Anticancer Response Research Articles

Role of ADCC, CDC, and CDCC in Vaccine-Mediated Protection against Her2 Mammary Carcinogenesis.

Amplification or mutation of the Her2 oncoantigen in human mammary glands leads to the development of an aggressive breast carcinoma. Several features of this breast carcinoma are reproduced in mammary carcinomas that spontaneously arise in female transgenic mice bearing the activated rat Her2 oncogene under transcriptional control of the mouse mammary tumor virus promoter-BALB-neuT (neuT) mice. We previously demonstrated that carcinoma progression in neuT mice can be prevented by DNA vaccination with RHuT, a plasmid coding for a chimeric rat/human Her2 protein. RHuT vaccination exerts an antitumor effect, mostly mediated by the induction of a strong anti-rat Her2 antibody response. IgG induced by RHuT vaccine mainly acts by blocking Her2 signaling, thus impairing cell cycle progression and inducing apoptosis of cancer cells, but other indirect effector mechanisms could be involved in the antibody-mediated protection. The recruitment of cells with perforin-dependent cytotoxic activity, able to perform antibody-dependent cellular cytotoxicity, has already been investigated. Less is known about the role of the complement system in sustaining antitumor response through complement-dependent cytotoxicity and cellular cytotoxicity in vaccinated mice. This work highlights that the weight of such mechanisms in RHuT-induced cancer protection is different in transplantable versus autochthonous Her2+ tumor models. These results may shed new light on the effector mechanisms involved in antibody-dependent anti-cancer responses, which might be exploited to ameliorate the therapy of Her2+ breast cancer.

Pan-Cancer Prediction of Cell-Line Drug Sensitivity Using Network-Based Methods.

The development of reliable predictive models for individual cancer cell lines to identify an optimal cancer drug is a crucial step to accelerate personalized medicine, but vast differences in cancer cell lines and drug characteristics make it quite challenging to develop predictive models that result in high predictive power and explain the similarity of cell lines or drugs. Our study proposes a novel network-based methodology that breaks the problem into smaller, more interpretable problems to improve the predictive power of anti-cancer drug responses in cell lines. For the drug-sensitivity study, we used the GDSC database for 915 cell lines and 200 drugs. The theory of optimal mass transport was first used to separately cluster cell lines and drugs, using gene-expression profiles and extensive cheminformatic drug features, represented in a form of data networks. To predict cell-line specific drug responses, random forest regression modeling was separately performed for each cell-line drug cluster pair. Post-modeling biological analysis was further performed to identify potential biological correlates associated with drug responses. The network-based clustering method resulted in 30 distinct cell-line drug cluster pairs. Predictive modeling on each cell-line-drug cluster outperformed alternative computational methods in predicting drug responses. We found that among the four drugs top-ranked with respect to prediction performance, three targeted the PI3K/mTOR signaling pathway. Predictive modeling on clustered subsets of cell lines and drugs improved the prediction accuracy of cell-line specific drug responses. Post-modeling analysis identified plausible biological processes associated with drug responses.

A Natural Polyphenol Exerts Antitumor Activity and Circumvents Anti-PD-1 Resistance through Effects on the Gut Microbiota.

The polyphenol castalagin isolated from a berry has an antitumor effect through direct interactions with commensal bacteria, thus reprogramming the tumor microenvironment. In addition, in preclinical ICI-resistant models, castalagin reestablishes the efficacy of anti-PD-1. Together, these results provide a strong biological rationale to test castalagin as part of a clinical trial. This article is highlighted in the In This Issue feature, p. 873.

Journey of Natural Killer Cells and their Role in Liver Diseases

Natural Killer (NK) cells are the key lymphocyte subset of the natural immune system that arbitrates antiviral and anticancer responses. In the human body NK cells inhabit in the bone marrow, lymph nodes, tonsils, skin, liver, gut, and lungs. This bibliographic study covers the origins and evolution of these cells. This review of NK cells includes synopsis of their well-known and evolving themes including their development, functions of cytokine production, anticancer cytotoxicity, clearing of viral infections and exhaustion. Within the liver, NK cells are enhanced in lymphocytes and possess distinctive phenotypic characters and useful properties, which contain tumour cytotoxicity and explicit cytokine profiles. NK cells, while providing innate immunity in the liver, play important roles in providing protection versus pathogens and tumours utilising their cytotoxicity and cytokine production. Accruing substantiation from the last few decades proposes that NK cells perform a vital role in regulating viral hepatitis and liver tumours. In addition, they contribute to the pathogenesis of liver damage including its inflammation. Understanding the description of hepatic NK cell functions has aided us in better understanding the pathogenesis of diseases of the liver and consequently divulging novel therapeutic goals for treating these illnesses.

