , Neumonía Viral/diagnóstico , Triaje/normas , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Antineoplásicos Inmunológicos/efectos adversos , Betacoronavirus/genética , Betacoronavirus/inmunología , Betacoronavirus/aislamiento & purificación , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Técnicas de Laboratorio Clínico/economía , Técnicas de Laboratorio Clínico/estadística & datos numéricos , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/economía , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Pruebas Diagnósticas de Rutina/economía , Pruebas Diagnósticas de Rutina/estadística & datos numéricos , Estudios de Factibilidad , Femenino , Humanos , Inmunosupresión/métodos , Masculino , Persona de Mediana Edad , Neoplasias/inmunología , Pandemias , Admisión del Paciente/economía , Admisión del Paciente/estadística & datos numéricos , Neumonía Viral/sangre , Neumonía Viral/inmunología , Neumonía Viral/virología , Guías de Práctica Clínica como Asunto , ARN Viral/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/economía , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/estadística & datos numéricos , Sensibilidad y Especificidad
5.
Anticancer Res ; 40(10): 5489-5496, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32988871

RESUMEN

BACKGROUND/AIM: Cytokine-induced killer (CIK) cells are a heterogenous population of immune cells showing promising applications in immunotherapeutic cancer treatment. Neuropilin (NRP) proteins have been proven to play an important role in cancer development and prognosis. In this study, CIK cells were tested for expression of NRPs, transmembrane proteins playing a role in the proliferation and survival of cancer cells. MATERIALS AND METHODS: CIK cells were analyzed at different time points via flow cytometry and quantitative real-time polymerase chain reaction for neuropilin expression. RESULTS: Phenotyping results showed CIK cells having developed properly, and low levels of NRP2 were detected. On the other hand, no NRP1 expression was found. Two cancer cell lines were tested by flow cytometry: A549 cells expressed NRP1 and NRP2; U251-MG cells expressed high amounts of NRP2. CIK cell showed low levels of NRP2 expression on day 14. CONCLUSION: The presence of NRP2, but not NRP1, was shown for CIK cells. Recognizing NRP2 in CIK cells might help to improve CIK cell cytotoxicity.


Asunto(s)
Inmunoterapia , Neoplasias/genética , Neuropilina-1/genética , Neuropilina-2/genética , Células A549 , Células Asesinas Inducidas por Citocinas/inmunología , Células Asesinas Inducidas por Citocinas/patología , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias/inmunología , Neuropilinas/genética , Pronóstico
6.
Anticancer Res ; 40(10): 5687-5700, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32988894

RESUMEN

BACKGROUND: We previously developed a novel technique for expanding highly activated and purified natural killer (NK) cells able to maximize the theoretical activation potential of NK cells; thus, we named this cell population zenithal-NK (ZNK). AIM: To evaluate the safety, feasibility, and preliminary efficacy of autologous ZNK cells in patients with different types of advanced cancer with measurable solid lesions. PATIENTS AND METHODS: In this phase I/IIb first-in-human, open-label, dose-escalation study (trial registration ID: UMIN-000011555), eligible patients received ZNK cells intravenously starting from 106 to 108 cells/patient/dose at 2-week dosing intervals. A maximum of six cycles were allowed. Safety and survival analyses were also carried out for cases that were excluded and never administered ZNK cells. RESULTS: As of April 20, 2017, a total of nine patients were enrolled in this study, with one recruited twice. Overall, neither grade 2 or higher toxicities (Common Terminology Criteria for Adverse Events v5.0) caused by cell administration, nor adverse events causing discontinuation of protocol treatment were found. In four cases, the number of administered ZNK cells was increased to 108 cells/body/dose without any serious dose-limiting toxicity; the maximally tolerated dose was therefore considered to be at least 108 cells. The overall response rate was 40.0% in 10 net cases, one of partial response and three of stable disease, and the patient with partial response is still alive after 4 year's observation. CONCLUSION: These results demonstrate that autologous ZNK cells are safe and well-tolerated in patients with different types of advanced solid tumors. Clinical studies using similarly active ZNK cells from human leukocyte antigen/killer cell immunoglobulin-like receptor-mismatched healthy donors under Good Manufacturing Practice-compliant manufacturing, and with modified treatment regimen, i.e. doses and frequencies, are warranted for further investigation to show the potential of ZNK cells in such patients.


