RESUMO
In recent years, immunotherapy has emerged as a crucial component of cancer treatment. However, its efficacy remains limited across various cancer types, highlighting unmet needs. Poliovirus receptor-related 2 (PVRL2) and Poliovirus receptor (PVR) are members of the Nectin and Nectin-like Molecules family, known for their role as cell-cell adhesion molecules. With the development of immunotherapy, their involvement in tumor immune mechanisms as immune checkpoint factors has garnered significant attention. PVRL2 and PVR are predominantly expressed on tumor cells and antigen-presenting cells, binding to PVRIG and TIGIT, respectively, which are primarily found on T and NK cells, thereby suppressing antitumor immunity. Notably, gynecological cancers such as ovarian and endometrial cancers exhibit high expression levels of PVRL2 and PVR, with similar trends observed in various other solid and hematologic tumors. Targeting these immune checkpoint pathways offers a promising therapeutic avenue, potentially in combination with existing treatments. However, the immunomodulatory mechanism involving these bindings, known as the DNAM-1 axis, is complex, underscoring the importance of understanding it for developing novel therapies. This article comprehensively reviews the immunomodulatory mechanisms centered on PVRL2 and PVR, elucidating their implications for various cancer types.
Assuntos
Imunoterapia , Nectinas , Neoplasias , Receptores Virais , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Nectinas/metabolismo , Nectinas/imunologia , Imunoterapia/métodos , Animais , Receptores Virais/imunologia , Receptores Virais/metabolismo , Ligantes , Moléculas de Adesão Celular/imunologia , Moléculas de Adesão Celular/metabolismo , Receptores Imunológicos/metabolismo , Receptores Imunológicos/imunologiaRESUMO
Drugs that target immune checkpoint have become the most popular weapon in cancer immunotherapy, yet only have practical benefits for a small percentage of patients. Tumor cells constantly interact with their microenvironment, which is made up of a variety of immune cells as well as endothelial cells and fibroblasts. Immune checkpoint expression and blocked signaling of immune cells in the tumor microenvironment (TME) are key to tumor progression. In this study, we perform deliberation convolution on the TCGA database for human lung, breast, and colorectal cancer to infer crosstalk between immune checkpoint receptors (ICRs) and ligands (ICLs) in TME of pan-carcinogenic solid tumor types, validated by flow cytometry. Analysis of immune checkpoints showed that there was little variation between different tumor types. It showed that CD160, LAG3, TIGIT were found to be highly expressed in CD8+ T cells instead of CD4+ T cells, PD-L1, PD-L2, CD86, LGALS9, TNFRSF14, LILRB4 and other ligands were highly expressed on macrophages, FVR, NECTIN2, FGL1 were highly expressed on Epithelial cells, CD200 was highly expressed in Endothelial cells, and CD80 was highly expressed in CD8 High expression on T cells. Overall, our study provides a new resource for the expression of immune checkpoints in TME on various types of cells. Significance: This study provides immune checkpoint expression of immune cells of multiple cancer types to infer immune mechanisms in the tumor microenvironment and provide ideas for the development of new immune checkpoint-blocking drugs.
Assuntos
Proteínas de Checkpoint Imunológico , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Proteínas de Checkpoint Imunológico/metabolismo , Proteínas de Checkpoint Imunológico/genética , Ligantes , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Antígenos CD/metabolismo , Antígenos CD/genética , Nectinas/metabolismo , Nectinas/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Proteína do Gene 3 de Ativação de Linfócitos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , FemininoRESUMO
Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, with a bad prognosis and lack of targeted therapeutic options. Characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression, TNBC is often associated with a significantly lower survival rate compared to other breast cancer subtypes. Our study aimed to explore the prognostic significance of 83 immune-related genes, by using transcriptomic data from the TCGA database. Our analysis identified the Poliovirus Receptor-Like 3 protein (PVRL3) as a critical negative prognostic marker in TNBC patients. Furthermore, we found that the Enhancer of Zeste Homolog 2 (EZH2), a well-known epigenetic regulator, plays a pivotal role in modulating PVRL3 levels in TNBC cancer cell lines expressing EZH2 along with high levels of PVRL3. The elucidation of the EZH2-PVRL3 regulatory axis provides valuable insights into the molecular mechanisms underlying TNBC aggressiveness and opens up potential pathways for personalized therapeutic intervention.
Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste , Regulação Neoplásica da Expressão Gênica , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Prognóstico , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Linhagem Celular Tumoral , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Nectinas/metabolismo , Nectinas/genéticaRESUMO
Nectin-4 (Nectin cell adhesion molecule 4), a type I transmembrane cell adhesion protein, was demonstrated to be overexpressed in a variety of tumors, making it an attractive antigen for targeted therapies such as antibody-drug conjugates (ADCs). Of great note, the US Food and Drug Administration (FDA)-approval of the first Nectin-4-directed ADC, enfortumab vedotin (EV), in urothelial cancer (UC) not only introduced Nectin-4 as a clinically validated and reliable target antigen but also confirmed the evolving role of Nectin-4-directed ADCs as novel and promising cancer therapeutics. In addition to EV, there have been or are currently being seven and eleven Nectin-4-directed ADCs, respectively, in various stages of clinical trials and preclinical development, offering a promising future for the treatment of Nectin-4-positive cancer patients. This study reviewed clinical- and preclinical-stage Nectin-4-directed ADCs.
Assuntos
Moléculas de Adesão Celular , Imunoconjugados , Humanos , Moléculas de Adesão Celular/imunologia , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/antagonistas & inibidores , Imunoconjugados/uso terapêutico , Imunoconjugados/farmacologia , Animais , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia , NectinasRESUMO
Antibody-drug conjugates (ADCs) represent a novel type of targeted cancer therapy combining the specificity of monoclonal antibodies with the cytotoxicity of conventional chemotherapy. Recently, ADCs have demonstrated practice-changing efficacy across diverse solid cancers. The anti-NECTIN-4 ADC enfortumab vedotin (EV) has just been approved for patients with urothelial cancer and is currently under investigation for patients with castration-resistant prostate cancer (CRPC e.g. Phase II ENCORE trial). Our objective was to evaluate the efficacy of EV in established prostate cancer (PCa) cell lines and to examine the membranous NECTIN-4 expression in primary tumours (PRIM) and distant metastases (MET). NECTIN-4 was heterogeneously expressed in the panel of PCa cell lines. EV led to growth inhibition in NECTIN-4 expressing PCa cells (22Rv1 and LNCaP), whereas the NECTIN-4-negative PC-3 cells were significantly less responsive to EV, emphasizing the dependence of EV response on its target expression. Immunohistochemical staining revealed moderate membranous NECTIN-4 expression only in a small subgroup of CRPC patients with lung and peritoneal MET [n = 3/22 with H-score ≥100, median H-score 140 (IQR 130-150)], while 100% of PRIM (n = 48/48) and 86.4% of common MET sites (n = 19/22), including lymph node, bone and liver MET, were NECTIN-4 negative. In summary, EV may be effective in NECTIN-4-positive PCa. However, our findings demonstrate that the tumoural NECTIN-4 expression is predominantly low in metastatic PCa, which suggests that EV may only be effective in a biomarker-stratified subgroup.
