PD-L1/PD-1 blockage enhanced the cytotoxicity of natural killer cell on the non-small cell lung cancer (NSCLC) by granzyme B secretion

Objective To explore the role of PD-L1/PD-1 blockage in the cytotoxicity of natural killer cell in NSCLC. Methods Two NSCLC cell lines, Calu-1 and H460, were tested for susceptibility to the cytolytic activity of freshly isolated healthy donor NK cells by a non-radioactive cellular cytotoxicity assay kit. Western blot analysis, FACS, ELISA and antibody blockage experiments were conducted to determine the mechanisms. NK cells isolated from NSCLC patients were also collected for functional assays. Results Calu-1 and H460 cells were lysed by NK cells in a dose-dependent manner. H460 cells showed less susceptibility to NK cell-mediated lysis than Calu-1 cells at all ratios. The expression of PD-L1 on H460 cells was higher than that on Calu-1 cells, as determined by FACS and western blot analysis. The specific lysis of H460 cells by NK cells was enhanced when the PD-L1/PD-1 interaction was blocked by anti-PD-L1 antibody. This finding was also demonstrated in NK cells isolated from NSCLC patients. Conclusions The present study revealed that PD-L1/PD-1 blockage enhanced the cytotoxicity of natural killer cells in NSCLC via granzyme B secretion. This study will greatly facilitate the precise treatment of lung cancer through determination of PD-L1 expression in tumors (AU)

Suppression of CD56bright NK cells in breast cancer patients is associated with the PD-1 and TGF-BRII expression

Background Natural killer (NK) cells, as professional cytotoxic cells, play a key role against cancer in the early and metastatic stages. Their functional defects are highly associated with the initiation or progression of breast cancer (BC). Here, we investigated the phenotypic characterization of NK cells in 26 newly diagnosed BC patients in comparison to 12 healthy counterparts. Methods Expression of CXCR3 and PD-1, and also NKG2D, and TGF-βRII were studied on CD56dim and CD56bright NK cells from fresh peripheral blood (PB) samples using flow cytometry. The plasma levels of IFN-γ and soluble MIC-A levels were also assessed by ELISA. Results Both CD56dim and CD56bright NK subtypes showed lower CXCR3 and NKG2D expression in BC patients than healthy subjects. Furthermore, patients’ CD56bright NK cells significantly showed higher expression levels of TGF-βRII and PD-1. Interestingly, increased concentration of MIC-A level in plasma of BC patients was associated with the higher TGF-βRII and PD-1 expression in all NK cells, while the plasma level of IFN-γ was associated with the lower TGF-βRII expression on CD56bright NK cells in these patients. Conclusion Our results demonstrated phenotypically suppressed-NK cells, especially in the CD56bright subset of BC patients. It specifies their potential incompetence and outlines decrement of their anti-tumor activity, which could be interrelated with the tumor pathogenesis, TME immunosuppression, and so disease progression. The induction of compensatory mechanisms revives NK cells function and could be used in combination with the conventional treatments as a putative therapeutic approach for targeted immunotherapy (AU)

Diagnostic and therapeutic approach to pulmonary infiltrates in cancer patients receiving immune checkpoint inhibitors

The advent of immune checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and the programmed cell death (PD-1)/PD-1 ligand 1 (PD-L1) axis has transformed the treatment paradigm for multiple cancer types. ICIs are able to restore T-cell-mediated antitumor responses and do not entail an increased risk of infection per se. However, immunotherapy is associated to a unique form of toxicity due to the off-target effects on healthy tissues of the excessively enhanced immune response in form of immune-related adverse events (irAEs). Although ICI-induced pneumonitis ranks the fifth of all irAEs in terms of frequency of occurrence, it is associated with a relevant attributable mortality. This review summarizes the incidence, risk factors, clinical and radiological presentation, and therapeutic approach of ICI-induced pneumonitis. Particular focus is on the differential diagnosis of new or worsening pulmonary infiltrates in cancer patients receiving ICI therapy. Finally, the impact on the risk of opportunistic infection of ICIs and immunosuppressive therapy used to treat associated irAEs is reviewed. The diagnosis and management of suspected ICI-induced pneumonitis remains clinically challenging. (AU)

