Frontiers in molecular medicine最新文献

{"title":"MCM10 expression is linked to cervical cancer aggressiveness.","authors":"Sumayyah M Q Ahmed, Suparna Laha, Ranajit Das, Mariam Anjum Ifthikar, Shankar Prasad Das","doi":"10.3389/fmmed.2023.1009903","DOIUrl":"10.3389/fmmed.2023.1009903","url":null,"abstract":"<p><p>Cervical cancer screening is a challenge mainly in developing countries. In developed countries, both incidence and mortality rates have been decreasing due to well organized screening programs. One of the potential biomarkers being exploited are the minichromosome maintenance proteins (MCMs), which show both specificity and sensitivity. MCM2-7 are involved in DNA replication initiation and elongation, and the MCM subunits are highly expressed in malignant tissues. Unlike other MCMs, MCM10, which is not part of the core helicase complex, is a critical determinant of origin activation and its levels are limiting in cancer cells. In this study, we performed bioinformatic analysis on the expression profile of all DNA replication associated MCM proteins in cervical cancer. MCM10 showed a relatively higher expression profile compared to the other MCMs. The mRNA expression levels of the MCMs were significantly increased in tumour tissues compared to normal, and MCM10 showed a fold change of 3.4. In order to understand if MCM10 is associated with the aggressiveness of cervical cancer, we looked into the mRNA expression pattern of MCM10 in three cervical cancer cell lines and one normal cervical cell line. MCM10 expression was significantly higher in the case of the more aggressive cancer cell line HeLa compared to controls. MCM10, therefore, can serve as a prominent biomarker for cancer progression and thus aid in early detection to control the spread of cancer cells. Our results show that MCM10 expression levels in cervical cancer cell lines are associated with cancer aggressiveness, demonstrating its clinical significance.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1009903"},"PeriodicalIF":0.0,"publicationDate":"2023-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49207663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer immunotherapies: A hope for the uncurable?","authors":"Firas Hamdan, Vincenzo Cerullo","doi":"10.3389/fmmed.2023.1140977","DOIUrl":"10.3389/fmmed.2023.1140977","url":null,"abstract":"<p><p>The use of cancer immunotherapies is not novel but has been used over the decades in the clinic. Only recently have we found the true potential of stimulating an anti-tumor response after the breakthrough of checkpoint inhibitors. Cancer immunotherapies have become the first line treatment for many malignancies at various stages. Nevertheless, the clinical results in terms of overall survival and progression free survival were not as anticipated. Majority of cancer patients do not respond to immunotherapies and the reasons differ. Hence, further improvements for cancer immunotherapies are crucially needed. In the review, we will discuss various forms of cancer immunotherapies that are being tested or already in the clinic. Moreover, we also highlight future directions to improve such therapies.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1140977"},"PeriodicalIF":0.0,"publicationDate":"2023-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46905787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Fault in Our Astrocytes - cause or casualties of proteinopathies of ALS/FTD and other neurodegenerative diseases?","authors":"Lynette M Bustos, Rita Sattler","doi":"10.3389/fmmed.2023.1075805","DOIUrl":"10.3389/fmmed.2023.1075805","url":null,"abstract":"<p><p>Many neurodegenerative diseases fall under the class of diseases known as proteinopathies, whereby the structure and localization of specific proteins become abnormal. These aberrant proteins often aggregate within cells which disrupts vital homeostatic and physiological cellular functions, ultimately contributing to cell death. Although neurodegenerative disease research is typically neurocentric, there is evidence supporting the role of non-neuronal cells in the pathogenesis of these diseases. Specifically, the role of astrocytes in neurodegenerative diseases has been an ever-growing area of research. Astrocytes are one of the most abundant cell types in the central nervous system (CNS) and provide an array of essential homeostatic functions that are disrupted in neurodegenerative diseases. Astrocytes can exhibit a reactive phenotype that is characterized by molecular changes, as well as changes in morphology and function. In neurodegenerative