RESUMO
Ferroptosis is an iron-dependent form of programmed cell death with the potential to reverse traditional cancer therapy resistance. The combination of ferroptosis with chemotherapy, photodynamic therapy and X-ray therapy has demonstrated remarkably improved therapeutic efficiency. Radiopharmaceutical therapy (RPT) is an emerging approach that achieves precise radiation to diseased tissues via radionuclide delivery. However, insufficient accumulation and retention of therapeutic radiopharmaceuticals in tumor region as well as cancer radioresistance impact treatment efficacy. Here, a nanoassembly of renal clearable ultrasmall iron nanoparticles (USINPs) and 131I-aPD-L1 is prepared via the affinity of fluorophenylboronic acid modified on the USINPs with 131I-aPD-L1. The 150 nm USINAs(131I-aPD-L1) nanoassembly is stable in blood circulation, effectively targets to the tumor and disassembles in the presence of ATP in the tumor microenvironment. Both in vitro and in vivo experiments prove that USINPs-induced ferroptosis boosted the tumor radiosensitization to 131I while 131I-mediated RPT further enhanced ferroptosis. Meanwhile, the immunogenic cell death caused by RPT and ferroptosis combined with PD-L1 immune checkpoint blockade therapy exhibits a strong antitumor immunity. This study provides a novel way to improve the tumor accumulation of ferroptosis inducer and radiopharmaceuticals, insights into the interaction between RPT and ferroptosis and an effective SPECT-guided ferroptosis-enhanced radio-immunotherapy.
Assuntos
Ferroptose , Radioisótopos do Iodo , Compostos Radiofarmacêuticos , Ferroptose/efeitos dos fármacos , Animais , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/uso terapêutico , Camundongos , Radioisótopos do Iodo/uso terapêutico , Radioisótopos do Iodo/química , Linhagem Celular Tumoral , Humanos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Ferro/química , Camundongos Endogâmicos BALB C , Imunoterapia/métodos , Radioimunoterapia/métodos , Feminino , Neoplasias/terapiaRESUMO
Drug resistance is a significant challenge in cancer chemotherapy and is a primary factor contributing to poor recovery for cancer patients. Although drug-loaded nanoparticles have shown promise in overcoming chemotherapy resistance, they often carry a combination of drugs and require advanced design and manufacturing processes. Furthermore, they seldom approach chemotherapy-resistant tumors from an immunotherapy perspective. In this study, we developed a therapeutic nanovaccine composed solely of chemotherapy-induced resistant tumor antigens (CIRTAs) and the immune adjuvant Toll-like receptor (TLR) 7/8 agonist R848 (CIRTAs@R848). This nanovaccine does not require additional carriers and has a simple production process. It efficiently delivers antigens and immune stimulants to dendritic cells (DCs) simultaneously, promoting DCs maturation. CIRTAs@R848 demonstrated significant tumor suppression, particularly when used in combination with the immune checkpoint blockade (ICB) anti-PD-1 (αPD-1). The combined therapy increased the infiltration of T cells into the tumor while decreasing the proportion of regulatory T cells (Tregs) and modulating the tumor microenvironment, resulting in long-term immune memory. Overall, this study introduces an innovative strategy for treating chemotherapy-resistant tumors from a novel perspective, with potential applications in personalized immunotherapy and precision medicine.
Assuntos
Vacinas Anticâncer , Desoxicitidina , Resistencia a Medicamentos Antineoplásicos , Gencitabina , Imunoterapia , Nanopartículas , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Desoxicitidina/farmacologia , Animais , Imunoterapia/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Nanopartículas/química , Camundongos , Humanos , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Feminino , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , NanovacinasRESUMO
Chemoimmunotherapy is an emerging paradigm in the clinic for treating several malignant diseases, such as non-small cell lung cancer, breast cancer, and large B-cell lymphoma. However, the efficacy of this strategy is still restricted by serious adverse events and a high therapeutic termination rate, presumably due to the lack of tumor-targeted distribution of both chemotherapeutic and immunotherapeutic agents. Targeted drug delivery has the potential to address this issue. Among the most promising nanocarriers in clinical translation, liposomes have drawn great attention in cancer chemoimmunotherapy in recent years. Liposomes-enabled cancer chemoimmunotherapy has made significant progress in clinics, with impressive therapeutic outcomes. This review summarizes the latest preclinical and clinical progress in liposome-enabled cancer chemoimmunotherapy and discusses the challenges and future directions of this field.