Assuntos
Anticorpos Monoclonais , Moléculas de Adesão Celular , Neoplasias da Próstata , Humanos , Masculino , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/genética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Linhagem Celular Tumoral , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Proliferação de Células/efeitos dos fármacos , NectinasRESUMO
PURPOSE: Improved survival rates have been observed in castration-resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody-drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop-2 and NECTIN-4 in cerebral metastasized CRPC (mCRPC). METHODS: Immunohistochemical staining of Trop-2 and NECTIN-4 with evaluation of H-score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop-2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti-Trop-2 ADC Sacituzumab govitecan (SG) in vitro. RESULTS: Our analysis revealed that most patients exhibited moderate to strong Trop-2 expression [n = 27/31 with H-score ≥100, median H-score 220 (IQR 180-280)], while NECTIN-4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop-2 expression levels in vitro. Overexpression of Trop-2 in Trop-2-negative PC-3 cells led to sensitization to SG, whereas CRISPR-Cas9-mediated knockdown of Trop-2 in Trop-2-expressing DU-145 cells conferred resistance to SG. CONCLUSION: The substantial expression of Trop-2 in cerebral metastases, along with our preclinical in vitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases.
Assuntos
Anticorpos Monoclonais Humanizados , Antígenos de Neoplasias , Neoplasias Encefálicas , Camptotecina , Moléculas de Adesão Celular , Imunoconjugados , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Imunoconjugados/uso terapêutico , Imunoconjugados/farmacologia , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/genética , Antígenos de Neoplasias/imunologia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Camptotecina/farmacologia , Linhagem Celular Tumoral , NectinasRESUMO
Antibody-drug conjugates have transformed treatment for urothelial cancer (UC). Enfortumab vedotin is the new standard of care in the first-line setting for advanced UC. A personalised approach targeting HER2 in UC is currently being explored.
Assuntos
Anticorpos Monoclonais , Carcinoma de Células de Transição , Moléculas de Adesão Celular , Receptor ErbB-2 , Humanos , Receptor ErbB-2/metabolismo , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Anticorpos Monoclonais/uso terapêutico , Moléculas de Adesão Celular/metabolismo , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/patologia , Imunoconjugados/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , NectinasRESUMO
Tigilanol tiglate (TT, also known as EBC-46) is a novel, plant-derived diterpene ester possessing anticancer and wound-healing properties. Here, we show that TT-evoked PKC-dependent S985 phosphorylation of the tyrosine kinase MET leads to subsequent degradation of tyrosine phosphorylated p-Y1003 and p-Y1234/5 MET species. PKC inhibition with BIM-1 blocked S985 phosphorylation of MET and led to MET cell surface accumulation. Treatment with metalloproteinase inhibitors prevented MET-ECD release into cell culture media, which was also blocked by PKC inhibitors. Furthermore, unbiased secretome analysis, performed using TMT-technology, identified additional targets of TT-dependent release of cell surface proteins from H357 head and neck cancer cells. We confirm that the MET co-signalling receptor syndecan-1 was cleaved from the cell surface in response to TT treatment. This was accompanied by rapid cleavage of the cellular junction adhesion protein Nectin-1 and the nerve growth factor receptor NGFRp75/TNFR16. These findings, that TT is a novel negative regulator of protumorigenic c-MET and NGFRp75/TNFR16 signalling, as well as regulating Nectin-1-mediated cell adhesion, further contribute to our understanding of the mode of action and efficacy of TT in the treatment of solid tumours.