Patient-derived organoids as a preclinical platform for precision medicine in colorectal cancer.

Patient‐derived organoids are being considered as models that can help guide personalized therapy through in vitro anticancer drug response evaluation. However, attempts to quantify in vitro drug responses in organoids and compare them with responses in matched patients remain inadequate. In this study, we investigated whether drug responses of organoids correlate with clinical responses of matched patients and disease progression of patients. Organoids were established from 54 patients with colorectal cancer who (except for one patient) did not receive any form of therapy before, and tumor organoids were assessed through whole‐exome sequencing. For comparisons of in vitro drug responses in matched patients, we developed an ‘organoid score’ based on the variable anticancer treatment responses observed in organoids. Very interestingly, a higher organoid score was significantly correlated with a lower tumor regression rate after the standard‐of‐care treatment in matched patients. Additionally, we confirmed that patients with a higher organoid score (≥ 2.5) had poorer progression‐free survival compared with those with a lower organoid score (< 2.5). Furthermore, to assess potential drug repurposing using an FDA‐approved drug library, ten tumor organoids derived from patients with disease progression were applied to a simulation platform. Taken together, organoids and organoid scores can facilitate the prediction of anticancer therapy efficacy, and they can be used as a simulation model to determine the next therapeutic options through drug screening. Organoids will be an attractive platform to enable the implementation of personalized therapy for colorectal cancer patients.

Lenalidomide in cancer cachexia: a randomized trial of an anticancer drug applied for anti‐cachexia

AbstractBackgroundCancer cachexia (CC) impacts quality of life, physical function, anticancer treatment response, and survival. Inflammation is a prominent pathomechanism of CC. This small‐scale study sets out to investigate the immunomodulatory drug lenalidomide in inflammatory CC in a randomized, double‐blind, placebo‐controlled trial.MethodsPatients with advanced solid malignancies, documented weight loss, no or unchanged anticancer treatment, and C‐reactive protein &gt; 30 mg/L were included. In a 2:2:1 randomization, patients received either lenalidomide 25 mg once daily or C‐reactive protein‐guided dose, starting with 5 mg lenalidomide once daily or placebo once a day for 8 weeks. Dose adaption and safety were assessed twice a week. Treatment response was defined as an increase of lean body mass of more than 2% in a lower lumbar computed tomography and an increase in dynamometer‐assessed handgrip strength of 4 kg. Secondary endpoints included adverse events, C‐reactive protein response, nutritional intake, and symptoms.ResultsOf 24 eligible patients, 16 were included (25% female). At baseline, the mean age was 67 (range 51–88) years, and mean body weight was 64.7 kg (range 39.8–87.2 kg). Five were diagnosed with mesothelioma, two with non‐small‐cell lung cancer, two with renal cell carcinoma, two with neuroendocrine tumours, and five with other malignancies. Mean survival was 43 days. Eleven adverse events (four of which were severe) were recorded with a probable link to study participation. Nine patients completed the study. No participant showed a treatment response. C‐reactive protein‐guided dosing did not result in lower doses of lenalidomide. Lean body mass decreased less in the treatment groups. For the lenalidomide and placebo groups respectively, handgrip strength decreased by 2.3 vs. 5.5 kg, nutritional intake decreased by 249 vs. 32 kcal/day, and C‐reactive protein increased by 35 mg/dL vs. decreased by 17 mg/dL. The study was closed prematurely due to slow accrual and the need for concurrent anticancer treatments.ConclusionsNo treatment response on muscle mass and muscle strength was observed with lenalidomide. Because of several limiting factors, including low recruitment caused in part by an ambitious study design and concomitant anticancer treatment, this study did not generate adequate data to draw reliable conclusions.

Modelling the tumor immune microenvironment for precision immunotherapy.