Assuntos
Imunoterapia , Lipossomos , Neoplasias , Lipossomos/química , Humanos , Imunoterapia/métodos , Animais , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagemRESUMO
The immune resistance of tumor microenvironment (TME) causes immune checkpoint blockade therapy inefficient to hepatocellular carcinoma (HCC). Emerging strategies of using chemotherapy regimens to reverse the immune resistance provide the promise for promoting the efficiency of immune checkpoint inhibitors. The induction of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) in tumor cells evokes the adaptive immunity and remodels the immunosuppressive TME. In this study, we report that mitoxantrone (MIT, a chemotherapeutic drug) activates the cGAS-STING signaling pathway of HCC cells. We provide an approach to augment the efficacy of MIT using a signal transducer and activator of transcription 3 (STAT3) inhibitor called napabucasin (NAP). We prepare an aminoethyl anisamide (AEAA)-targeted polyethylene glycol (PEG)-modified poly (lactic-co-glycolic acid) (PLGA)-based nanocarrier for co-delivery of MIT and NAP. The resultant co-nanoformulation can elicit the cGAS-STING-based immune responses to reshape the immunoresistant TME in the mice orthotopically grafted with HCC. Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.
Assuntos
Carcinoma Hepatocelular , Imunoterapia , Neoplasias Hepáticas , Proteínas de Membrana , Mitoxantrona , Nucleotidiltransferases , Fator de Transcrição STAT3 , Mitoxantrona/farmacologia , Mitoxantrona/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Animais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Humanos , Nucleotidiltransferases/metabolismo , Proteínas de Membrana/metabolismo , Fator de Transcrição STAT3/metabolismo , Camundongos , Imunoterapia/métodos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Benzofuranos , NaftoquinonasRESUMO
Osteosarcoma, a malignant bone tumor often characterized by high hedgehog signaling activity, residual tumor cells, and substantial bone defects, poses significant challenges to both treatment response and postsurgical recovery. Here, we developed a nanocomposite hydrogel for the sustained co-delivery of bioactive magnesium ions, anti-PD-L1 antibody (αPD-L1), and hedgehog pathway antagonist vismodegib, to eradicate residual tumor cells while promoting bone regeneration post-surgery. In a mouse model of tibia osteosarcoma, this hydrogel-mediated combination therapy led to remarkable tumor growth inhibition and hence increased animal survival by enhancing the activity of tumor-suppressed CD8+ T cells. Meanwhile, the implanted hydrogel improved the microenvironment of osteogenesis through long-term sustained release of Mg2+, facilitating bone defect repair by upregulating the expression of osteogenic genes. After 21 days, the expression levels of ALP, COL1, RUNX2, and BGLAP in the Vis-αPD-L1-Gel group were approximately 4.1, 5.1, 5.5, and 3.4 times higher than those of the control, respectively. We believe that this hydrogel-based combination therapy offers a potentially valuable strategy for treating osteosarcoma and addressing the tumor-related complex bone diseases.
Assuntos
Neoplasias Ósseas , Hidrogéis , Imunoterapia , Nanocompostos , Osteossarcoma , Osteossarcoma/patologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/terapia , Animais , Hidrogéis/química , Nanocompostos/química , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Camundongos , Imunoterapia/métodos , Linhagem Celular Tumoral , Regeneração Óssea/efeitos dos fármacos , Humanos , Osteogênese/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Camundongos Endogâmicos BALB C , Magnésio/químicaRESUMO
Metastasis stands as the primary contributor to mortality associated with tumors. Chemotherapy and immunotherapy are frequently utilized in the management of metastatic solid tumors. Nevertheless, these therapeutic modalities are linked to serious adverse effects and limited effectiveness in preventing metastasis. Here, we report a novel therapeutic strategy named starvation-immunotherapy, wherein an immune checkpoint inhibitor is combined with an ultra-long-acting L-asparaginase that is a fusion protein comprising L-asparaginase (ASNase) and an elastin-like polypeptide (ELP), termed ASNase-ELP. ASNase-ELP's thermosensitivity enables it to generate an in-situ depot following an intratumoral injection, yielding increased dose tolerance, improved pharmacokinetics, sustained release, optimized biodistribution, and augmented tumor retention compared to free ASNase. As a result, in murine models of oral cancer, melanoma, and cervical cancer, the antitumor efficacy of ASNase-ELP by selectively and sustainably depleting L-asparagine essential for tumor cell survival was substantially superior to that of ASNase or Cisplatin, a first-line anti-solid tumor medicine, without any observable adverse effects. Furthermore, the combination of ASNase-ELP and an immune checkpoint inhibitor was more effective than either therapy alone in impeding melanoma metastasis. Overall, the synergistic strategy of starvation-immunotherapy holds excellent promise in reshaping the therapeutic landscape of refractory metastatic tumors and offering a new alternative for next-generation oncology treatments.