diseases, there is potential for reactive astrocytes to assume a loss-of-function phenotype in homeostatic operations such as synapse maintenance, neuronal metabolic support, and facilitating cell-cell communication between glia and neurons. They are also able to concurrently exhibit gain-of-function phenotypes that can be destructive to neural networks and the astrocytes themselves. Additionally, astrocytes have been shown to internalize disease related proteins and reflect similar or exacerbated pathology that has been observed in neurons. Here, we review several major neurodegenerative disease-specific proteinopathies and what is known about their presence in astrocytes and the potential consequences regarding cell and non-cell autonomous neurodegeneration.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1075805"},"PeriodicalIF":0.0,"publicationDate":"2023-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11334001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48074426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Definition of a microbial signature as a predictor of endoscopic post-surgical recurrence in patients with Crohn's disease.","authors":"Lia Oliver, Blau Camps, David Julià-Bergkvist, Joan Amoedo, Sara Ramió-Pujol, Marta Malagón, Anna Bahí, Paola Torres, Eugeni Domènech, Jordi Guardiola, Mariona Serra-Pagès, Jesus Garcia-Gil, Xavier Aldeguer","doi":"10.3389/fmmed.2023.1046414","DOIUrl":"10.3389/fmmed.2023.1046414","url":null,"abstract":"<p><p><b>Background and aims:</b> Although there are several effective drugs for the treatment of Crohn's disease (CD), almost 70% of patients will require surgical resection during their lifetime. This procedure is not always curative, as endoscopic recurrence occurs in 65%-90% of patients in the first year after surgery. The aetiology of the recurrence is unknown; however, several studies have shown how the resident microbiota is modified after surgery. The aim of this study was to evaluate samples from patients with Crohn's disease before and after an intestinal resection to determine whether there were differences in the abundance of different microbial markers, which may predict endoscopic recurrence at baseline. <b>Methods:</b> In this observational study, a stool sample was obtained from 25 patients with Crohn's disease before undergoing surgery, recruited at three Catalan hospitals. From each sample, DNA was purified and the relative abundance of nine microbial markers was quantified using qPCR. <b>Results:</b> An algorithm composed of four microbial markers (<i>E. coli</i>, <i>F. prausnitzii phylogroup I</i>, <i>Bacteroidetes</i>, and <i>Eubacteria</i>) showed a sensitivity and specificity of 90.91% and 85.71%, respectively, and a positive and negative predictive value of 83.33% and 92.31%, respectively. <b>Conclusion:</b> A microbial signature to determine patients who will have post-surgical recurrence was identified. This tool might be very useful in daily clinical practice, allowing the scheduling of personalized therapy and enabling preventive treatment only in patients who really require it.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1046414"},"PeriodicalIF":0.0,"publicationDate":"2023-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45296581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Why should we care about astrocytes in a motor neuron disease?","authors":"Katarina Stoklund Dittlau, Ludo Van Den Bosch","doi":"10.3389/fmmed.2023.1047540","DOIUrl":"10.3389/fmmed.2023.1047540","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults, causing progressive degeneration of motor neurons, which results in muscle atrophy, respiratory failure and ultimately death of the patients. The pathogenesis of ALS is complex, and extensive efforts have focused on unravelling the underlying molecular mechanisms with a large emphasis on the dying motor neurons. However, a recent shift in focus towards the supporting glial population has revealed a large contribution and influence in ALS, which stresses the need to explore this area in more detail. Especially studies into astrocytes, the residential homeostatic supporter cells of neurons, have revealed a remarkable astrocytic dysfunction in ALS, and therefore could present a target for new and promising therapeutic entry points. In this review, we provide an overview of general astrocyte function and summarize the current literature on the role of astrocytes in ALS by categorizing the potentially underlying molecular mechanisms. We discuss the current efforts in astrocyte-targeted therapy, and highlight the potential and shortcomings of available models.