Assuntos
Neoplasias de Cabeça e Pescoço , Proteínas Proto-Oncogênicas c-met , Humanos , Proteínas Proto-Oncogênicas c-met/metabolismo , Fosforilação/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Linhagem Celular Tumoral , Secretoma/metabolismo , Diterpenos/farmacologia , Proteínas de Membrana/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sindecana-1/metabolismo , Nectinas/metabolismo , Proteína Quinase C/metabolismoRESUMO
BACKGROUND: Gastric cancer represents a highly lethal malignancy with an elevated mortality rate among cancer patients, coupled with a suboptimal postoperative survival prognosis. Nectin-4, an overexpressed oncological target for various cancers, has been exploited to create antibody-drug conjugates (ADCs) to treat solid tumors. However, there is limited research on Nectin-4 ADCs specifically for gastric cancer, and conventional immunoglobulin G (IgG)-based ADCs frequently encounter binding site barriers. Based on the excellent tumor penetration capabilities inherent in nanobodies (Nbs), we developed Nectin-4-targeting Nb drug conjugates (NDCs) for the treatment of gastric cancer. RESULTS: An immunized phage display library was established and employed for the selection of Nectin-4-specific Nbs using phage display technology. Subsequently, these Nbs were engineered into homodimers to enhance Nb affinity. To prolong in vivo half-life and reduce immunogenicity, we fused an Nb targeting human serum albumin (HSA), resulting in the development of trivalent humanized Nbs. Further, we site-specifically conjugated a monomethyl auristatin E (MMAE) at the C-terminus of the trivalent Nbs, creating Nectin-4 NDC (huNb26/Nb26-Nbh-MMAE) with a drug-to-antibody ratio (DAR) of 1. Nectin-4 NDC demonstrated excellent in vitro cell-binding activities and cytotoxic efficacy against cells with high Nectin-4 expression. Subsequent administration of Nectin-4 NDC to mice bearing NCI-N87 human gastric cancer xenografts demonstrated rapid tissue penetration and high tumor uptake through in vivo imaging. Moreover, Nectin-4 NDC exhibited noteworthy dose-dependent anti-tumor efficacy in in vivo studies. CONCLUSION: We have engineered a Nectin-4 NDC with elevated affinity and effective tumor uptake, further establishing its potential as a therapeutic agent for gastric cancer.
Assuntos
Antineoplásicos , Moléculas de Adesão Celular , Imunoconjugados , Camundongos Nus , Anticorpos de Domínio Único , Neoplasias Gástricas , Neoplasias Gástricas/tratamento farmacológico , Humanos , Animais , Anticorpos de Domínio Único/química , Anticorpos de Domínio Único/farmacologia , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Camundongos , Imunoconjugados/química , Imunoconjugados/farmacologia , Imunoconjugados/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/química , Camundongos Endogâmicos BALB C , Feminino , Ensaios Antitumorais Modelo de Xenoenxerto , Oligopeptídeos/química , Oligopeptídeos/farmacologia , NectinasRESUMO
Nectin cell adhesion molecule 4 (nectin-4) is a transmembrane protein overexpressed on a variety of cancers and plays an important role in oncogenic and metastatic processes. The nectin-4-targeted antibody-drug conjugate enfortumab vedotin has been approved for treating locally advanced or metastatic urothelial cancer, but the efficacy in other types of cancer remains to be explored. The aim of this study was to evaluate the feasibility of nectin-4-targeted PET imaging with 68Ga-N188 as a noninvasive method to quantify membranous nectin-4 expression in multiple tumor types-an approach that may provide insight for patient stratification and treatment selection. Methods: Sixty-two patients with 16 types of cancer underwent head-to-head 68Ga-N188 and 18F-FDG PET/CT imaging for initial staging or detection of recurrence and metastases. Correlation between lesion SUVmax and nectin-4 expression determined by immunohistochemistry staining was analyzed in 36 of 62 patients. Results: The SUVmax of 68Ga-N188 had a positive correlation with membranous nectin-4 expression in the various tumor types tested (r = 0.458; P = 0.005), whereas no association was observed between the SUVmax and cytoplasmic nectin-4 expression. The detection rates for patient-based analysis of 68Ga-N188 and 18F-FDG PET/CT examinations were comparable (95.00% [57/60] vs. 93.33% [56/60]). In patients with pancreatic cancer, 68Ga-N188 exhibited a potential advantage for detecting residual or locally recurrent tumors; this advantage may assist in clinical decision-making. Conclusion: The correlation between nectin-4-targeted 68Ga-N188 PET imaging and membranous nectin-4 expression indicates the potential of 68Ga-N188 as an effective tool for selecting patients who may benefit from enfortumab vedotin treatment. The PET imaging results provided evidence to explore nectin-4-targeted therapy in a variety of tumors. 68Ga-N188 may improve the restaging of pancreatic cancer but requires further evaluation in a powered, prospective setting.