Assuntos
Asparaginase , Inibidores de Checkpoint Imunológico , Imunoterapia , Animais , Asparaginase/uso terapêutico , Asparaginase/farmacologia , Asparaginase/química , Imunoterapia/métodos , Feminino , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Camundongos , Humanos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Elastina/química , Elastina/metabolismo , Metástase Neoplásica , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Distribuição TecidualRESUMO
Stimulator of interferon genes (STING) agonists have shown promise in cancer treatment by stimulating the innate immune response, yet their clinical potential has been limited by inefficient cytosolic entry and unsatisfactory pharmacological activities. Moreover, aggressive tumors with "cold" and immunosuppressive microenvironments may not be effectively suppressed solely through innate immunotherapy. Herein, we propose a multifaceted immunostimulating nanoparticle (Mn-MC NP), which integrates manganese II (Mn2+) coordinated photosensitizers (chlorin e6, Ce6) and STING agonists (MSA-2) within a PEGylated nanostructure. In Mn-MC NPs, Ce6 exerts potent phototherapeutic effects, facilitating tumor ablation and inducing immunogenic cell death to elicit robust adaptive antitumor immunity. MSA-2 activates the STING pathway powered by Mn2+, thereby promoting innate antitumor immunity. The Mn-MC NPs feature a high drug-loading capacity (63.42 %) and directly ablate tumor tissue while synergistically boosting both adaptive and innate immune responses. In subsutaneous tumor mouse models, the Mn-MC NPs exhibit remarkable efficacy in not only eradicating primary tumors but also impeding the progression of distal and metastatic tumors through synergistic immunotherapy. Additionally, they contribute to preventing tumor recurrence by fostering long-term immunological memory. Our multifaceted immunostimulating nanoparticle holds significant potential for overcoming limitations associated with insufficient antitumor immunity and ineffective cancer treatment.
Assuntos
Imunoterapia , Manganês , Nanopartículas , Animais , Imunoterapia/métodos , Manganês/química , Nanopartículas/química , Camundongos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Linhagem Celular Tumoral , Humanos , Porfirinas/química , Porfirinas/farmacologia , Clorofilídeos , Neoplasias/terapia , Neoplasias/imunologia , Fotoquimioterapia/métodos , Imunidade Inata/efeitos dos fármacos , Feminino , Camundongos Endogâmicos C57BL , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/químicaRESUMO
Tumor immunotherapies have emerged as a promising frontier in the realm of cancer treatment. However, challenges persist in achieving localized, durable immunostimulation while counteracting the tumor's immunosuppressive environment. Here, we develop a natural mussel foot protein-based nanomedicine with spatiotemporal control for tumor immunotherapy. In this nanomedicine, an immunoadjuvant prodrug and a photosensitizer are integrated, which is driven by their dynamic bonding and non-covalent assembling with the protein carrier. Harnessing the protein carrier's bioadhesion, this nanomedicine achieves a drug co-delivery with spatiotemporal precision, by which it not only promotes tumor photothermal ablation but also broadens tumor antigen repertoire, facilitating in situ immunotherapy with durability and maintenance. This nanomedicine also modulates the tumor microenvironment to overcome immunosuppression, thereby amplifying antitumor responses against tumor progression. Our strategy underscores a mussel foot protein-derived design philosophy of drug delivery aimed at refining combinatorial immunotherapy, offering insights into leveraging natural proteins for cancer treatment.