Asunto(s)
Tratamiento Basado en Trasplante de Células y Tejidos , Células Asesinas Naturales/trasplante , Neoplasias/terapia , Trasplante Autólogo/métodos , Adulto , Anciano , Anciano de 80 o más Años , Proliferación Celular/genética , Relación Dosis-Respuesta Inmunológica , Femenino , Humanos , Células Asesinas Naturales/inmunología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/inmunología , Neoplasias/patología
7.
Medicine (Baltimore) ; 99(36): e21869, 2020 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-32899017

RESUMEN

BACKGROUND: Tai Chi has been reported to be potentially effective for health and well-being of cancer survivors. It is worth to assess the effectiveness and safety of Tai Chi on immunological function in people with cancer. METHODS: All relevant randomized controlled trials (RCT) will be reviewed on Tai Chi for immunological function in cancer survivors. Literature searching will be conducted until March 9, 2019 from major English and Chinese databases: Cochrane Library, Excerpta Medica Database (EMBASE), PubMed, CINAHL, Sprotdicus, American Association for Cancer Research Journals, Sino-Med database, China National Knowledge Infrastructure, Chinese Science and Technique Journals Database, and Wanfang Data Chinese database. Two authors will conduct data selection and extraction independently. Quality assessment will be conducted using the risk of bias tool recommended by the Cochrane Collaboration. We will conduct data analysis using Cochrane's RevMan software (V.5.3). Forest plots and summary of findings tables will illustrate the results from a meta-analysis if sufficient studies with the same outcomes are identified. Funnel plots will be developed to evaluate reporting bias. RESULTS: This review will summarize the evidence on Tai Chi for immunological function in cancer survivors. CONCLUSIONS: We hope that the results of this study will provide significant evidence to assess the value Tai Chi practice on immunological function in cancer survivors. ETHICS AND DISSEMINATION: Ethics approval is not required as this study will not involve patients. The results of this study will be submitted to a peer-reviewed journal for publication.


Asunto(s)
Supervivientes de Cáncer , Tai Ji , Humanos , Neoplasias/inmunología , Revisiones Sistemáticas como Asunto
8.
Nat Commun ; 11(1): 4545, 2020 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-32917858

RESUMEN

TGF-ß1, ß2 and ß3 bind a common receptor to exert vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Global TGF-ß inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-ß1 production by Tregs with antibodies against GARP:TGF-ß1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARP:TGF-ß1/PD-1 blockade are immune-mediated, do not require FcγR-dependent functions and increase effector functions of anti-tumor CD8+ T cells without augmenting immune cell infiltration or depleting Tregs within tumors. We find GARP-expressing Tregs and evidence that they produce TGF-ß1 in one third of human melanoma metastases. Our results suggest that anti-GARP:TGF-ß1 mAbs, by selectively blocking a single TGF-ß isoform emanating from a restricted cellular source exerting tumor-promoting activity, may overcome resistance to PD-1/PD-L1 blockade in patients with cancer.


Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas de la Membrana/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Animales , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral/trasplante , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/inmunología , Células HEK293 , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Neoplasias/inmunología , Neoplasias/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo
9.
Nature ; 585(7824): 277-282, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32879489

RESUMEN

Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours1-4, but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8+ T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach.


Asunto(s)
Sistema de Transporte de Aminoácidos L/metabolismo , Linfocitos T CD8-positivos/metabolismo , Histonas/metabolismo , Metionina/metabolismo , Metilación , Neoplasias/metabolismo , Sistema de Transporte de Aminoácidos L/deficiencia , Animales , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Epigénesis Genética , Femenino , Histonas/química , Humanos , Ratones , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , Receptores de Antígenos de Linfocitos T/metabolismo , Factor de Transcripción STAT5/metabolismo
10.
Lancet Oncol ; 21(9): e419-e430, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32888471

RESUMEN

Notable advances have been achieved in the treatment of cancer since the advent of immunotherapy, and immune checkpoint inhibitors have shown clinical benefit across a wide variety of tumour types. Nevertheless, most patients still progress on these treatments, highlighting the importance of unravelling the underlying mechanisms of primary resistance to immunotherapy. A well described biomarker of non-responsiveness to immune checkpoint inhibitors is the absence or low presence of lymphocytes in the tumour microenvironment, so-called cold tumours. There are five mechanisms of action that have the potential to turn cold tumours into so-called hot and inflamed tumours, hence increasing the tumour's responsiveness to immunotherapy-increasing local inflammation, neutralising immunosuppression at the tumour site, modifying the tumour vasculature, targeting the tumour cells themselves, or increasing the frequency of tumour-specific T cells. In this Review, we discuss preclinical data that serves as the basis for ongoing immunotherapy clinical trials for the treatment of non-immunoreactive tumours, as well as reviewing clinical and translational data where available. We explain how improving our understanding of the underlying mechanisms of primary resistance to immunotherapy will help elucidate an increasingly granular view of the tumour microenvironment cellular composition, functional status, and cellular localisation, with the goal of further therapy refinement.


