tbuckley/cabot-search huggingface dataset:
B cells and the coordination of immune checkpoint inhibitor response in patients with solid tumors
Authors: Ronan Flippot, Marcus Teixeira, Macarena Rey-Cardenas, Lucia Carril-Ajuria, Larissa Rainho, Natacha Naoun, Jean-Mehdi Jouniaux, Lisa Boselli, Marie Naigeon, Francois-Xavier Danlos, Bernard Escudier, Jean-Yves Scoazec, Lydie Cassard, Laurence Albiges, Nathalie Chaput
Journal: Journal for ImmunoTherapy of Cancer (2024)

Immunotherapy profoundly changed the landscape of cancer therapy by providing long-lasting responses in subsets of patients and is now the standard of care in several solid tumor types. However, immunotherapy activity beyond conventional immune checkpoint inhibition is plateauing, and biomarkers are overall lacking to guide treatment selection. Most studies have focused on T cell engagement and response, but there is a growing evidence that B cells may be key players in the establishment of an organized immune response, notably through tertiary lymphoid structures. Mechanisms of B cell response include antibody-dependent cellular cytotoxicity and phagocytosis, promotion of CD4+ and CD8+ T cell activation, maintenance of antitumor immune memory. In several solid tumor types, higher levels of B cells, specific B cell subpopulations, or the presence of tertiary lymphoid structures have been associated with improved outcomes on immune checkpoint inhibitors. The fate of B cell subpopulations may be widely influenced by the cytokine milieu, with versatile roles for B-specific cytokines B cell activating factor and B cell attracting chemokine-1/CXCL13, and a master regulatory role for IL-10. Roles of B cell-specific immune checkpoints such as TIM-1 are emerging and could represent potential therapeutic targets. Overall, the expanding field of B cells in solid tumors of holds promise for the improvement of current immunotherapy strategies and patient selection.
Combinational therapy of CAR T-cell and HDT/ASCT demonstrates impressive clinical efficacy and improved CAR T-cell behavior in relapsed/refractory large B-cell lymphoma
Authors: Wei Liu, Wei Liu, Hesong Zou, Lianting Chen, Wenyang Huang, Rui Lv, Yan Xu, Huimin Liu, Yin Shi, Kefei Wang, Yi Wang, Wenjie Xiong, Shuhui Deng, Shuhua Yi, Weiwei Sui, Guangxin Peng, Yueshen Ma, Huijun Wang, Lulu Lv, Jianxiang Wang, Jun Wei, Lugui Qiu, Wenting Zheng, Dehui Zou
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Approximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to poor outcomes. Previous studies have suggested that intensified lymphodepletion and hematological stem cell infusion can promote adoptively transferred T-cell expansion, enhancing antitumor effects. Therefore, we conducted a phase I/II clinical trial in which CNCT19 (an anti-CD19 CAR T-cell) was administered after myeloablative high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT) in patients with R/R LBCL. Methods Transplant-eligible patients with LBCL who were refractory to first-line immunochemotherapy or experiencing R/R status after salvage chemotherapy were enrolled. The study aimed to evaluate the safety and efficacy of this combinational therapy. Additionally, frozen peripheral blood mononuclear cell samples from this trial and CNCT19 monotherapy studies for R/R LBCL were used to evaluate the impact of the combination therapy on the in vivo behavior of CNCT19 cells. Results A total of 25 patients with R/R LBCL were enrolled in this study. The overall response and complete response rates were 92.0% and 72.0%, respectively. The 2-year progression-free survival rate was 62.3%, and the overall survival was 68.5% after a median follow-up of 27.0 months. No unexpected toxicities were observed. All cases of cytokine release syndrome were of low grade. Two cases (8%) experienced grade 3 or higher CAR T-cell-related encephalopathy syndrome. The comparison of CNCT19 in vivo behavior showed that patients in the combinational therapy group exhibited enhanced in vivo expansion of CNCT19 cells and reduced long-term exhaustion formation, as opposed to those receiving CNCT19 monotherapy. Conclusions The combinational therapy of HDT/ASCT and CNCT19 demonstrates impressive efficacy, improved CNCT19 behavior, and a favorable safety profile. Trial registration numbers ChiCTR1900025419 and NCT04690192 .