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1047540"},"PeriodicalIF":0.0,"publicationDate":"2023-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45659543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole patient knowledge modeling of COVID-19 symptomatology reveals common molecular mechanisms.","authors":"Stephan Brock, David B Jackson, Theodoros G Soldatos, Klaus Hornischer, Anne Schäfer, Francesca Diella, Maximilian Y Emmert, Simon P Hoerstrup","doi":"10.3389/fmmed.2022.1035290","DOIUrl":"10.3389/fmmed.2022.1035290","url":null,"abstract":"<p><p>Infection with SARS-CoV-2 coronavirus causes systemic, multi-faceted COVID-19 disease. However, knowledge connecting its intricate clinical manifestations with molecular mechanisms remains fragmented. Deciphering the molecular basis of COVID-19 at the whole-patient level is paramount to the development of effective therapeutic approaches. With this goal in mind, we followed an iterative, expert-driven process to compile data published prior to and during the early stages of the pandemic into a comprehensive COVID-19 knowledge model. Recent updates to this model have also validated multiple earlier predictions, suggesting the importance of such knowledge frameworks in hypothesis generation and testing. Overall, our findings suggest that SARS-CoV-2 perturbs several specific mechanisms, unleashing a pathogenesis spectrum, ranging from \"a perfect storm\" triggered by acute hyper-inflammation, to accelerated aging in protracted \"long COVID-19\" syndromes. In this work, we shortly report on these findings that we share with the community <i>via</i> 1) a synopsis of key evidence associating COVID-19 symptoms and plausible mechanisms, with details presented within 2) the accompanying \"COVID-19 Explorer\" webserver, developed specifically for this purpose (found at https://covid19.molecularhealth.com). We anticipate that our model will continue to facilitate clinico-molecular insights across organ systems together with hypothesis generation for the testing of potential repurposing drug candidates, new pharmacological targets and clinically relevant biomarkers. Our work suggests that whole patient knowledge models of human disease can potentially expedite the development of new therapeutic strategies and support evidence-driven clinical hypothesis generation and decision making.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"2 1","pages":"1035290"},"PeriodicalIF":0.0,"publicationDate":"2023-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46545767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel therapeutic for multiple sclerosis protects white matter function in EAE mouse model.","authors":"Sarah Zerimech, Hung Nguyen, Arthur A Vandenbark, Halina Offner, Selva Baltan","doi":"10.3389/fmmed.2023.1237078","DOIUrl":"10.3389/fmmed.2023.1237078","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a chronic demyelinating disease with prominent axon dysfunction. Our previous studies in an MS mouse model, experimental autoimmune encephalomyelitis (EAE), demonstrated that major histocompatibility complex Class II constructs can reverse clinical signs of EAE. These constructs block binding and downstream signaling of macrophage migration inhibitory factors (MIF-1/2) through CD74, thereby inhibiting phosphorylation of extracellular signal-regulated kinase (ERK) activation and tissue inflammation and promoting remyelination. To directly assess the effects of a novel third generation construct, DRhQ, on axon integrity in EAE, we compared axon conduction properties using electrophysiology on corpus callosum slices and optic nerves. By using two distinct white matter (WM) tracts, we aimed to assess the impact of the EAE and the benefit of DRhQ on myelinated and unmyelinated axons as well as to test the clinical value of DRhQ on demyelinating lesions in CC and optic myelitis. Our study found that EAE altered axon excitability, delayed axon conduction and slowed spatiotemporal summation correlated with diffuse astrocyte and microglia activation. Because MS predisposes patients to stroke, we also investigated and showed that vulnerability to WM ischemia is increased in the EAE MS mouse model. Treatment with DRhQ after the onset of EAE drastically inhibited microglial and astrocyte activation, improved functional integrity of the myelinated axons and enhanced recovery after ischemia. These results demonstrate that DRhQ administered after the onset of EAE promotes WM integrity and function, and reduces subsequent vulnerability to ischemic injury, suggesting important therapeutic potential for treatment of progressive MS.