Tumor microenvironment and its clinicopathological and prognostic associations in surgically resected cutaneous angiosarcoma

PurposeCutaneous angiosarcoma (CAS) is a rare but typically aggressive malignant vascular neoplasm of the skin. Tumor microenvironment (TME) of CAS and its associations with baseline clinicopathological features and patient outcomes are very important, especially when considering the recent advances in understanding of the tumor biology.Methods/patientsWe retrospectively reviewed medical records of patients who underwent surgical resection for CAS at a tertiary Hospital. The pretreated specimens were evaluated by immunohistochemistry for programmed cell death protein 1 (PD-1) and its ligand (PD-L1), densities of tumor infiltrative lymphocytes (TILs) (CD3+, CD4+, CD8+, CD45RO+, FoxP3+), as well as c-MYC and Ki-67 expressions. Overall survival (OS) was estimated by Kaplan–Meier method and compared with Log-rank test.ResultsA total of 21 CAS patients were identified. Median age was 67 (ranges: 20–81) years, 14 (66.7%) were male, and over 50% had lesions of scalp. Histopathological examination showed a predominantly spindle cell type (57.1%). All patients underwent surgery, 16 (76.2%) were treated further. PD-L1 was positively stained (> 1%) in tumor cells (42.9%) and TILs (23.8%). PD-1 expression (> 1%) was identified in TILs of 11 (52.4%) cases. PD-1/PD-L1 expressions were significantly associated with the higher densities of CD3+, CD4+, CD8+, CD45RO+, and Foxp3+ TILs, but not with patient characteristics or c-MYC or Ki-67 expression. Median OS was 18.5 months (95% CI 6.0–35.9), although no prognostic significance was observed with respect to any clinicopathological features.ConclusionWe characterized TME and its clinical and prognostic association in CAS. PD-1/PD-L1 expressions were significantly associated with TILs subtypes but not with OS.

PD1/PDL1 expression is associated with increased TIM3 expression and tumor-infiltrating T lymphocytes in fibroblastic tumors

PurposeThe combined therapy of inhibiting T cell immunoglobulin domain and mucin domain 3 (TIM3) and programmed cell death 1/programmed death-ligand 1 (PD1/PDL1) has shown encouraging therapeutic effects in some solid tumors. However, the expression of PD1/PDL1 and TIM3 in fibroblastic tumors is ill defined, which has limited the application of these immune checkpoint inhibitors in such tumors.MethodsImmunostaining of 68 tissue microarray cores of fibroblastic tumors, including intermediate dermatofibrosarcoma protuberans and malignant myxofibrosarcoma and adult-type fibrosarcoma, was used to determine the expression of PD1, PDL1 and TIM3, as well as their relationship with the accumulation of tumor-infiltrating T lymphocytes (TILs).ResultsBoth PD1 and PDL1 expression was only observed in a small proportion of fibroblastic tumors, whereas TIM3 was expressed in almost all tumors. However, only the positive expression of PDL1 was related to tumors with high grade and staging. A considerable number of TILs, including CD4- and CD8A-positive T cells and a small group of FoxP3-positive T cells, was also observed in most tumors. The density of TIM3 was positively correlated with that of TILs. Furthermore, higher densities of TIM3, CD4, CD8A and FoxP3 were observed in PD1 and PDL1 double-positive fibroblastic tumors.ConclusionsThis study indicates that TILs with high expression of TIM3 may contribute to immunosuppression in the tumor microenvironment of fibroblastic tumors. Patients with fibroblastic tumors with high expression of PD1/PDL1 and TIM3 may therefore benefit from combination therapy with PD1/PDL1 and TIM3 inhibitors.