Preclinical evaluation and first-in-dog clinical trials of PBMC-expanded natural killer cells for adoptive immunotherapy in dogs with cancer
Authors: Aryana M Razmara, Lauren E Farley, Rayna M Harris, Sean J Judge, Marshall Lammers, Khurshid R Iranpur, Eric G Johnson, Cordelia Dunai, William J Murphy, C Titus Brown, Robert B Rebhun, Michael S Kent, Robert J Canter
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Natural killer (NK) cells are cytotoxic cells capable of recognizing heterogeneous cancer targets without prior sensitization, making them promising prospects for use in cellular immunotherapy. Companion dogs develop spontaneous cancers in the context of an intact immune system, representing a valid cancer immunotherapy model. Previously, CD5 depletion of peripheral blood mononuclear cells (PBMCs) was used in dogs to isolate a CD5 dim -expressing NK subset prior to co-culture with an irradiated feeder line, but this can limit the yield of the final NK product. This study aimed to assess NK activation, expansion, and preliminary clinical activity in first-in-dog clinical trials using a novel system with unmanipulated PBMCs to generate our NK cell product. Methods Starting populations of CD5-depleted cells and PBMCs from healthy beagle donors were co-cultured for 14 days, phenotype, cytotoxicity, and cytokine secretion were measured, and samples were sequenced using the 3’-Tag-RNA-Seq protocol. Co-cultured human PBMCs and NK-isolated cells were also sequenced for comparative analysis. In addition, two first-in-dog clinical trials were performed in dogs with melanoma and osteosarcoma using autologous and allogeneic NK cells, respectively, to establish safety and proof-of-concept of this manufacturing approach. Results Calculated cell counts, viability, killing, and cytokine secretion were equivalent or higher in expanded NK cells from canine PBMCs versus CD5-depleted cells, and immune phenotyping confirmed a CD3-NKp46+ product from PBMC-expanded cells at day 14. Transcriptomic analysis of expanded cell populations confirmed upregulation of NK activation genes and related pathways, and human NK cells using well-characterized NK markers closely mirrored canine gene expression patterns. Autologous and allogeneic PBMC-derived NK cells were successfully expanded for use in first-in-dog clinical trials, resulting in no serious adverse events and preliminary efficacy data. RNA sequencing of PBMCs from dogs receiving allogeneic NK transfer showed patient-unique gene signatures with NK gene expression trends in response to treatment. Conclusions Overall, the use of unmanipulated PBMCs appears safe and potentially effective for canine NK immunotherapy with equivalent to superior results to CD5 depletion in NK expansion, activation, and cytotoxicity. Our preclinical and clinical data support further evaluation of this technique as a novel platform for optimizing NK immunotherapy in dogs.
Spatial comparison of molecular features associated with resistance to pembrolizumab in BCG unresponsive bladder cancer
Authors: Khyati Meghani, Noah Frydenlund, Yanni Yu, Bonnie Choy, Joshua J Meeks
Journal: Journal for ImmunoTherapy of Cancer (2024)

Intravenous immune checkpoint inhibition achieves a 40% 3-month response in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ. Yet, only half of the early responders will continue to be disease-free by 12 months, and resistance mechanisms are poorly defined. We performed spatial profiling of BCG-unresponsive tumors from patients responsive or resistant to intravenous pembrolizumab treatment, analyzing samples both before initiating and 3 months post-intravenous pembrolizumab treatment. We analyzed 119 regions of interest, which included 59 pairs of epithelial and adjacent stromal segments across five patients: two responders and three non-responders. We demonstrate that BCG unresponsive tumors with an inflamed PanCK+ tumor area and an infiltrated stromal segment respond better to intravenous pembrolizumab. Furthermore, using segment-specific gene signatures generated from a cohort of BCG unresponsive NMIBC treated with intravesical BCG+pembrolizumab, we find that non-inflamed, immune-cold tumors that do not respond to intravenous pembrolizumab exhibit a favorable outcome to the combined application of BCG and pembrolizumab. For the first time, we have identified molecular features of tumors associated with response and resistance to intravenous pembrolizumab in BCG unresponsive NMIBCs. Further research with more patients and alternative checkpoint inhibitors is essential to validate our findings. We anticipate that using a transcriptomics signature like the one described here can help identify tumors with a higher possibility of responding to intravenous pembrolizumab.