Assuntos
Moléculas de Adesão Celular , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Moléculas de Adesão Celular/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Adulto , Anticorpos Monoclonais/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Idoso de 80 Anos ou mais , Pesquisa Translacional Biomédica , NectinasRESUMO
Effective diagnosis and understanding of the mechanism of intrapulmonary metastasis (IM) from multiple primary lung cancers (MPLC) aid clinical management. However, the actual detection panels used in the clinic are variable. Current research on tumor microenvironment (TME) of MPLC and IM is insufficient. Therefore, additional investigation into the differential diagnosis and discrepancies in TME between two conditions is crucial. Two hundred and fourteen non-small cell lung cancer patients with multiple tumors were enrolled and 507 samples were subjected to DNA sequencing (NGS 10). Then, DNA and RNA sequencing (master panel) were performed on the specimens from 32 patients, the TME profiles between tumors within each patient and across patients and the differentially expressed genes were compared. Four patients were regrouped with NGS 10 results. Master panel resolved the classifications of six undetermined patients. The TME in MPLC exhibited a high degree of infiltration by natural killer (NK) cells, CD56dim NK cells, endothelial cells, etc., Pâ <â 0.05. Conversely, B cells, activated B cells, regulatory cells, immature dendritic cells, etc., Pâ <â 0.001, were heavily infiltrated in the IM. NECTIN4 and LILRB4 mRNA were downregulated in the MPLC (Pâ <â 0.0001). Additionally, NECTIN4 (Pâ <â 0.05) and LILRB4 were linked to improved disease-free survival in the MPLC. In conclusion, IM is screened from MPLC by pathology joint NGS 10 detections, followed by a large NGS panel for indistinguishable patients. A superior prognosis of MPLC may be associated with an immune-activating TME and the downregulation of NECTIN4 and LILRB4 considered as potential drug therapeutic targets.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Pulmonares , Transcriptoma , Microambiente Tumoral , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Masculino , Feminino , Microambiente Tumoral/genética , Pessoa de Meia-Idade , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Idoso , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Prognóstico , Genômica/métodos , Perfilação da Expressão Gênica , Nectinas/genética , Células Matadoras Naturais/imunologiaRESUMO
Cancer-associated fibroblasts play a crucial role within the tumor microenvironment. However, a comprehensive characterization of CAF in colorectal cancer (CRC) is still missing. We combined scRNA-seq and spatial proteomics to decipher fibroblast heterogeneity in healthy human colon and CRC at high resolution. Analyzing nearly 23,000 fibroblasts, we identified 11 distinct clusters and verified them by spatial proteomics. Four clusters, consisting of myofibroblastic CAF (myCAF)-like, inflammatory CAF (iCAF)-like and proliferating fibroblasts as well as a novel cluster, which we named "T cell-inhibiting CAF" (TinCAF), were primarily found in CRC. This new cluster was characterized by the expression of immune-interacting receptors and ligands, including CD40 and NECTIN2. Co-culture of CAF and T cells resulted in a reduction of the effector T cell compartment, impaired proliferation, and increased exhaustion. By blocking its receptor interaction, we demonstrated that NECTIN2 was the key driver of T cell inhibition. Analysis of clinical datasets showed that NECTIN2 expression is a poor prognostic factor in CRC and other tumors. In conclusion, we identified a new class of immuno-suppressive CAF with features rendering them a potential target for future immunotherapies.