Mechanisms of primary and acquired resistance to PD-1/PD-L1 blockade and the emerging role of gut microbiome

As a very promising immunotherapy, PD-1/PD-L1 blockade has revolutionized the treatment of a variety of tumor types, resulting in significant clinical efficacy and lasting responses. However, these therapies do not work for a large proportion of patients initially, which is called primary resistance. And more frustrating is that most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms that lead to primary and acquired resistance to PD-1/PD-L1 inhibition have remained largely unclear. Recently, the gut microbiome has emerged as a potential regulator for PD-1/PD-L1 blockade. This review elaborates on the current understanding of the mechanisms in terms of PD-1 related signaling pathways and necessary factors. Moreover, this review discusses new strategies to increase the efficacy of immunotherapy from the perspectives of immune markers and gut microbiome (AU)

PD-1 and PD-L1 gene expressions and their association with Epstein-Barr virus infection in chronic lymphocytic leukemia

PurposeThe PD-1 (programmed cell death-1) receptor is expressed on the surface of activated T cells. Its ligand, programmed cell death ligand-1 (PD-L1), is expressed on the surface of dendritic cells or macrophages. The PD-1/PD-L1 interaction ensures prevention of autoimmunity by activating the immune system only when needed. In cancers, PD-L1 expressed on the tumour cells binds to PD-1 receptors on the activated T cells, leading to inhibition of the cytotoxic T cells and immunosuppression. PD-1/PD-L1 pathway is upregulated in EBV infection that is known to worsen the CLL prognosis. Therefore, we aimed to study the association between PD-1 and PD-L1 expressions, EBV status and the CLL prognosis.Methods and patientsThe study was conducted on 80 newly diagnosed CLL patients and 80 controls. We analyzed PD-1 and PD-L1 expressions and EBV-DNA load by real-time PCR. The cytogenetic abnormalities and expression of ZAP70 and CD38 were detected by FISH and Flow cytometry, respectively.ResultsPD-1/PD-L1 expressions were significantly upregulated in CLL patients compared to controls. In addition, their mRNA levels were significantly higher in EBV( +) versus EBV( −) patients. High expression of PD-1/PD-L1 was associated with poor prognostic markers (RAI stages of CLL, del 17p13, ZAP70, and CD38 expression), failure of complete remission, shorter progression-free survival, and overall survival.ConclusionHigh expression of PD-1 and PD-L1, together with high EBD-DNA load were linked to worse prognosis in CLL. In addition, PD-1 and PD-L1 might represent suitable therapeutic targets for patients suffering from aggressive CLL. (AU)

The effect of PD-1 expression on tumor-associated macrophage in T cell lymphoma

Purpose Our study aimed to explore the programmed death 1 (PD-1) expression on tumor-associated macrophage (TAM) in T cell non-Hodgkin lymphoma (T-NHL) and its relationship with lymphoma prognosis. The effect of PD-1 expression on the function of macrophages was also studied. Methods Multispectral image quantitative analysis was applied for detecting PD-1 expression on macrophages in T cell lymphoma tissues. The Kaplan–Meier analysis was performed to evaluate the value of PD-1 expression of TAM in predicting the overall survival of T-NHL. PD-1 overexpression THP-1-derived macrophage was constructed and was cocultured with Jurkat cells to explore the effect of PD-1 on macrophage function. Results In 17 T cell lymphoma cases, the 1-year overall survival rate was significantly lower in patients with higher PD-1 expression on TAMs (0.25 vs 0.86, p < 0.05). After co-cultured with Jurkat cells, classically activated (M1)-related markers on PD-1 overexpressed macrophages were significantly lower than those on controls, while the expressions of alternatively activated (M2) related markers were similar. The PD-1 overexpressed macrophages showed inhibited phagocytosis (4.42% vs 40.7%, p < 0.001) and increased IL-10 secretion (144.48 pg/ml vs 32.32 pg/ml, p < 0.001). Conclusion High PD-1 expression on TAMs in T-NHL may predict poor prognosis. The PD-1 overexpression of macrophages significantly inhibited polarization of M1 macrophages and phagocytosis, and more IL-10 was excreted. These changes may enhance the pro-tumor effects of tumor microenvironmen (AU)

Nuevas inmunoterapias en el cáncer de vejiga no músculo-invasivo de alto riesgo: estado actual y perspectivas de futuro / New immunotherapies for high-risk non-muscle invasive bladder cancer: Current state and future perspectives