The complexity of the cellular and acellular players within the tumor microenvironment (TME) allows for significant variation in TME constitution and role in anticancer treatment response. Spatial alterations in populations of tumor cells and adjacent non‐malignant cells, including endothelial cells, fibroblasts and tissue‐infiltrating immune cells, often have a major role in determining disease progression and treatment response in cancer. Many current standard systemic antineoplastic treatments target the cancer cells and could be further refined to directly target commonly dysregulated cell populations of the TME. Recent developments in immuno‐oncology and bioengineering have created an attractive potential to model these complexities at the level of the individual patient. These developments, along with the increasing momentum in precision medicine research and application, have catalysed exciting new discoveries in understanding drug–TME interactions, target identification, and improved efficacy of therapies. While rapid progress has been made, there are still many challenges to overcome in the development of accurate in vitro, in vivo and ex vivo models incorporating the cellular interactions that take place in the TME. In this review, we describe how advances in immuno‐oncology and patient‐derived models, such as patient‐derived organoids and explant cultures, have enhanced the landscape of personalised immunotherapy prediction and treatment of solid organ malignancies. We describe and compare different immunological targets and perspectives on two‐dimensional and three‐dimensional modelling approaches that may be used to better rationalise immunotherapy use, ultimately providing a knowledge base for the integration of the autologous TME into these predictive models.

MTOR regulates aerobic glycolysis through NEAT1 and nuclear paraspeckle-mediated mechanism in hepatocellular carcinoma.

Background: Hepatocellular Carcinoma (HCC) is a major form of liver cancer and a leading cause of cancer-related death worldwide. New insights into HCC pathobiology and mechanism of drug actions are urgently needed to improve patient outcomes. HCC undergoes metabolic reprogramming of glucose metabolism from respiration to aerobic glycolysis, a phenomenon known as the 'Warburg Effect' that supports rapid cancer cell growth, survival, and invasion. mTOR is known to promote Warburg Effect, but the underlying mechanism(s) remains poorly defined. The aim of this study is to understand the mechanism(s) and significance of mTOR regulation of aerobic glycolysis in HCC.Methods: We profiled mTORC1-dependent long non-coding RNAs (lncRNAs) by RNA-seq of HCC cells treated with rapamycin. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to explore the transcriptional regulation of NEAT1 by mTORC1. [U-13C]-glucose labeling and metabolomic analysis, extracellular acidification Rate (ECAR) by Seahorse XF Analyzer, and glucose uptake assay were used to investigate the role of mTOR-NEAT1-NONO signaling in the regulation of aerobic glycolysis. RNA immunoprecipitation (RIP) and NONO-binding motif scanning were performed to identify the regulatory mechanism of pre-mRNA splicing by mTOR-NEAT1. Myristoylated AKT1 (mAKT1)/NRASV12-driven HCC model developed by hydrodynamic transfection (HDT) was employed to explore the significance of mTOR-NEAT1 signaling in HCC tumorigenesis and mTOR-targeted therapy.Results: mTOR regulates lncRNA transcriptome in HCC and that NEAT1 is a major mTOR transcriptional target. Interestingly, although both NEAT1_1 and NEAT1_2 are down-regulated in HCC, only NEAT1_2 is significantly correlated with poor overall survival of HCC patients. NEAT1_2 is the organizer of nuclear paraspeckles that sequester the RNA-binding proteins NONO and SFPQ. We show that upon oncogenic activation, mTORC1 suppresses NEAT1_2 expression and paraspeckle biogenesis, liberating NONO/SFPQ, which in turn, binds to U5 within the spliceosome, stimulating mRNA splicing and expression of key glycolytic enzymes. This series of actions lead to enhanced glucose transport, aerobic glycolytic flux, lactate production, and HCC growth both in vitro and in vivo. Furthermore, the paraspeckle-mediated mechanism is important for the anticancer action of US FDA-approved drugs rapamycin/temsirolimus.Conclusions: These findings reveal a molecular mechanism by which mTOR promotes the 'Warburg Effect', which is important for the metabolism and development of HCC, and anticancer response of mTOR-targeted therapy.

Optimization of Expression and Purification of Recombinant Mouse plac1.