Asunto(s)
Resistencia a Antineoplásicos/inmunología , Inmunoterapia/efectos adversos , Inflamación/terapia , Neoplasias/terapia , Microambiente Tumoral/efectos de los fármacos , Antineoplásicos Inmunológicos/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/inmunología , Ensayos Clínicos como Asunto , Humanos , Inmunidad Celular/inmunología , Inflamación/inmunología , Inflamación/patología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Neoplasias/inmunología , Neoplasias/patología , Microambiente Tumoral/inmunología
11.
Nature ; 585(7823): 96-101, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32814898

RESUMEN

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation1-3. Expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial ALS and FTD (C9-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased C9orf72 protein expression in brain and peripheral blood cells4-6. Here we show in mice that loss of C9orf72 from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout of C9orf72. Dendritic cells isolated from C9orf72-/- mice show marked early activation of the type I interferon response, and C9orf72-/- myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein-a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished in C9orf72-/- myeloid cells, and blocking STING suppresses hyperactive type I interferon responses in C9orf72-/- immune cells as well as splenomegaly and inflammation in C9orf72-/- mice. Moreover, mice lacking one or both copies of C9orf72 are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with C9-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with C9-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with C9-ALS/FTD have an altered immunophenotype because their reduced levels of C9orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING.


Asunto(s)
Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Inflamación/metabolismo , Inflamación/prevención & control , Proteínas de la Membrana/metabolismo , Células Mieloides/metabolismo , Envejecimiento/inmunología , Esclerosis Amiotrófica Lateral/genética , Animales , Proteína C9orf72/deficiencia , Células Dendríticas/citología , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Humanos , Inflamación/genética , Inflamación/inmunología , Interferón Tipo I/biosíntesis , Interferón Tipo I/inmunología , Proteínas de la Membrana/antagonistas & inhibidores , Ratones , Células Mieloides/inmunología , Neoplasias/inmunología , Linfocitos T/citología , Linfocitos T/inmunología
12.
J Cancer Res Clin Oncol ; 146(11): 2721-2730, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32772231

RESUMEN

Activation Induced cytidine Deaminase (AID) is an essential enzyme of the adaptive immune system. Its canonical activity is restricted to B lymphocytes, playing an essential role in the diversification of antibodies by enhancing specificity and changing affinity. This is possible through its DNA deaminase function, leading to mutations in DNA. In the last decade, AID has been assigned an additional function: that of a powerful DNA demethylator. Adverse cellular conditions such as chronic inflammation can lead to its deregulation and overexpression. It is an important driver of B-cell lymphoma due to its natural ability to modify DNA through deamination, leading to mutations and epigenetic changes. However, the deregulation of AID is not restricted to lymphoid cells. Recent findings have provided new insights into the role that this protein plays in the development of non-lymphoid cancers, with some research shedding light on novel AID-driven mechanisms of cellular transformation. In this review, we provide an updated narrative of the normal physiological functions of AID. Additionally, we review and discuss the recent research studies that have implicated AID in carcinogenesis in varying tissue types including lymphoid and non-lymphoid cancers. We review the mechanisms, whereby AID promotes carcinogenesis and highlight important areas of future research.


Asunto(s)
Inmunidad Adaptativa/fisiología , Citidina Desaminasa/fisiología , Neoplasias/enzimología , Animales , Transformación Celular Neoplásica/inmunología , Humanos , Neoplasias/inmunología
13.
Life Sci ; 258: 118163, 2020 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-32738363