CONTEXTO: El tratamiento estándar de los tumores de vejiga no músculo-invasivos (TVNMI) de alto riesgo es la resección transuretral de vejiga e instilaciones de bacilo de Calmette-Guérin (BCG). Sin embargo, las respuestas son limitadas. Es necesario buscar nuevas alternativas terapéuticas para estos pacientes. Los resultados en tumores avanzados de los inhibidores de puntos de control han dado lugar al interés en el uso de estas moléculas en TVNMI. MÉTODOS: Hemos realizado una búsqueda en PubMed utilizando los términos «bladder cancer» y «check point inhibitors». Para la búsqueda de ensayos clínicos, hemos utilizado los buscadores clinicaltrials.gov y clinicaltrialsregister.eu RESULTADOS: Actualmente hay 5 ensayos en marcha de pacientes no tratados con BCG. No hay resultados disponibles. En cuanto a los pacientes no respondedores a BCG, existen 15 ensayos en marcha, 2 de ellos con resultados preliminares: el Keynote 057, con resultados prometedores con pembrolizumab y que ha llevado a la FDA a aprobar su uso en enero de 2020 y el SWOG S1605, que ha mostrado resultados similares con atezolizumab. Otros ensayos administran estos fármacos intravesicalmente, una opción atractiva si resulta efectiva para el control oncológico. CONCLUSIONES: Los inhibidores de puntos de control ofrecen una nueva posibilidad para los pacientes no respondedores al BCG. Probablemente en el futuro se podrán usar en pacientes no tratados previamente con BCG. Los datos preliminares de ensayos clínicos muestran resultados prometedores. Es importante un buen conocimiento de estas moléculas por los urólogos y la formación de equipos multidisciplinares para ofrecer las mejores alternativas terapéuticas a estos pacientes

BACKGROUND: The standard treatment for high-risk non-muscle invasive bladder tumors (NMIBT) is transurethral resection of the bladder and BCG instillations. However, responses are limited, and new therapeutic alternatives for these patients are required. The results of checkpoint inhibitors in advanced tumors have led to interest in the use of these molecules in NMIBT. METHODS: We conducted a search on PubMed using the terms «bladder cancer» and «check point inhibitors». We have used the search engines clinicaltrials.gov and clinicaltrialsregister.eu for the search of clinical trials. RESULTS: There are currently 5 trials in progress on BCG untreated patients. There are no results available. As for BCG non-responders, there are 15 ongoing trials, two of them with preliminary results: Keynote 057, with promising results with pembrolizumab, which has led the FDA to approve its use in January 2020, and SWOG S1605, which has shown similar results with atezolizumab. Other trials are using intravesical administration of these drugs, which is an attractive option if it is effective for cancer control. CONCLUSIONS: Checkpoint inhibitors offer a new possibility for patients who do not respond to BCG. These will probably be used in the future for previously BCG untreated patients. Preliminary data from clinical trials show promising results. A good understanding of these molecules by urologists and the creation of multidisciplinary teams are crucial in order to offer the best therapeutic alternatives to these patients

FR-Cemiplimab, primer fármaco aprobado para el tratamiento del carcinoma cutáneo de células escamosas metastásico o irresecable / RF-Cemiplimab: First Drug Approved for the Treatment of Metastatic or Unresectable Cutaneous Squamous Cell Carcinoma

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Efectividad y seguridad de inhibidores de puntos de control inmunitario en pacientes excluidos de ensayos clínicos / Effectiveness and safety of immune ckeckpoint inhibitors on patients excluded from clinical trials

La inmunoterapia ha revolucionado la terapéutica del cáncer en los últimos años y sigue siendo el objetivo principal de numerosas líneas de investigación. Los inhibidores de puntos de control inmunitario (ICIs) son una alternativa muy atractiva para clínicos y pacientes porque han conseguido alcanzar mejores tasas de respuesta y de supervivencia a largo plazo. Además, presentan un buen perfil de tolerancia frente a la terapia oral y los eventos adversos relacionados con la inmunoterapia (irAE) en muy pocos casos causan una morbilidad destacable y la mayoría de pacientes disfruta de una excelente calidad de vida con síntomas mínimos durante el tratamiento. Sin embargo, existe una gran brecha en el conocimiento sobre la seguridad y la efectividad de estos fármacos en algunos tipos de pacientes que por sus características suelen ser excluidos de los ensayos clínicos, resultando difícil inferir los resultados a este tipo de pacientes. Se trata de aquellos pacientes con un sistema inmunológico exacerbado (pacientes con enfermedades autoinmunes) o comprometido (pacientes que han sido sometidos a trasplante hematológico o de órgano sólido o pacientes con infecciones virales crónicas). El objetivo de esta revisión es describir la experiencia del uso de ICIs en este tipo de pacientes y ofrecer al lector, de manera resumida, algunos aspectos clave con el fin de motivar su interés por la investigación en este campo