Assuntos
Imunoterapia , Nanomedicina , Animais , Imunoterapia/métodos , Nanomedicina/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Terapia Fototérmica/métodos , Camundongos , Humanos , Microambiente Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral , Proteínas/química , Feminino , Neoplasias/terapia , Neoplasias/imunologia , Adesivos/química , Camundongos Endogâmicos C57BL , Adjuvantes Imunológicos/farmacologiaRESUMO
The challenges generated by insufficient T cell activation and infiltration have constrained the application of immunotherapy. Making matters worse, the complex tumor microenvironment (TME), resistance to apoptosis collectively poses obstacles for cancer treatment. The carrier-free small molecular self-assembly strategy is a current research hotspot to overcome these challenges. This strategy can transform multiple functional agents into sustain-released hydrogel without the addition of any excipients. Herein, a coordination and hydrogen bond mediated tricomponent hydrogel (Cel hydrogel) composed of glycyrrhizic acid (GA), copper ions (Cu2+) and celastrol (Cel) was initially constructed. The hydrogel can regulate TME by chemo-dynamic therapy (CDT), which increases reactive oxygen species (ROS) in conjunction with GA and Cel, synergistically expediting cellular apoptosis. What's more, copper induced cuproptosis also contributes to the anti-tumor effect. In terms of regulating immunity, ROS generated by Cel hydrogel can polarize tumor-associated macrophages (TAMs) into M1-TAMs, Cel can induce T cell proliferation as well as activate DC mediated antigen presentation, which subsequently induce T cell proliferation, elevate T cell infiltration and enhance the specific killing of tumor cells, along with the upregulation of PD-L1 expression. Upon co-administration with aPD-L1, this synergy mitigated both primary and metastasis tumors, showing promising clinical translational value.
Assuntos
Cobre , Hidrogéis , Inibidores de Checkpoint Imunológico , Imunoterapia , Ativação Linfocitária , Triterpenos Pentacíclicos , Espécies Reativas de Oxigênio , Linfócitos T , Microambiente Tumoral , Triterpenos Pentacíclicos/farmacologia , Hidrogéis/química , Animais , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Camundongos , Ativação Linfocitária/efeitos dos fármacos , Cobre/química , Microambiente Tumoral/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Humanos , Camundongos Endogâmicos C57BL , Ácido Glicirrízico/farmacologia , Ácido Glicirrízico/química , Feminino , Triterpenos/farmacologia , Triterpenos/químicaRESUMO
In this chapter, we outline the steps for designing and conducting a rigorous systematic review and meta-analysis, focusing on the efficacy of immune checkpoint inhibitors (ICIs) in elderly patients. ICIs have improved survival rates in advanced cancers, yet their effectiveness in older populations remains unclear. We detail the essential processes involved in both systematic reviews and meta-analyses. We can evaluate the efficacy of ICIs in elderly patients with advanced cancer, examining outcomes such as overall survival and progression-free survival.
Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Idoso , Resultado do Tratamento , Intervalo Livre de Progressão , Imunoterapia/métodosRESUMO
BACKGROUND: In order for cancers to progress, they must evade elimination by CD8 T cells or other immune mechanisms. CD8 T cells recognize and kill tumor cells that display immunogenic tumor peptides bound to MHC I molecules. One of the ways that cancers can escape such killing is by reducing expression of MHC I molecules, and loss of MHC I is frequently observed in tumors. There are multiple different mechanisms that can underly the loss of MHC I complexes on tumor and it is currently unclear whether there are particular mechanisms that occur frequently and, if so, in what types of cancers. Also of importance to know is whether the loss of MHC I is reversible and how such loss and/or its restoration would impact responses to immunotherapy. Here, we investigate these issues for loss of IRF1 and IRF2, which are transcription factors that drive expression of MHC I pathway genes and some killing mechanisms. METHODS: Bioinformatics analyses of IRF2 and IRF2-dependent gene transcripts were performed for all human cancers in the TCGA RNAseq database. IRF2 protein-DNA-binding was analyzed in ChIPseq databases. CRISRPcas9 was used to knock out IRF1 and IRF2 genes in human and mouse melanoma cells and the resulting phenotypes were analyzed in vitro and in vivo. RESULTS: Transcriptomic analysis revealed that IRF2 expression was reduced in a substantial subset of cases in almost all types of human cancers. When this occurred there was a corresponding reduction in the expression of IRF2-regulated genes that were needed for CD8 T cell recognition. To test cause and effect for these IRF2 correlations and the consequences of IRF2 loss, we gene-edited IRF2 in a patient-derived melanoma and a mouse melanoma. The IRF2 gene-edited melanomas had reduced expression of transcripts for genes in the MHC I pathway and decreased levels of MHC I complexes on the cell surface. Levels of Caspase 7, an IRF2 target gene involved in CD8 T cell killing of tumors, were also reduced. This loss of IRF2 caused both human and mouse melanomas to become resistant to immunotherapy with a checkpoint inhibitor. Importantly, these effects were reversible. Stimulation of the IRF2-deficient melanomas with interferon induced the expression of a functionally homologous transcription factor, IRF1, which then restored the MHC I pathway and responsiveness to CPI. CONCLUSIONS: Our study shows that a subset of cases within most types of cancers downregulates IRF2 and that this can allow cancers to escape immune control. This can cause resistance to checkpoint blockade immunotherapy and is reversible with currently available biologics.
Assuntos
Imunoterapia , Fator Regulador 2 de Interferon , Melanoma , Animais , Humanos , Camundongos , Fator Regulador 2 de Interferon/genética , Fator Regulador 2 de Interferon/metabolismo , Melanoma/genética , Melanoma/imunologia , Melanoma/tratamento farmacológico , Melanoma/terapia , Imunoterapia/métodos , Melanoma Experimental/imunologia , Melanoma Experimental/genética , Melanoma Experimental/terapia , Linhagem Celular TumoralRESUMO
Purines and pyrimidines are signaling molecules in the tumor microenvironment that affect cancer immunity. The purinergic signaling pathways have been shown to play an important role in the development and progression of cancer. CD39 and CD73 are ectonucleotidases responsible for breaking down ATP or ADP into adenosine, which regulates immunosuppression in various types of cancer. These enzymes have been studied as a potential therapeutic target in immunotherapy, and recent research suggests a correlation between ectonucleotidases and clinical outcomes in cancer.Prostate cancer is the most diagnosed cancer in men, after non-melanoma skin tumors, and is the second leading cause of death in men in the world. Despite having long survival periods, patients often receive excessive or insufficient treatment. Within this complex landscape, the adenosine/CD73 pathway plays a crucial role. Therefore, this review aims to highlight new findings on the potential role of purinergic signaling in cancer treatment and emphasizes the importance of anti-CD73 as a pharmacological strategy for prostate cancer therapy.
Assuntos
5'-Nucleotidase , Neoplasias da Próstata , Transdução de Sinais , Humanos , 5'-Nucleotidase/metabolismo , 5'-Nucleotidase/imunologia , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/imunologia , Microambiente Tumoral/imunologia , Adenosina/metabolismo , Imunoterapia/métodos , Terapia de Alvo MolecularRESUMO
Background: Immunotherapy has revolutionized skin cutaneous melanoma treatment, but response variability due to tumor heterogeneity necessitates robust biomarkers for predicting immunotherapy response. Methods: We used weighted gene co-expression network analysis (WGCNA), consensus clustering, and 10 machine learning algorithms to develop the immunotherapy-related gene model (ITRGM) signature. Multi-omics analyses included bulk and single-cell RNA sequencing of melanoma patients, mouse bulk RNA sequencing, and pathology sections of melanoma patients. Results: We identified 66 consensus immunotherapy prognostic genes (CITPGs) using WGCNA and differentially expressed genes (DEGs) from two melanoma cohorts. The CITPG-high group showed better prognosis and enriched immune activities. DEGs between CITPG-high and CITPG-low groups in the TCGA-SKCM cohort were analyzed in three additional melanoma cohorts using univariate Cox regression, resulting in 44 consensus genes. Using 101 machine learning algorithm combinations, we constructed the ITRGM signature based on seven model genes. The ITRGM outperformed 37 published signatures in predicting immunotherapy prognosis across the training cohort, three testing cohorts, and a meta-cohort. It effectively stratified patients into high-risk or low-risk groups for immunotherapy response. The low-risk group, with high levels of model genes, correlated with increased immune characteristics such as tumor mutation burden and immune cell infiltration, indicating immune-hot tumors with a better prognosis. The ITRGM's relationship with the tumor immune microenvironment was further validated in our experiments using pathology sections with GBP5, an important model gene, and CD8 IHC analysis. The ITRGM also predicted better immunotherapy response in eight cohorts, including urothelial carcinoma and stomach adenocarcinoma, indicating broad applicability. Conclusions: The ITRGM signature is a stable and robust predictor for stratifying melanoma patients into 'immune-hot' and 'immune-cold' tumors, enhancing prognosis and response to immunotherapy.