RESUMEN

The tumor microenvironment (TME) provides a guarantee for the survival and development of solid tumors. In recent years, treatment strategies for TME have set off a great upsurge in the field of cancer research. Tumor angiogenesis and tumor immune microenvironment are two important research branches of TME, and antiangiogenic therapy and immunotherapy have gradually become one important focus of cancer treatment research. More interestingly, increasing number of studies have indicated that there are complex regulatory interactions between the two treatment strategies, with multiple regulatory mechanisms involved. Based on these findings, clinical studies on the combination of immunotherapy and antiangiogenic therapy have also been carried out gradually. This combination strategy has shown good results in many types of tumors, but it also faces many challenges. The paper analysed the potential mechanism of the immunotherapy and antiangiogenic therapy combination, discussed the latest significant clinical trial progress and the existing challenges and problems, aiming to offer some available insights on the effective clinical application of this combination pattern.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Inmunoterapia/métodos , Neoplasias/terapia , Neovascularización Patológica/terapia , Animales , Terapia Combinada , Humanos , Neoplasias/complicaciones , Neoplasias/inmunología , Neoplasias/patología , Neovascularización Patológica/complicaciones , Neovascularización Patológica/inmunología , Neovascularización Patológica/patología , Microambiente Tumoral/efectos de los fármacos
14.
Life Sci ; 258: 118170, 2020 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-32735883

RESUMEN

AIMS: Coronavirus disease 2019 (COVID-19), which is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is a major health concern worldwide. Due to the lack of specific medication and vaccination, drug-repurposing attempts has emerged as a promising approach and identified several human proteins interacting with the virus. This study aims to provide a comprehensive molecular profiling of the immune cell-enriched SARS-CoV-2 interacting protein USP13. MATERIALS AND METHODS: The list of immune cell-enriched proteins interacting with SARS-CoV-2 was retrieved from The Human Protein Atlas. Genomic alterations were identified using cBioPortal. Survival analysis was performed via Kaplan-Meier Plotter. Analyses of protein expression and tumor infiltration levels were carried out by TIMER. KEY FINDINGS: 14 human proteins that interact with SARS-CoV-2 were enriched in immune cells. Among these proteins, USP13 had the highest frequency of genomic alterations. Higher USP13 levels were correlated with improved survival in breast and lung cancers, while resulting in poor prognosis in ovarian and gastric cancers. Furthermore, copy number variations of USP13 significantly affected the infiltration levels of distinct subtypes of immune cells in head & neck, lung, ovarian and stomach cancers. Although our results suggested a tumor suppressor role for USP13 in lung cancer, in other cancers, its role seemed to be context-dependent. SIGNIFICANCE: It is critical to identify and characterize human proteins that interact with SARS-CoV-2 in order to have a better understanding of the disease and to develop better therapies/vaccines. Here, we provided a comprehensive molecular profiling the immune cell-enriched SARS-CoV-2 interacting protein USP13, which will be useful for future studies.


Asunto(s)
Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Endopeptidasas/inmunología , Leucocitos/inmunología , Neoplasias/inmunología , Neumonía Viral/inmunología , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/virología , Variaciones en el Número de Copia de ADN , Bases de Datos de Proteínas , Endopeptidasas/genética , Humanos , Leucocitos/virología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/virología , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/virología , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/genética , Neumonía Viral/virología , Pronóstico
15.
Int J Biol Sci ; 16(13): 2464-2476, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32760213

RESUMEN

In 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused infections worldwide. However, the correlation between the immune infiltration and coronavirus disease 2019 (COVID-19) susceptibility or severity in cancer patients remains to be fully elucidated. ACE2 expressions in normal tissues, cancers and cell lines were comprehensively assessed. Furthermore, we compared ACE2 expression between cancers and matched normal tissues through Gene Expression Profiling Interactive Analysis (GEPIA). In addition, we performed gene set enrichment analysis (GSEA) to investigate the related signaling pathways. Finally, the correlations between ACE2 expression and immune infiltration were investigated via Tumor Immune Estimation Resource (TIMER) and GEPIA. We found that ACE2 was predominantly expressed in both adult and fetal tissues from the digestive, urinary and male reproductive tracts; moreover, ACE2 expressions in corresponding cancers were generally higher than that in matched healthy tissues. GSEA showed that various metabolic and immune-related pathways were significantly associated with ACE2 expression across multiple cancer types. Intriguingly, we found that ACE2 expression correlated significantly with immune cell infiltration in both normal and cancer tissues, especially in the stomach and colon. These findings proposed a possible fecal-oral and maternal-fetal transmission of SARS-CoV-2 and suggested that cancers of the respiratory, digestive or urinary tracts would be more vulnerable to SARS-CoV-2 infection.