Assuntos
Fibroblastos Associados a Câncer , Neoplasias Colorretais , Transdução de Sinais , Humanos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Fibroblastos Associados a Câncer/imunologia , Proliferação de Células , Técnicas de Cocultura , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Nectinas/metabolismo , Nectinas/genética , Proteômica/métodos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente TumoralRESUMO
Research and development on Nectin-4 antibody-drug conjugates (ADC) have been greatly accelerated since the approval of enfortumab vedotin to treat uroepithelial cancer. During the course of this study, we identified that autophagy serves as a cytoprotective mechanism during Nectin-4-MMAE treatment and proposed a strategy to enhance the antitumor effects of Nectin-4-MMAE in bladder cancer. Nectin-4-MMAE rapidly internalized into bladder cancer cells in 30 minutes and released MMAE, inducing the onset of caspase-mediated apoptosis and leading to the inhibition of tumor cell growth. Transcriptomics showed significant alterations in autophagy-associated genes in bladder cancer cells treated with Nectin-4-MMAE, which suggested autophagy was activated by Nectin-4-MMAE. Furthermore, autophagy activation was characterized by ultrastructural analysis of autophagosome accumulation, immunofluorescence of autophagic flux, and immunoblotting autophagy marker proteins SQSTM1 and LC3 I/II. Importantly, inhibiting autophagy by LY294002 and chloroquine significantly enhances the cytotoxicity effects of Nectin-4-MMAE in bladder cancer cells. Additionally, we detected the participation of the AKT/mTOR signaling cascade in the induction of autophagy by Nectin-4-MMAE. The combination of Nectin-4-MMAE and an autophagy inhibitor demonstrated enhanced antitumor effects in the HT1376 xenograft tumor model. After receiving a single dose of Nectin-4-MMAE, the group that received the combination treatment showed a significant decrease in tumor size compared to the group that received only one type of treatment. Notably, one mouse in the combination treatment group achieved complete remission of the tumor. The combination group exhibited a notable rise in apoptosis and necrosis, as indicated by H&E staining and immunohistochemistry (cleaved caspase-3, ki67). These findings demonstrated the cytoprotective role of autophagy during Nectin-4-MMAE treatment and highlighted the potential of combining Nectin-4-MMAE with autophagy inhibitors for bladder cancer treatment.
Assuntos
Autofagia , Moléculas de Adesão Celular , Morfolinas , Nectinas , Neoplasias da Bexiga Urinária , Autofagia/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/genética , Humanos , Animais , Linhagem Celular Tumoral , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/genética , Camundongos , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Oligopeptídeos/farmacologia , Apoptose/efeitos dos fármacos , Camundongos Nus , Cromonas/farmacologia , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Camundongos Endogâmicos BALB C , Feminino , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Enfortumab vedotin is an antibody-drug conjugate comprised of a human monoclonal antibody directed to Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The objectives of this review are to summarize the clinical pharmacology of enfortumab vedotin monotherapy and demonstrate that the appropriate dose has been selected for clinical use. Pharmacokinetics (PK) of enfortumab vedotin (antibody-drug conjugate and total antibody) and free MMAE were evaluated in five clinical trials of patients with locally advanced or metastatic urothelial carcinoma (n = 748). Intravenous enfortumab vedotin 0.5-1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle showed linear, dose-proportional PK. No significant differences in exposure or safety of enfortumab vedotin and free MMAE were observed in mild, moderate, or severe renal impairment versus normal renal function. Patients with mildly impaired versus normal hepatic function had a 37% increase in area under the concentration-time curve (0-28 days), a 31% increase in maximum concentration of free MMAE, and a similar adverse event profile. No clinically significant PK differences were observed based on race/ethnicity with weight-based dosing, and no clinically meaningful QT prolongation was observed. Concomitant use with dual P-glycoprotein and strong cytochrome P450 3A4 inhibitors may increase MMAE exposure and the risk of adverse events. Approximately 3% of patients developed antitherapeutic antibodies against enfortumab vedotin 1.25 mg/kg. These findings support enfortumab vedotin 1.25 mg/kg monotherapy on days 1, 8, and 15 of a 28-day cycle. No dose adjustments are required for patients with renal impairment or mild hepatic impairment, or by race/ethnicity.