Background:Placenta-specific 1 (PLAC1) is one of the recently-discovered Cancer-Testis-Placenta (CTP) antigen with restricted normal tissue and ectopic expression in a wide range of cancer cells from different histological origins. The production of recombinant human PLAC1 has already been optimized; however, no study has been reported so far on the production and purification of mouse plac1. In this study, mouse plac1 expression and purification was optimized in a prokaryotic system and the effects of the generated proteins on inducing humoral responses in mice were investigated.Methods:A fusion protein containing full extracellular domain of mouse plac1, immunostimulatory peptides, tetanus toxin P2P30 and PADRE and KDEL3 signal (main plac1), and the same fragment without immunostimulatory peptides (control plac1) was produced. To optimize production and purification steps, different parameters including bacterial strain, cultivation temperature, cultivation time, IPTG concentration, culture medium, and also different buffers for purification of the recombinant proteins were tested. After confirming the identity of recombinant plac1 proteins with Western Blotting (WB) and ELISA assays, these proteins were subcutaneously injected in mice with Freund's adjuvant and the anti-plac1 antibody response was detected by ELISA.Results:The optimal expression level of main and control plac1 was obtained in BL21 (DE3) and TB culture medium in the presence of 0.25 mM IPTG after 24 hr of induction at 15°C. The buffer containing 2% sarkosyl produced higher yield and purity. Our results showed specific reactivity of anti-human recombinant plac1 polyclonal antibody with both main and control plac1 recombinant proteins in WB and ELISA analysis. Both proteins induced humoral responses in mice; however, anti-plac1 antibody titer was significantly higher in sera of mice immunized with main compared to control plac1.Conclusion:In this study, an optimized protocol for production and purification of mouse plac1 was reported and it was shown that insertion of immunostimulatory peptides in gene construct could efficiently enhance humoral immune responses against mouse plac1, which could potentially augment cellular immune responses against plac1 leading to more effective anti-cancer responses.

Establishment of Patient-derived Preclinical Models for Invasive Papillary Cholangiocarcinoma.

Invasive papillary cholangio-carcinoma (IPC) is a minor subtype of extrahepatic cholangiocarcinoma. However, its etiology and characteristics remain unknown because of the unavailability of in vitro and in vivo models. We aimed to establish a novel preclinical model for translational research of IPC. A patient-derived xenograft (PDX) was engrafted in NOG mice and the cell line National Cancer Center human IPC (NCChIPC) was subsequently established from the PDX tumors. Immunohistochemistry and RNA-sequencing were used to determine the retention of original characteristics of patient tissues. PDX tumors showed successful amplification, and the NCChIPC-derived xenograft largely retained the histopathological features of the original tumor with CK19, MUC1 and MUC5AC expression. Transcriptome analysis showed a high correlation between patient and preclinical models. Additionally, anticancer drugs response was analyzed in the NCChIPC PDX. These novel preclinical models here will help elucidate IPC etiology and facilitate translational research.

Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E.

Selinexor is an FDA approved selective inhibitor of the nuclear export protein exportin-1 (XPO1) and causes specific cancer cell death via nuclear accumulation of tumor suppressor proteins. Design of rational studies for the use of selinexor in combination with other therapeutic agents, such as immunotherapies, requires a fundamental understanding of the effects of selinexor on the immune system. One important emerging area of immunotherapy are natural killer (NK) cell based therapeutics. NK cell function is tightly regulated by a balance of signals derived from multiple activating and inhibitory receptors. Thus in cancer, up-regulation of stress ligands recognised by activating receptors or down-regulation of HLA class I recognised by inhibitory receptors can result in an anti-cancer NK cell response. Changes in XPO1 function therefore have the potential to affect NK cell function through shifting this balance. We therefore sought to investigate how selinexor may affect NK cell function. Selinexor pre-treatment of lymphoma cells significantly increased NK cell mediated cytotoxicity against SU-DHL-4, JeKo-1 and Ramos cells, concurrent with increased CD107a and IFNγ expression on NK cells. In addition, selinexor enhanced ADCC against lymphoma cells coated with the anti-CD20 antibodies rituximab and obinutuzumab. In probing the likely mechanism, we identified that XPO1 inhibition significantly reduced the surface expression of HLA-E on lymphoma cell lines and on primary chronic lymphocytic leukemia cells. HLA-E binds the inhibitory receptor NKG2A and in accordance with this, selinexor selectively increased activation of NKG2A+ NK cells. Our data reveals that selinexor, in addition to its direct cytotoxic activity, also activates an anti-cancer immune response via disruption of the inhibitory NKG2A:HLA-E axis.