Assuntos
Biomarcadores Tumorais , Imunoterapia , Aprendizado de Máquina , Melanoma , Humanos , Melanoma/terapia , Melanoma/imunologia , Melanoma/genética , Imunoterapia/métodos , Biomarcadores Tumorais/genética , Prognóstico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/genética , Animais , Perfilação da Expressão Gênica , Transcriptoma , Regulação Neoplásica da Expressão Gênica , Camundongos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Resultado do Tratamento , Redes Reguladoras de GenesRESUMO
The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway in hepatocellular carcinoma (HCC) is limited. NOD-like receptors (NLRs) comprise a highly evolutionarily conserved family of cytosolic bacterial sensors, yet their impact on antitumor immunity against HCC remains unclear. In this study, we uncovered that NOD1, a well-studied member of NLR family, exhibits predominant expression in tumor-associated macrophages (TAMs) and correlates positively with improved prognosis and responses to anti-PD-1 treatments in patients with HCC. Activation of NOD1 in vivo augments antitumor immunity and enhances the effectiveness of anti-PD-1 therapy. Mechanistically, NOD1 activation resulted in diminished expression of perilipin 5, thereby hindering fatty acid oxidation and inducing free fatty acid accumulation in TAMs. This metabolic alteration promoted membrane localization of the costimulatory molecule OX40L in a lipid modification-dependent manner, thereby activating CD8+ T cells. These findings unveil a previously unrecognized role for NOD1 in fortifying antitumor T cell immunity in HCC, potentially advancing cancer immunotherapy.
Assuntos
Linfócitos T CD8-Positivos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteína Adaptadora de Sinalização NOD1 , Macrófagos Associados a Tumor , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Animais , Humanos , Camundongos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Linhagem Celular Tumoral , Imunoterapia/métodos , Masculino , Microambiente Tumoral/imunologiaRESUMO
INTRODUCTION: Recalcirant warts are resistant to conventional therapeutic option with high recurrence rate. In recent year, treatment of warts with different immunotherapeutic agent has shown good results, as it regulate epidermal cell proliferation and are involved in the formation of anti microbial peptides. Hence, this study was undertaken to evaluate the efficacy of immunotherapy with intralesional vitamin D in wart. METHODS: A descriptive cross-sectional study was conducted from 1 January 2021 to 2 February 2023 at Kathmandu Medical College after approval from the Institutional Review Committee (Reference number: 0110202002). Ninety - two patients with recalcitrant wart of varying sizes and duration were included in the study. Injection vitamin D ( 600000 IU, 15mg/ ml) was injected about (0.2-0.5 ml) to the base of the wart. Maximum of five warts were injected per month, and was repeated after 4 weeks for 3 sessions. RESULTS: Among 92 patient, complete response was seen in 70 patient (76.08%), partial response was seen in 17 patients ( 18.47%) and 5 patient(5.43%)showed no response. Mild pain as observed at the time of injection. Signs of hypervitaminosis D was not observed. CONCLUSIONS: Intralesional administration of Vitamin D is an effective treatment option for reclacitrant warts and is, highly effective, cost-efficient, with minimal adverse effects, and can be perfomed in our clinical set up.