Asunto(s)
Biología Computacional , Infecciones por Coronavirus/inmunología , Neoplasias/inmunología , Neumonía Viral/inmunología , Adulto , Betacoronavirus , Infecciones por Coronavirus/complicaciones , Enterocitos/metabolismo , Células Epiteliales/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Regulación Viral de la Expresión Génica , Genotipo , Células Caliciformes/metabolismo , Hepatocitos/metabolismo , Humanos , Sistema Inmunológico , Túbulos Renales/embriología , Masculino , Neoplasias/complicaciones , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/complicaciones , Pronóstico , RNA-Seq , Transducción de Señal
16.
Adv Biol Regul ; 77: 100739, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32773105

RESUMEN

The COVID-19 pandemic has put a serious strain on health treatments as well at the economies of many nations. Unfortunately, there is not currently available vaccine for SARS-Cov-2/COVID-19. Various types of patients have delayed treatment or even routine check-ups and we are adapting to a virtual world. In many cases, surgeries are delayed unless they are essential. This is also true with regards to cancer treatments and screening. Interestingly, some existing drugs and nutraceuticals have been screened for their effects on COVID-19. Certain FDA approved drugs, vitamin, natural products and trace minerals may be repurposed to treat or improve the prevention of COVID-19 infections and disease progression. This review article will summarize how the treatments of various cancer patients has changed during the COVID-19 era as well as discuss the promise of some existing drugs and other agents to be repurposed to treat this disease.


Asunto(s)
Antineoplásicos/uso terapéutico , Antivirales/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/epidemiología , Neoplasias/tratamiento farmacológico , Neoplasias/epidemiología , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/epidemiología , Betacoronavirus/efectos de los fármacos , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , Comorbilidad , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Reposicionamiento de Medicamentos , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Hidroxicloroquina/uso terapéutico , Neoplasias/inmunología , Neoplasias/virología , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/inmunología , Neumonía Viral/inmunología , Neumonía Viral/virología , Transducción de Señal/genética , Transducción de Señal/inmunología , Glicoproteína de la Espiga del Coronavirus/antagonistas & inhibidores , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Oligoelementos/uso terapéutico , Vitaminas/uso terapéutico
17.
Cancer Treat Rev ; 89: 102084, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32738738

RESUMEN

Accurate identification of patients with solid tumors likely to respond to immunotherapy is crucial. Tumor mutational burden (TMB) measures the number of somatic mutations in a tumor and is an emerging prognostic and predictive biomarker for anti-programmed cell death (PD) 1/anti-PD-ligand 1 therapy and other immunotherapeutic agents. Tumor mutational burden is assessed optimally by whole exome sequencing, but next generation sequencing provides TMB estimates in a more timely and cost-effective manner. Blood-based measurement of TMB in plasma offers an alternative to the need for adequate tumor tissue for molecular testing, and has demonstrated the ability to identify patients who derive benefit from immunotherapy. Tumor mutational burden has diverse prognostic impact in different solid tumor types and also has a demonstrated role in predicting improved survival in patients receiving immunotherapy. There are challenges to TMB adoption into standard clinical practice, including variations in its definition, with the mutational number defining TMB-high appearing to vary across cancer types. The magnitude of TMB also varies across different tumor types, with the highest levels reported in melanoma and other skin cancers (where ultraviolet light is the dominant mutational process), followed by non-small cell lung cancer and other squamous carcinomas. Concerns regarding inter-laboratory and inter-platform variations in analysis methods have been raised, highlighting the need for standardization. Integration of other genomic or pathological biomarkers with TMB may increase its prognostic and predictive capabilities and validation of individual or combination models in prospective trials is warranted.


Asunto(s)
Biomarcadores de Tumor/genética , Análisis Mutacional de ADN/métodos , Neoplasias/genética , Neoplasias/terapia , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase III como Asunto , Pruebas Genéticas , Humanos , Neoplasias/inmunología , Neoplasias/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Ensayos Clínicos Controlados Aleatorios como Asunto
18.
Front Immunol ; 11: 1548, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32733487