Vitamin D Modulation of Mitochondrial Oxidative Metabolism and mTOR Enforces Stress Adaptations and Anticancer Responses.

ABSTRACTThe relationship between the active form of vitamin D3 (1,25‐dihydroxyvitamin D, 1,25(OH)2D) and reactive oxygen species (ROS), two integral signaling molecules of the cell, is poorly understood. This is striking, given that both factors are involved in cancer cell regulation and metabolism. Mitochondria (mt) dysfunction is one of the main drivers of cancer, producing more mitochondria, higher cellular energy, and ROS that can enhance oxidative stress and stress tolerance responses. To study the effects of 1,25(OH)2D on metabolic and mt dysfunction, we used the vitamin D receptor (VDR)‐sensitive MG‐63 osteosarcoma cell model. Using biochemical approaches, 1,25(OH)2D decreased mt ROS levels, membrane potential (ΔΨmt), biogenesis, and translation, while enforcing endoplasmic reticulum/mitohormetic stress adaptive responses. Using a mitochondria‐focused transcriptomic approach, gene set enrichment and pathway analyses show that 1,25(OH)2D lowered mt fusion/fission and oxidative phosphorylation (OXPHOS). By contrast, mitophagy, ROS defense, and epigenetic gene regulation were enhanced after 1,25(OH)2D treatment, as well as key metabolic enzymes that regulate fluxes of substrates for cellular architecture and a shift toward non‐oxidative energy metabolism. ATACseq revealed putative oxi‐sensitive and tumor‐suppressing transcription factors that may regulate important mt functional genes such as the mTORC1 inhibitor, DDIT4/REDD1. DDIT4/REDD1 was predominantly localized to the outer mt membrane in untreated MG‐63 cells yet sequestered in the cytoplasm after 1,25(OH)2D and rotenone treatments, suggesting a level of control by membrane depolarization to facilitate its cytoplasmic mTORC1 inhibitory function. The results show that 1,25(OH)2D activates distinct adaptive metabolic responses involving mitochondria to regain redox balance and control the growth of osteosarcoma cells. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Abstract P105: Targeting VSIG4, a novel macrophage checkpoint, repolarizes suppressive macrophages which induces an inflammatory response in primary cell in vitro assays and fresh human tumor cultures

Abstract VSIG4 (V-set immunoglobulin-domain-containing 4) is a B7 family related protein with known roles as a complement receptor involved in pathogen clearance, via interactions with C3 fragments, as well as a negative regulator of T cell activation by an undetermined mechanism. VSIG4 is expressed in tumor associated macrophages with exquisite specificity. In cancer, increased expression of VSIG4 has been associated with worse survival in multiple indications, including non-small cell lung cancer, multiple myeloma, ovarian cancer, stomach cancer and glioma, suggesting an important role in tumor immune evasion. Based upon computational analysis of transcript data across thousands of primary cancer and normal tissue samples, we hypothesized that VSIG4 has an important regulatory role in promoting M2-like immune suppressive macrophages in the tumor microenvironment, and that targeting VSIG4 via a monoclonal antibody could relieve VSIG4-mediated macrophage suppression by repolarizing tumor associated macrophages (TAMs) to an inflammatory phenotype capable of coordinating an anti-tumor immune response. Through a series of in vitro and ex vivo assays we demonstrate that anti-VSIG4 antibodies repolarize M2 macrophages and induce an immune response culminating in T cell activation. Anti-VSIG4 antibodies upregulate pro-inflammatory cytokines in M-CSF plus IL-10 driven monocyte-derived M2c macrophages, as well as in TAM-like macrophages in vitro derived from monocytes cultured in the presence of ascites fluid from ovarian cancer patients. To determine whether anti-VSIG4-induced macrophage repolarization can activate T cells, monocyte-derived M2c macrophages were co-cultured with autologous T cells in the presence of staphylococcal enterotoxin B (SEB) activation and anti-VSIG4 antibodies. Here, anti-VSIG4 antibodies upregulate both pro-inflammatory myeloid-derived cytokines (GM-CSF) and T cell-derived cytokines (IFNγ). To extend these observations to a relevant translational model, we treated fresh, patient-derived tumor samples with anti-VSIG4 antibodies and relevant controls ex vivo. Across numerous patient-derived samples, which included multiple tumor types, anti-VSIG4 treatment resulted in a significant upregulation of cytokines involved in TAM repolarization and T cell activation, and chemokines involved in immune cell recruitment, at levels greater than observed by treatment with anti-PD-1 or a clinical macrophage repolarizing agent (anti-ILT-4). Taken together, these data suggest that VSIG4 represents a promising new target capable of stimulating an anti-cancer response via multiple key immune mechanisms. Citation Format: Steve Sazinsky, Ani Nguyen, Mohammad Zafari, Ryan Phennicie, Joe Wahle, Veronica Komoroski, Kathryn Rooney, Craig Mizzoni, Boris Klebanov, Jessica Ritter, Denise Manfra, Igor Feldman, Tatiana Novobrantseva. Targeting VSIG4, a novel macrophage checkpoint, repolarizes suppressive macrophages which induces an inflammatory response in primary cell in vitro assays and fresh human tumor cultures [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P105.