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10627517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47489942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The COVID-19 explorer-An integrated, whole patient knowledge model of COVID-19 disease.","authors":"Stephan Brock, Theodoros G Soldatos, David B Jackson, Francesca Diella, Klaus Hornischer, Anne Schäfer, Simon P Hoerstrup, Maximilian Y Emmert","doi":"10.3389/fmmed.2022.1035215","DOIUrl":"10.3389/fmmed.2022.1035215","url":null,"abstract":"<p><p>Since early 2020 the COVID-19 pandemic has paralyzed the world, resulting in more than half a billion infections and over 6 million deaths within a 28-month period. Knowledge about the disease remains largely disjointed, especially when considering the molecular mechanisms driving the diversity of clinical manifestations and symptoms. Despite the recent availability of vaccines, there remains an urgent need to develop effective treatments for cases of severe disease, especially in the face of novel virus variants. The complexity of the situation is exacerbated by the emergence of COVID-19 as a complex and multifaceted systemic disease affecting independent tissues and organs throughout the body. The development of effective treatment strategies is therefore predicated on an integrated understanding of the underlying disease mechanisms and their potentially causative link to the diversity of observed clinical phenotypes. To address this need, we utilized a computational technology (the Dataome platform) to build an integrated clinico-molecular view on the most important COVID-19 clinical phenotypes. Our results provide the first integrated, whole-patient model of COVID-19 symptomatology that connects the molecular lifecycle of SARS-CoV-2 with microvesicle-mediated intercellular communication and the contact activation and kallikrein-kinin systems. The model not only explains the clinical pleiotropy of COVID-19, but also provides an evidence-driven framework for drug development/repurposing and the identification of critical risk factors. The associated knowledge is provided in the form of the open source COVID-19 Explorer (https://covid19.molecularhealth.com), enabling the global community to explore and analyze the key molecular features of systemic COVID-19 and associated implications for research priorities and therapeutic strategies. Our work suggests that knowledge modeling solutions may offer important utility in expediting the global response to future health emergencies.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1035215"},"PeriodicalIF":0.0,"publicationDate":"2022-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43578020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three year results of Blessed: Expanded access for DeltaRex-G for an intermediate size population with advanced pancreatic cancer and sarcoma (NCT04091295) and individual patient use of DeltaRex-G for solid malignancies (IND# 19130).","authors":"Sant P Chawla, Steven Wong, Doris Quon, Ania Moradkhani, Victoria S Chua, Don A Brigham, Rebecca A Reed, William Swaney, Frederick L Hall, Erlinda M Gordon","doi":"10.3389/fmmed.2022.1092286","DOIUrl":"10.3389/fmmed.2022.1092286","url":null,"abstract":"<p><p><b>Background:</b> Innovative treatments are urgently needed for metastatic cancer. DeltaRex-G, a tumor-targeted retrovector encoding a dominant-negative/cytocidal cyclin G1 (CCNG1 gene) inhibitor construct-has been tested in over 280 cancer patients worldwide in phase 1, phase 2 studies and compassionate use studies, demonstrating long term (>10 years) survivorship in patients with advanced cancers, including pancreatic cancer, osteosarcoma, malignant peripheral nerve sheath tumor, breast cancer, and B-cell lymphoma. <b>Patient and Methods:</b> Endpoints: Survival, response, treatment-related adverse events. Study one is entitled \"Blessed: Expanded Access for DeltaRex-G for Advanced Pancreatic Cancer and Sarcoma (NCT04091295)\". Study two is entitled \"Individual Patient Use of DeltaRex-G for Solid Malignancies (Investigational New Drug#19130). In both studies, patients will receive DeltaRex-G at 1-3 x 10e11 cfu i.v. over 30-45 min, three x a week until significant disease progression or unacceptable toxicity or death occurs. <b>Results:</b> Seventeen patients were enrolled, nine sarcoma, two pancreatic adenocarcinoma, one non-small cell lung cancer, two breast carcinoma, one prostate cancer, one cholangiocarcinoma