RESUMEN

Background: The COVID-19 pandemic has been causing varying severities of illness. Some are asymptomatic and some develop severe disease leading to mortality across ages. This contrast triggered us explore the causes, with the background that a vaccine for effective immunization or a drug to tackle COVID-19 is not too close to reality. We have discussed strategies to combat COVID-19 through immune enhancement, using simple measures including nutritional supplements. Discussion: A literature search on mortality-related comorbid conditions was performed. For those conditions, we analyzed the pro-inflammatory cytokines, which could cause the draining of the immune reservoir. We also analyzed the immune markers necessary for the defense mechanism/immune surveillance against COVID-19, especially through simple means including immune enhancing nutritional supplement consumption, and we suggest strategies to combat COVID-19. Major comorbid conditions associated with increased mortality include cardiovascular disease (CVD), diabetes, being immunocompromised by cancer, and severe kidney disease with a senile immune system. Consumption of Aureobasidium pullulans strain (AFO-202) beta 1,3-1,6 glucan supported enhanced IL-8, sFAS macrophage activity, and NK cells' cytotoxicity, which are major defense mechanisms against viral infection. Conclusion: People with co-morbid conditions who are more prone to COVID-19-related deaths due to immune dysregulation are likely to benefit from consuming nutritional supplements that enhance the immune system. We recommend clinical studies to validate AFO-202 beta glucan in COVID-19 patients to prove its efficacy in overcoming a hyper-inflammation status, thus reducing the mortality, until a definite vaccine is made available.


Asunto(s)
Betacoronavirus , Enfermedades Cardiovasculares/epidemiología , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Diabetes Mellitus/epidemiología , Suplementos Dietéticos , Neoplasias/epidemiología , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Insuficiencia Renal Crónica/epidemiología , Actinobacteria/química , Biomarcadores/sangre , Enfermedades Cardiovasculares/inmunología , Comorbilidad , Infecciones por Coronavirus/dietoterapia , Infecciones por Coronavirus/mortalidad , Citocinas/sangre , Diabetes Mellitus/inmunología , Humanos , Huésped Inmunocomprometido , Neoplasias/inmunología , Pandemias , Neumonía Viral/dietoterapia , Neumonía Viral/mortalidad , Insuficiencia Renal Crónica/inmunología , beta-Glucanos/farmacología , beta-Glucanos/uso terapéutico
19.
Nat Commun ; 11(1): 4128, 2020 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-32807809

RESUMEN

Individual MHC genotype constrains the mutational landscape during tumorigenesis. Immune checkpoint inhibition reactivates immunity against tumors that escaped immune surveillance in approximately 30% of cases. Recent studies demonstrated poorer response rates in female and younger patients. Although immune responses differ with sex and age, the role of MHC-based immune selection in this context is unknown. We find that tumors in younger and female individuals accumulate more poorly presented driver mutations than those in older and male patients, despite no differences in MHC genotype. Younger patients show the strongest effects of MHC-based driver mutation selection, with younger females showing compounded effects and nearly twice as much MHC-II based selection. This study presents evidence that strength of immune selection during tumor development varies with sex and age, and may influence the availability of mutant peptides capable of driving effective response to immune checkpoint inhibitor therapy.


Asunto(s)
Mutación/genética , Neoplasias/genética , Neoplasias/inmunología , Factores de Edad , Alelos , Femenino , Genotipo , Humanos , Complejo Mayor de Histocompatibilidad/genética , Complejo Mayor de Histocompatibilidad/inmunología , Masculino , Factores Sexuales
20.
Eur J Cancer ; 137: 235-239, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32805640

RESUMEN

The outbreak of the Coronavirus disease (COVID-19) pandemic has deeply challenged healthcare systems and care of patients with cancer. Phase 1 studies are among the most complicated clinical trials and require thorough patient selection, as well as intensive patient monitoring. In this perspective, we discuss the key factors that should be considered for the conduct of phase 1 trials and management of COVID-19-positive patients with cancer enrolled in such trials. We notably present the risks and challenges raised by COVID-19-infected phase 1 patients, in terms of safety, toxicity causality assessment, drug efficacy evaluation and clinical research priorities. We finally propose some guidelines for the conduct of phase 1 trials and management of COVID-19-infected patients in a pandemic time.


Asunto(s)
Antineoplásicos/efectos adversos , Ensayos Clínicos Fase I como Asunto/normas , Infecciones por Coronavirus/terapia , Neoplasias/tratamiento farmacológico , Selección de Paciente , Neumonía Viral/terapia , Betacoronavirus/inmunología , Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Medicina Basada en la Evidencia/normas , Humanos , Control de Infecciones/normas , Oncología Médica/normas , Neoplasias/inmunología , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Neumonía Viral/virología , Guías de Práctica Clínica como Asunto , Resultado del Tratamiento
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