Tunicate‐Inspired Photoactivatable Proteinic Nanobombs for Tumor‐Adhesive Multimodal Therapy (Adv. Healthcare Mater. 23/2021)

NIR-Responsive Nanotherapeutics In article number 2101212, Hyung Joon Cha and co-workers develop NIR-activatable tumoradhesive proteinic nanoparticles by using tunicate-inspired bioinorganic chemistry to realize effective photothermal activity with high bioavailability and achieve multimodal tumor-specific therapy. The vanadium ion-doped adhesive nanoparticles exhibit a remarkable photothermal capability, on-demand NO gas, and anticancer drug release in a “bomb-like” manner, and robust retention of multiple therapeutics within tumors, thereby leading to excellent anticancer responses.

Au naturale: use of biologically derived cyclic di-nucleotides for cancer immunotherapy.

Cyclic di-nucleotides (CDNs) are widespread second messenger signalling molecules that regulate fundamental biological processes across the tree of life. These molecules are also potent modulators of the immune system, inducing a Type I interferon response upon binding to the eukaryotic receptor STING. Such a response in tumours induces potent immune anti-cancer responses and thus CDNs are being developed as a novel cancer immunotherapy. In this review, I will highlight the use, challenges and advantages of using naturally occurring CDNs to treat cancer.

Methods for modeling tumor growth in mice in experimental studies of human gastric cancer

Gastric cancer (GC) is a group of malignant tumors originating from the gastric mucosa cells. The highest incidence of GC is recorded in Japan, China and Russia, and the lowest one in the USA and New Zealand. Extensive molecular genetic research of GC has revealed its heterogeneity associated with the genomic instability of the tumor and the complexity of its phenotype due to simultaneous changes in several oncogenes and suppressors. This was the basis for the creation of the GC classification by molecular subtypes. The creation of a realistic preclinical model is essential for translational GC studies. Cancer cell lines and xenografts derived from them are among the most common preclinical models. They are easy to generate, but they also have limitations, since these models cannot sufficiently reproduce the unique characteristics of each cancer patient. Patient-derived xenografts (PDX) are currently the best model for testing targets and predictors of response to therapy. PDX models are created by transplanting surgically resected human tumors into immunodeficient mice. These models maintain morphological similarity and replicate the molecular characteristics of parental tumors providing an indispensable tool for assessing anticancer drug response. Statistical data from preclinical studies with PDX models can significantly save the time and resources required for clinical trials. Transgenic and knockout mouse models are also widely used in scientific laboratories in order to study specific genetic pathways of oncogenesis and develop experimental therapy for GC. This review discusses the molecular classifications of GC and experimental murine models that reproduce cancer in situ and are a universal platform for preclinical research in experimental oncology.

Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy

Cytotoxic chemotherapeutics primarily function through DNA damage-induced tumor cell apoptosis, although the inflammation provoked by these agents can stimulate anti-cancer immune responses. The mechanisms that control these distinct effects and limit immunogenic responses to DNA-damage mediated cell death in vivo are currently unclear. Using a mouse model of BCR-ABL+ B-cell acute lymphoblastic leukemia, we show that chemotherapy-induced anti-cancer immunity is suppressed by the tumor microenvironment through production of the cytokine IL-6. The chemotherapeutic doxorubicin is curative in IL-6-deficient mice through the induction of CD8+ T-cell-mediated anti-cancer responses, while moderately extending lifespan in wild type tumor-bearing mice. We also show that IL-6 suppresses the effectiveness of immune-checkpoint inhibition with anti-PD-L1 blockade. Our results suggest that IL-6 is a key regulator of anti-cancer immune responses induced by genotoxic stress and that its inhibition can switch cancer cell clearance from primarily apoptotic to immunogenic, promoting and maintaining durable anti-tumor immune responses.

Targeting cellular senescence in cancer by plant secondary metabolites: A systematic review

Senescence suppresses tumor growth, while also developing a tumorigenic state in the nearby cells that is mediated by senescence-associated secretory phenotypes (SASPs). The dual function of cellular senescence stresses the need for identifying multi-targeted agents directed towards the promotion of cell senescence in cancer cells and suppression of the secretion of pro-tumorigenic signaling mediators in neighboring cells. Natural secondary metabolites have shown favorable anticancer responses in recent decades, as some have been found to target the senescence-associated mediators and pathways. Furthermore, phenolic compounds and polyphenols, terpenes and terpenoids, alkaloids, and sulfur-containing compounds have shown to be promising anticancer agents through the regulation of paracrine and autocrine pathways. Plant secondary metabolites are potential regulators of SASPs factors that suppress tumor growth through paracrine mediators, including growth factors, cytokines, extracellular matrix components/enzymes, and proteases. On the other hand, ataxia-telangiectasia mutated, ataxia-telangiectasia and Rad3-related, extracellular signal-regulated kinase/mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, nuclear factor-κB, Janus kinase/signal transducer and activator of transcription, and receptor tyrosine kinase-associated mediators are main targets of candidate phytochemicals in the autocrine senescence pathway. Such a regulatory role of phytochemicals on senescence-associated pathways is associated with cell cycle arrest and the attenuation of apoptotic/inflammatory/oxidative stress pathways. The current systematic review highlights the critical roles of natural secondary metabolites in the attenuation of autocrine and paracrine cellular senescence pathways, while also elucidating the chemopreventive and chemotherapeutic capabilities of these compounds. Additionally, we discuss current challenges, limitations, and future research indications.

Assessment of green and chemically synthesized copper oxide nanoparticles against hepatocellular carcinoma

Copper oxide nanoparticle (CuO-NPs) attracts the attentions of human beings due to unique physicochemical and biological properties. The chemical and green synthesis approaches were used to synthesis of CuO-NPs and plant leaves extract Azadirachta indica (A. indica) was preferred in green synthesis approach. The XRD analysis was used to analyze the monoclinic crystal structure and calculate the average crystallite size in the range of 15 ∼ 16 nm. While, the information about different rotational and vibrational modes attached on the spectrum of CuO-NPs was identified by FTIR. After that the UV–VIS analysis provided the information about the absorbance spectrums in the range of 235 and 220 nm. The MTT assay was perfomed to investigate liver carcinoma (HepG2 cells) interaction and absorbance of CuO-NPs towards mentioned cell lines were recorded and loss in HepG2 cells viability. In an overall assessment, anticancer response of comparative study of CuO-NPs towards liver carcinoma treatment contributes significantly after successful demonstration of essential steps of suggested experimental study. Finally, comparative study of experimental and mathematical modeling of anticancer activity towards normal and liver cancer cell lines were conducted and investigated.

Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment.

Similar to Janus, the two-faced god of Roman mythology, the tumor microenvironment operates two opposing and often conflicting activities, on the one hand fighting against tumor cells, while on the other hand, favoring their proliferation, survival and migration to other sites to establish metastases. In the tumor microenvironment, cytotoxic T cells—the specialized tumor-cell killers—also show this dual nature, operating their tumor-cell directed killing activities until they become exhausted and dysfunctional, a process promoted by cancer cells themselves. Here, we discuss the opposing activities of immune cells populating the tumor microenvironment in both cancer progression and anti-cancer responses, with a focus on cytotoxic T cells and on the molecular mechanisms responsible for the efficient suppression of their killing activities as a paradigm of the power of cancer cells to shape the microenvironment for their own survival and expansion.