In recent years, immunotherapy has revolutionized the treatment of cancer and remains the main objective of many lines of research. Immune checkpoint inhibitors (ICIs) are a very attractive alternative treatment because they have been achieved better response rates and long-term survival rates in several types of cancer. Furthermore, ICIs have favorable tolerance profiles and immune related adverse events (irAEs) do not usually result in significant morbidity and most patients enjoy an excellent quality of life with minimal symptoms during treatment. However, there is a gap in knowledge on the safety and effectiveness of ICIs in patients who are often excluded from clinical trials due to their characteristics, making it difficult to infer the results of clinical trials to these patients. They are patients with autoimmune diseases or with a compromised immune system (solid organ/hematological transplant patients or with chronic viral infections). The aim of this review is to extend current knowledge of the use of ICIs in these patients, in clinical practice and to propose new research topics

Inmunoterapia en cáncer cutáneo no melanoma / Immunotherapy in Nonmelanoma Skin Cancer

La inmunoterapia en el cáncer emerge como un tratamiento novedoso y prometedor en una gran variedad de tumores, incluido el cáncer cutáneo no melanoma. Los anticuerpos inhibidores de proteínas de control inmunitario están dirigidos fundamentalmente a las moléculas de superficie CTLA-4 (antígeno citotóxico de los linfocitos T) y PD-1 (molécula de muerte programada 1). En el presente artículo se revisan las vías de CTLA-4 y PD-1/PD-L1 (PD-1/ligando de la PD-1) y las evidencias actuales de tratamiento con inhibidores de puntos de control inmunitario en los principales tipos de cáncer cutáneo no melanoma

Immunotherapy is emerging as a new and promising treatment for a great variety of tumors, including nonmelanoma skin cancer. Checkpoint inhibitors -antibodies that block proteins that regulate the immune system- mainly target the surface protein CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) and the PD-1/PD-L1 (programmed cell death protein 1/PD-ligand 1) axis. We review the CTLA-4 and PD-1/PD-L1 pathways and current evidence supporting checkpoint inhibitor therapy in the main types of nonmelanoma skin cancer

What do we know about cancer immunotherapy? Long-term survival and immune-related adverse events

Immunotherapy delivered a new therapeutic option to the oncologist: Ipilimumab (anti-CTLA-4), Nivolumab and Pembrolizumab (anti-PD1), and Atezolizumab (anti-PD-L1) increase overall survival and show a better safety profile compared to chemotherapy in patients with metastatic melanoma, lung, renal cancer among others. But all that glitters is not gold and there is an increasing number of reports of adverse effects while using immune-checkpoint inhibitors. While chemotherapy could weaken the immune system, this novel immunotherapy could hyper-activate it, resulting in a unique and distinct spectrum of adverse events, called immune-related adverse events (IRAEs). IRAEs, ranging from mild to potentially life-threatening events, can involve many systems, and their management is radically different from that of cytotoxic drugs: immunosuppressive treatments, such as corticoids, infliximab or mycophenolate mofetil, usually result in complete reversibility, but failing to do so can lead to severe toxicity or even death. Patient selection is an indirect way to reduce adverse events minimizing the number of subjects exposed to this drugs: unfortunately PDL-1, the actual predictive biomarker, would not allow clinicians select or exclude patients for treatment with checkpoint inhibitors

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Perspective on immune oncology with liquid biopsy, peripheral blood mononuclear cells, and microbiome with non-invasive biomarkers in cancer patients

Antibodies against immune checkpoint inhibitors such as anti-programmed cell death protein 1 (PD-1) and anti-programmed death ligand 1 (PD-L1) play a key role in the treatment of advanced lung cancer. To examine the clinical benefits of these agents, preclinical and clinical studies have been conducted to identify definitive biomarkers associated with cancer status. Analysis of the blood and feces of tumor patients has attracted attention in recent studies attempting to identify non-invasive biomarkers such as cytokines, soluble PD-L1, peripheral blood mononuclear cells, and gut microbiota. These factors are believed to interact with each other to produce synergistic effects and contribute to the formation of the tumor immune microenvironment through the seven steps of the cancer immunity cycle. The immunogram was first introduced as a novel indicator to define the immunity status of cancer patients. In this review, we discuss the progress in the identification of predictive biomarkers as well as future prospects for anti-PD-1/PD-L1 therapy