and one basal cell carcinoma and actinic keratosis. Three patients were enrolled in Study 1 and 14 patients were enrolled in Study 2. Twelve of 17 enrolled patients were treated with DeltaRex-G monotherapy or in combination with United States Food and Drug Administration-approved cancer therapies. Five patients died before receiving DeltaRex-G. Efficacy Analysis: Of the 12 treated patients, 5 (42%) are alive 15-36 months from DeltaRex-G treatment initiation. Two patients with early-stage HR + HER2+ positive or triple receptor negative invasive breast cancer who received DeltaRex-G as adjuvant/first line therapy are alive in complete remission 23 and 16 months after DeltaRex-G treatment initiation respectively; three patients with metastatic chordoma, chondrosarcoma and advanced basal cell carcinoma are alive 36, 31, and 15 months after DeltaRex-G treatment initiation respectively. Safety Analysis: There were no treatment-related adverse events reported. <b>Conclusion:</b> Taken together, the data suggest that 1) DeltaRex-G may evoke tumor growth stabilization after failing standard chemotherapy, 2) DeltaRex-G may act synergistically with standard chemotherapy/targeted therapies, and 3) Adjuvant/first line therapy with DeltaRex-G for early-stage invasive carcinoma of breast may be authorized by the USFDA when patients refuse to receive toxic chemotherapy.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1092286"},"PeriodicalIF":0.0,"publicationDate":"2022-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44751046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel modular chimeric antigen receptor spacer for T cells derived from signal regulatory protein alpha Ig-like domains.","authors":"Jan Koski, Farhana Jahan, Annu Luostarinen, Diana Schenkwein, Seppo Ylä-Herttuala, Helka Göös, Hector Monzo, Päivi M Ojala, Pilvi Maliniemi, Matti Korhonen","doi":"10.3389/fmmed.2022.1049580","DOIUrl":"10.3389/fmmed.2022.1049580","url":null,"abstract":"<p><p><b>Background:</b> T cells equipped with chimeric antigen receptors (CAR) have shown remarkable efficacy in targeting B lineage malignancies. Improvement of the CAR structure is needed, however, with a view to developing flexibly modifiable spacers that are inert in interactions with unwanted cells. Specifically, binding to cells carrying receptors for IgG's crystallizable fragment (FcR), that recognize IgG-derived domains in CARs is to be avoided. <b>Methods:</b> Two novel CARs targeting the CD19 antigen where the IgG1-CH2 and -CH3 domains were replaced with Ig-like domains from signal-regulatory protein α (SIRPα) were designed <i>in silico</i>. An IgG1-based CAR and a CAR lacking both SIRPα and IgG1 domains were used as comparators. The phenotype and memory phenotype of the expanded cells were analyzed by flow cytometry, and CAR T cell activation and cytotoxic efficacy were assessed in co-culture experiments in response to CD19⁺ target cells. Unwanted interactions with FcR-expressing myeloid cells were interrogated in co-culture assays with THP-1 monocytic cells. <b>Results:</b> T cells carrying the novel SIRPα-based CARs enacted potent <i>in vitro</i> cytotoxicity against CD19 positive B-lineage leukemia cells, comparable to traditional IgG1-based CAR T cells. Co-culture of IgG1-based CAR T cells with FcR-expressing THP-1 monocytic cells led to prominent cell surface expression of CD69 on T cells together with production of Interleukin (IL)-2 and Interferon-γ, and production of IL-1β, indicating activation of the T cells and monocytes, respectively. Longer co-culture led to killing of the monocytes. No signs of T cell nor monocyte activation were detected in co-cultures of SIRPα-based CAR T cells with THP-1 cells. Arming T cells with the SIRPα-based CARs favored differentiation towards CD4⁺ phenotype during expansion, while the effects on memory phenotype of the T cells were equivalent between the SIRPα- and IgG1-based CARs. In a pilot experiment, T cells modified with one of the SIRPα-based CARs showed dose dependent leukemia cell control. <b>Conclusion:</b> The novel SIRPα based spacers offer a suitable backbone for developing chimeric antigen receptors that evade the off-target binding to FcR while the cells retain a favorable memory phenotype and efficient cytotoxicity, establishing a promising candidate for future <i>in vivo</i> and clinical testing.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1049580"},"PeriodicalIF":0.0,"publicationDate":"2022-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41938783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}