Assuntos
Imunoterapia , Injeções Intralesionais , Centros de Atenção Terciária , Vitamina D , Verrugas , Humanos , Verrugas/tratamento farmacológico , Verrugas/terapia , Estudos Transversais , Masculino , Feminino , Adulto , Vitamina D/administração & dosagem , Adolescente , Adulto Jovem , Imunoterapia/métodos , Criança , Nepal , Resultado do Tratamento , Vitaminas/administração & dosagem , Pessoa de Meia-IdadeRESUMO
Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 40% of all malignant lymphomas, making it the most common subtype. Molecular genetic studies have elucidated the pathogenesis of DLBCL and the causes of its poor prognosis. This basic research has led to the development of novel molecularly targeted therapies that target molecules and cellular antigens in relevant signaling pathways or epigenetic enzymes. Treatment with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone has become the standard of care for newly diagnosed CD20-positive DLBCL with an International Prognostic Index score of 2 to 5, based on its reported efficacy for this indication. In addition, the development of immunotherapy such as anti-CD19-chimeric antigen receptor (CAR)-T therapy and bispecific antibodies such as epcoritamab, mosunetuzumab, and glofitamab has led to a paradigm shift in treatment of relapsed/refractory DLBCL. This review summarizes the evolution of treatment development for DLBCL, as well as the results of the current clinical standard of care and new therapies that are expected to become the standard of care.
Assuntos
Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Imunoterapia/métodos , Terapia de Alvo Molecular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
INTRODUCTION: Neoadjuvant immunotherapy plus chemotherapy has ushered in a new era for surgical treatment for patients with NSCLC. This study aimed to examine the efficacy and safety of neoadjuvant immunotherapy plus chemotherapy in NSCLC. METHODS: Eligible studies were identified from PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and conference meeting abstracts. The endpoints included major pathological response (MPR), complete pathological response (pCR), surgical resection rate, R0 resection, treatment-related adverse events (TRAEs), severe adverse events (SAEs), surgical complications, treatment discontinuation, surgical delay, and treatment-related death. Stata 18 software was used for statistical analysis, and p < 0.05 was considered statistically significant. Twenty-two studies including a total of 1108 patients were eligible for this study. RESULTS: Among the patients who received neoadjuvant immunotherapy plus chemotherapy, the pooled MPR rate was 51% (95% CI [0.44-0.58]), and pCR rate was 34% (95% CI [0.28-0.40]). The pooled surgical resection rate was 85% (95% CI [0.81-0.89]), and the pooled R0 rate was 94% (95% CI [0.91-0.96]). The pooled rate of pathological tumor downstaging was 84% (95% CI [0.79-0.88]), and the pooled rate of pathological nodal downstaging was 38% (95% CI [0.23-0.57]). During the treatment of neoadjuvant immunotherapy plus chemotherapy with or without surgery, the pooled rate of TRAEs (any grade) was 84% (95% CI [0.73-0.91]), and the pooled rate of SAEs was 29% (95% CI [0.21-0.38]). Surgical complications pooled rate was 25% (95% CI [0.14-0.41]). The pooled rate of treatment discontinuation (11%, 95% CI [0.09-0.13]), surgical delay (3%, 95% CI [0.02-0.05]), and treatment-related death (2%, 95% CI [0.02-0.03]) were conducted. CONCLUSION: Neoadjuvant immunotherapy plus chemotherapy provides a high pathological response, surgical resection rate, R0 resection rate, and pathological downstage rate and has a low risk of increasing the incidence of SAEs, surgical complications, treatment discontinuation, surgical delay, and treatment-related death. The validation of prospective and large sample studies is needed to confirm this conclusion.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Terapia Neoadjuvante , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/efeitos adversos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Imunoterapia/métodos , Imunoterapia/efeitos adversos , Resultado do Tratamento , Pneumonectomia/métodos , Pneumonectomia/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Masculino , Feminino , Estadiamento de NeoplasiasRESUMO
Ferroptosis is a new form of cell death that differs from traditional forms of death. It is ferroptosis-dependent lipid peroxidation death. Colorectal cancer(CRC) is the most common tumor in the gastrointestinal tract with a long occultation period and a poor five-year prognosis. Exploring effective systemic treatments for CRC remains a great challenge worldwide. Numerous studies have demonstrated that ferroptosis can participate in the biological malignant process of various tumor, including CRC, so understanding the role and regulatory mechanisms of ferroptosis in CRC plays a crucial role in the treatment of CRC. In this paper, we reviews the mechanisms of ferroptosis in CRC, the associated regulatory factors and their interactions with various immune cells in the immune microenvironment. In addition, targeting ferroptosis has emerged as an encouraging strategy for CRC treatment. Finally, to inform subsequent research and clinical diagnosis and treatment, we review therapeutic approaches to CRC radiotherapy, immunotherapy, and herbal therapy targeting ferroptosis.