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Inmunoterapia contra el cáncer y la ruta del punto de control PD-1/PD-L1 / Cancer immunotherapy and the PD-1/PD-L1 checkpoint pathway

La supervivencia a largo plazo para pacientes con cáncer avanzado de vejiga es precaria, con una supervivencia a 5 años de apenas el 5% en los casos metastásicos. Normalmente, la unión de PD-L1 a PD-1 altera la actividad inmunitaria modulándola para inhibir enfermedades autoinmunes e inflamaciones crónicas. Sin embargo, algunos canceres utilizan esta vía para bloquear la respuesta inmune del paciente y continuar creciendo. La nueva inmunoterapia contra el cáncer vesical pretende bloquear la capacidad de las células tumorales para resistir a la respuesta inmune del paciente mediante la actuación sobre los puntos de control de las células inmunitarias. Dichos fármacos son capaces de bloquear el receptor PD-1 presente en la superficie de los linfocitos, o bien los ligandos PD-L1 y PD-L2 expresados por las células cancerosas, esto impediría la unión de ambos bloqueando la señal inmunomoduladora y permitiendo que las células T continúen activas contra el tumor. La diana terapéutica del Pembrolizumab y el Nivolumab, es PD-1, la proteína receptora de PD-L1 en células inmunitarias. El resto de moléculas aprobadas para distintos tipos de cáncer como Atezolizumab, Avelumab o Durvalumab actúan sobre la proteína PD-L1 que es expresada en concentraciones altas en algunas células cancerosas. Los inhibidores del punto de control ofrecen una alternativa efectiva para los pacientes para los que anteriormente había pocas opciones de respuestas duraderas, incluidos aquellos que no son elegibles para los regímenes basados en cisplatino o que están en riesgo de toxicidad significativa. Esta revisión describe los datos más recientes sobre los agentes que inhiben la PD-L1, que se encuentran en la superficie de las células tumorales, y la PD-1 que se encuentra en las células T y B activadas y los macrófagos. Se están llevando a cabo investigaciones para categorizar aún más las respuestas, definir poblaciones de pacientes ideales e investigar combinaciones de inhibidores de puntos de control para abordar múltiples vías en el funcionamiento del sistema inmunitario

Long-term survival for patients with advanced bladder cancer is precarious, with a 5-year survival of just 5% in metastatic cases. Normally, the binding of PD-L1 to PD-1 alters the immune activity by modulating it to inhibit autoimmune diseases or chronic inflammation. However, some cancers use this route to block the immune response of the patient and continue growing. The new immunotherapy against bladder cancer aims to block the ability of tumor cells to resist patient's immune response by acting on the checkpoints of immune cells. These drugs are able to block the PD-1 receptor present on the surface of the lymphocytes, or the PD-L1 and PD-L2 ligands expressed by the cancer cells; this would prevent the binding of both blocking the immunomodulatory signal and allowing the T cells continue active against the tumor. The therapeutic target of Pembrolizumab and Nivolumab is PD-1, the receptor protein of PD-L1 in immune cells. The rest of molecules approved for different types of cancer such as Atezolizumab, Avelumab or Durvalumab act on the PD-L1 protein that is expressed in high concentrations in some cancer cells. The checkpoint inhibitors offer an effective alternative for patients for whom previously there were few options for durable responses, including those who are ineligible for cisplatin-based regimens or who are at risk of significant toxicity. This review describes the most recent data on agents that inhibit PD-L1, found on the surface of tumor cells, and PD-1 found on activated T and B cells and macrophages. Research is ongoing to further categorize responses, define ideal patient populations, and investigate combinations of checkpoint inhibitors to address multiple pathways in the functioning immune system

Endocrinopatías autoinmunitarias inducidas por anticuerpos inmunomoduladores en el tratamiento del cáncer / Autoimmune endocrinopathies induced by immunomodulating antibodies in the treatment of cancer

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