Assuntos
Anticorpos Monoclonais , Imunoconjugados , Nectinas , Humanos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Imunoconjugados/farmacocinética , Imunoconjugados/administração & dosagem , Imunoconjugados/farmacologia , Imunoconjugados/efeitos adversos , Imunoconjugados/uso terapêutico , Oligopeptídeos/farmacocinética , Oligopeptídeos/administração & dosagem , Oligopeptídeos/uso terapêutico , Oligopeptídeos/farmacologia , Oligopeptídeos/efeitos adversos , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/patologia , Relação Dose-Resposta a Droga , Carcinoma de Células de Transição/tratamento farmacológico , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologiaRESUMO
PURPOSE: The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. MATERIALS AND METHODS: We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non-EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. RESULTS: NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup (P < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. CONCLUSION: NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.
Assuntos
Moléculas de Adesão Celular , Amplificação de Genes , Humanos , Moléculas de Adesão Celular/genética , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Anticorpos Monoclonais/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Hibridização in Situ Fluorescente , Variações do Número de Cópias de DNA , Idoso de 80 Anos ou mais , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologia , NectinasRESUMO
INTRODUCTION: NECTINs are transmembrane proteins mediating cell-to-cell adhesion. NECTINs interact with integrins or other membrane receptors to trigger multiple cellular functions. Aberrant NECTIN expression is associated with cancer progression and poor outcomes. While NECTIN2 is overexpressed in various cancer types, its role in lung cancer is not well understood. MATERIAL AND METHODS: We investigated the function of NECTIN2 in lung adenocarcinoma (LUAD) using the Cancer Genome Atlas (TCGA) dataset and clinical samples of 105 LUAD patients who had undergone surgical resection. Cell proliferation, apoptosis, migration and invasion were investigated using human lung adenocarcinoma cell lines. RESULTS: We found that high NECTIN2 expression correlated with reduced overall survival in LUAD in TCGA database. In clinical samples, high NECTIN2 expression was associated with lower recurrence-free survival in all patients (P < 0.001) and in stage I patients (P = 0.001). Functional analyses demonstrated that NECTIN2 knockout promoted cell apoptosis and diminished cell proliferation and migration capacity. NECTIN2 overexpression did not significantly affect cellular functions. DISCUSSION: Our results suggest that NECTIN2 plays a significant role in cell apoptosis and cancer cell migration, leading to increased postoperative recurrence. Furthermore, NECTIN2 serves as a prognostic indicator and a potential therapeutic target in LUAD. CONCLUSIONS: High NECTIN2 expression in LUAD was found to be associated with postoperative recurrence, and was observed to play an important role in cell apoptosis and migration.
Assuntos
Adenocarcinoma de Pulmão , Apoptose , Biomarcadores Tumorais , Movimento Celular , Proliferação de Células , Neoplasias Pulmonares , Nectinas , Humanos , Nectinas/genética , Nectinas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Prognóstico , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Apoptose/genética , Proliferação de Células/genética , Movimento Celular/genética , Masculino , Feminino , Linhagem Celular Tumoral , Pessoa de Meia-Idade , Idoso , Invasividade NeoplásicaRESUMO
Poliovirus receptor-related 2 (PVRL2, also known as nectin-2 or CD112) is believed to act as an immune checkpoint protein in cancer; however, most insight into its role is inferred from studies on its known receptor, poliovirus receptor (PVR)-related immunoglobulin domain protein (PVRIG, also known as CD112R). Here, we study PVRL2 itself. PVRL2 levels were found to be high in tumor cells and tumor-derived exosomes. Deletion of PVRL2 in multiple syngeneic mouse models of cancer showed a dramatic reduction in tumor growth that was immune dependent. This effect was even greater than that seen with deletion of PD-L1. PVRL2 was shown to function by suppressing CD8+ T and natural killer cells in the tumor microenvironment. The loss of PVRL2 suppressed tumor growth even in the absence of PVRIG. In contrast, PVRIG loss showed no additive effect in the absence of PVRL2. T-cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade combined with PVRL2 deletion resulted in a near complete block in tumor growth. This effect was not recapitulated by the combined deletion of PVRL2 with its paralog, PVR, which is the ligand for TIGIT. These data uncover PVRL2 as a distinct inhibitor of the antitumor immune response with functions beyond that of its known receptor PVRIG. Moreover, the data provide a strong rationale for combinatorial targeting of PVRL2 and TIGIT for cancer immunotherapy.