Assuntos
Neoplasias Colorretais , Ferroptose , Microambiente Tumoral , Humanos , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Microambiente Tumoral/imunologia , Animais , Imunoterapia/métodosRESUMO
Background: A multitude of randomized controlled trials (RCTs) conducted in both the initial and subsequent treatment settings for patients diagnosed with metastatic colorectal cancer (mCRC) have provided clinical evidence supporting the efficacy of immunotherapy with the use of immune checkpoint inhibitors (ICIs). In light of these findings, the U.S. Food and Drug Administration (FDA) has authorized the use of several ICIs in specific subpopulations of mCRC patients. Nevertheless, there remains a dearth of direct comparative RCTs evaluating various treatment options. Consequently, the most effective ICI therapeutic strategy for microsatellite-stable (MSS) subgroup and microsatellite instability (MSI) subgroup in the first- and second-line therapies remains undefined. To address this gap, the present study employs a Bayesian network meta-analysis to ascertain the most effective first- and second-line ICI therapeutic strategies. Methods: A comprehensive literature search was conducted across multiple databases, including PubMed, EMBASE, Cochrane Library, and Web of Science, with the retrieval date ranging from the databases' inception to August 20, 2024. A total of 875 studies were identified, and seven were ultimately included in the analysis after a screening process. A systematic review and network meta-analysis were conducted on the basis of the search results. Results: This comprehensive analysis, comprising seven RCTs, evaluated first-line and second-line immunotherapy regimens in 1,358 patients diagnosed with mCRC. The treatments under investigation consisted of five initial treatments, including three focusing on MSS patients and two on MSI patients, as well as two secondary immunotherapy regimens, both focusing on MSS patients. A total of 1051 individuals underwent first-line treatment, while 307 received second-line treatment. The application of ICIs proved to offer varying degrees clinical benefits when compared to standard-of-care therapy alone, both in two subgroups of the first and the second treatment phases. Of particular note is the performance of Nivolumab combination with ipilimumab, which demonstrated superior efficacy in improving progression-free survival (PFS) (HR=0.21; 95% CI, 0.13-0.34),. Moreover, the treatment demonstrated an optimal safety profile, with a relatively low risk of adverse events (OR = 0.33; 95% CI, 0.19-0.56), compared to other first-line treatment modalities for MSI subgroup. Regarding MSS subgroup, the improvement of PFS by Nivolumab plus standard-of-care (SOC) was relatively significant (HR = 0.74; 95% CI, 0.53-1.02). In the realm of second-line therapies for MSS subgroup, the administration of Atezolizumab plus SOC has proven to be an effective approach for prolonging PFS, exhibiting an HR of 0.66 (95% CI, 0.44-0.99). These findings underscore the clinical benefits and safety profiles of ICIs in the treatment of mCRC across various treatment lines. Conclusions: The clinical application of ICIs in both first- and second-line treatment strategies for patients with mCRC yields substantial therapeutic benefits. A detailed assessment in this study indicates that first-line treatment with Nivolumab combination with ipilimumab may represent an efficacious and well-tolerated therapeutic approach for MSI subgroup. In terms of MSS subgroup in first-line therapy, Nivolumab plus SOC may be a relative superior choice. In the context of second-line therapy for MSS subgroup, it is evident that a combination of Atezolizumab and SOC represents a preferable option for enhancing PFS. Furthermore, it is noteworthy that other ICIs treatment regimens also exhibit great value in various aspects, with the potential to inform the development of future clinical treatment guidelines and provide a stronger rationale for the selection of ICIs in both first- and second-line therapeutic strategies for mCRC. Systematic review registration: https://www.crd.york.ac.uk/prospero/#recordDetails, identifier CRD42024543400.