Assuntos
Nectinas , Receptores de Superfície Celular , Receptores Imunológicos , Microambiente Tumoral , Animais , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Nectinas/metabolismo , Camundongos , Humanos , Microambiente Tumoral/imunologia , Linhagem Celular Tumoral , Transdução de Sinais , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Linfócitos T CD8-Positivos/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismoRESUMO
Force transmission at cell-cell junctions critically regulates embryogenesis, tissue homeostasis, and diseases including cancer. The cadherin-catenin linkage has been considered the keystone of junctional force transmission, but new findings challenge this paradigm, arguing instead that the nectin-afadin linkage plays the more important role in mature junctions in the intestinal epithelium.
Assuntos
Junções Intercelulares , Proteínas dos Microfilamentos , Nectinas , Caderinas/metabolismo , Cateninas/metabolismo , Proteínas dos Microfilamentos/metabolismo , Nectinas/metabolismo , Junções Intercelulares/química , HumanosRESUMO
Initial studies indicated that NECTIN4 expression is widespread in metastatic urothelial cancer (mUC), which led to approval of the anti-NECTIN4 antibody-drug conjugate (ADC) enfortumab vedotin (EV) for unselected patients with mUC. However, the recent literature suggests that there has been overestimation of membranous NECTIN4 expression in UC, which is a prerequisite for EV binding. It is well established from the development of Her2-targeting ADCs that treatment response is strongly dependent on membranous expression level of the relevant target antigen. In this context, it has been demonstrated that membranous NECTIN4 expression correlates with EV responses and outcomes. Another promising biomarker could be NECTIN4 copy number alteration, a genomic alteration that occurs in approximately 25% of mUC cases, which is associated with strong membranous NECTIN4 expression. Patients with NECTIN4 amplification exhibit an objective response rate of >90% to EV monotherapy and long-term survival. Given the heterogeneous expression of NECTIN4 in UC, future biomarker research is essential for the development of biomarker-driven mUC treatment strategies to further improve outcomes for patients with mUC. PATIENT SUMMARY: We reviewed current evidence on biomarkers for predicting response to enfortumab vedotin (EV) treatment for metastatic urinary tract cancer (mUC). Studies to date have shown that patients with high levels of the protein NECTIN4 on their cancer cells respond well to EV. This information has the potential to guide future treatment strategies for mUC.
Assuntos
Anticorpos Monoclonais , Biomarcadores Tumorais , Moléculas de Adesão Celular , Imunoconjugados , Humanos , Moléculas de Adesão Celular/metabolismo , Imunoconjugados/uso terapêutico , Imunoconjugados/farmacologia , Anticorpos Monoclonais/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , NectinasRESUMO
Nectin and nectin-like (Necl) co-receptor axis, comprised of receptors DNAM-1, TIGIT, CD96, PVRIG, and nectin/Necl ligands, is gaining prominence in immuno-oncology. Within this axis, the inhibitory receptor PVRIG recognizes Nectin-2 with high affinity, but the underlying molecular basis remains unknown. By determining the crystal structure of PVRIG in complex with Nectin-2, we identified a unique CC' loop in PVRIG, which complements the double-lock-and-key binding mode and contributes to its high affinity for Nectin-2. The association of the corresponding charged residues in the F-strands explains the ligand selectivity of PVRIG toward Nectin-2 but not for Necl-5. Moreover, comprehensive comparisons of the binding capacities between co-receptors and ligands provide innovative insights into the intra-axis immunoregulatory mechanism. Taken together, these findings broaden our understanding of immune recognition and regulation mediated by nectin/Necl co-receptors and provide a rationale for the development of immunotherapeutic strategies targeting the nectin/Necl axis.