A Novel Conductive Polypyrrole‐Chitosan Hydrogel Containing Human Endometrial Mesenchymal Stem Cell‐Derived Exosomes Facilitated Sustained Release for Cardiac Repair (Adv. Healthcare Mater. 10/2024)
Authors: Changping Yan, Xinzhu Wang, Qi Wang, Haiyan Li, Huifang Song, Jingli Zhou, Zexu Peng, Wenjuan Yin, Xuemei Fan, Kun Yang, Bingrui Zhou, Yuxiang Liang, Zengyu Jiang, Yuwei Shi, Sanyuan Zhang, Sheng He, Ren‐Ke Li, Jun Xie
Journal: Advanced Healthcare Materials (2024)
Ferrous/Ferric Ions Crosslinked Type II Collagen Multifunctional Hydrogel for Advanced Osteoarthritis Treatment (Adv. Healthcare Mater. 10/2024)
Authors: Lili Wang, Xian Chen, Shenghong Wang, Jianrui Ma, Xiaxia Yang, Hongli Chen, Jianxi Xiao
Journal: Advanced Healthcare Materials (2024)
Reversible Host–Guest Crosslinks in Supramolecular Hydrogels for On‐Demand Mechanical Stimulation of Human Mesenchymal Stem Cells (Adv. Healthcare Mater. 10/2024)
Authors: Philipp Linke, Natalie Munding, Esther Kimmle, Stefan Kaufmann, Kentaro Hayashi, Masaki Nakahata, Yoshinori Takashima, Masaki Sano, Martin Bastmeyer, Thomas Holstein, Sascha Dietrich, Carsten Müller‐Tidow, Akira Harada, Anthony D. Ho, Motomu Tanaka
Journal: Advanced Healthcare Materials (2024)
Hippocampal cholecystokinin-expressing interneurons regulate temporal coding and contextual learning
Authors: Dámaris K. Rangel Guerrero, Kira Balueva, Uladzislau Barayeu, Peter Baracskay, Igor Gridchyn, Michele Nardin, Chiara Nina Roth, Peer Wulff, Jozsef Csicsvari
Journal: Neuron (2024)

Cholecystokinin-expressing interneurons (CCKIs) are hypothesized to shape pyramidal cell-firing patterns and regulate network oscillations and related network state transitions. To directly probe their role in the CA1 region, we silenced their activity using optogenetic and chemogenetic tools in mice. Opto-tagged CCKIs revealed a heterogeneous population, and their optogenetic silencing triggered wide disinhibitory network changes affecting both pyramidal cells and other interneurons. CCKI silencing enhanced pyramidal cell burst firing and altered the temporal coding of place cells: theta phase precession was disrupted, whereas sequence reactivation was enhanced. Chemogenetic CCKI silencing did not alter the acquisition of spatial reference memories on the Morris water maze but enhanced the recall of contextual fear memories and enabled selective recall when similar environments were tested. This work suggests the key involvement of CCKIs in the control of place-cell temporal coding and the formation of contextual memories.
Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages
Authors: Jay K. Mandula, Rosa A. Sierra-Mondragon, Rachel V. Jimenez, Darwin Chang, Eslam Mohamed, Shiun Chang, Julio A. Vazquez-Martinez, Yu Cao, Carmen M. Anadon, Sae Bom Lee, Satyajit Das, Léo Rocha-Munguba, Vincent M. Pham, Roger Li, Ahmad A. Tarhini, Muhammad Furqan, William Dalton, Michelle Churchman, Carlos M. Moran-Segura, Jonathan Nguyen, Bradford Perez, Douglas J. Kojetin, Alyssa Obermayer, Xiaoqing Yu, Ann Chen, Timothy I. Shaw, Jose R. Conejo-Garcia, Paulo C. Rodriguez
Journal: Immunity (2024)
Preclinical evaluation of two phylogenetically distant arenavirus vectors for the development of novel immunotherapeutic combination strategies for cancer treatment
Authors: Josipa Raguz, Catarina Pinto, Theresa Pölzlbauer, Mohamed Habbeddine, Sandra Rosskopf, Judith Strauß, Valentin Just, Sarah Schmidt, Katell Bidet Huang, Felix Stemeseder, Timo Schippers, Ethan Stewart, Jakub Jez, Pedro Berraondo, Klaus K. Orlinger, Henning Lauterbach
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Engineered arenavirus vectors have recently been developed to leverage the body’s immune system in the fight against chronic viral infections and cancer. Vectors based on Pichinde virus (artPICV) and lymphocytic choriomeningitis virus (artLCMV) encoding a non-oncogenic fusion protein of human papillomavirus (HPV)16 E6 and E7 are currently being tested in patients with HPV16+ cancer, showing a favorable safety and tolerability profile and unprecedented expansion of tumor-specific CD8 + T cells. Although the strong antigen-specific immune response elicited by artLCMV vectors has been demonstrated in several preclinical models, PICV-based vectors are much less characterized. Methods To advance our understanding of the immunobiology of these two vectors, we analyzed and compared their individual properties in preclinical in vivo and in vitro systems. Immunogenicity and antitumor effect of intratumoral or intravenous administration of both vectors, as well as combination with NKG2A blockade, were evaluated in naïve or TC-1 mouse tumor models. Flow cytometry, Nanostring, and histology analysis were performed to characterize the tumor microenvironment (TME) and T-cell infiltrate following treatment. Results Despite being phylogenetically distant, both vectors shared many properties, including preferential infection and activation of professional antigen-presenting cells, and induction of potent tumor-specific CD8 + T-cell responses. Systemic as well as localized treatment induced a proinflammatory shift in the TME, promoting the infiltration of inducible T cell costimulator (ICOS) + CD8 + T cells capable of mediating tumor regression and prolonging survival in a TC-1 mouse tumor model. Still, there was evidence of immunosuppression built-up over time, and increased expression of H2-T23 (ligand for NKG2A T cell inhibitory receptor) following treatment was identified as a potential contributing factor. NKG2A blockade improved the antitumor efficacy of artARENA vectors, suggesting a promising new combination approach. This demonstrates how detailed characterization of arenavirus vector-induced immune responses and TME modulation can inform novel combination therapies. Conclusions The artARENA platform represents a strong therapeutic vaccine approach for the treatment of cancer. The induced antitumor immune response builds the backbone for novel combination therapies, which warrant further investigation.
Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides
Authors: Maria Alejandra Garcia-Marquez, Martin Thelen, Eugen Bauer, Lukas Maas, Kerstin Wennhold, Jonas Lehmann, Diandra Keller, Miloš Nikolić, Julie George, Thomas Zander, Wolfgang Schröder, Philipp Müller, Ali M Yazbeck, Christiane Bruns, Roman Thomas, Birgit Gathof, Alexander Quaas, Martin Peifer, Axel M Hillmer, Michael von Bergwelt-Baildon, Hans Anton Schlößer
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The individual HLA-I genotype is associated with cancer, autoimmune diseases and infections. This study elucidates the role of germline homozygosity or allelic imbalance of HLA-I loci in esophago-gastric adenocarcinoma (EGA) and determines the resulting repertoires of potentially immunogenic peptides. Methods HLA genotypes and sequences of either (1) 10 relevant tumor-associated antigens (TAAs) or (2) patient-specific mutation-associated neoantigens (MANAs) were used to predict good-affinity binders using an in silico approach for MHC-binding ( www.iedb.org ). Imbalanced or lost expression of HLA-I-A/B/C alleles was analyzed by transcriptome sequencing. FluoroSpot assays and TCR sequencing were used to determine peptide-specific T-cell responses. Results We show that germline homozygosity of HLA-I genes is significantly enriched in EGA patients (n=80) compared with an HLA-matched reference cohort (n=7605). Whereas the overall mutational burden is similar, the repertoire of potentially immunogenic peptides derived from TAAs and MANAs was lower in homozygous patients. Promiscuity of peptides binding to different HLA-I molecules was low for most TAAs and MANAs and in silico modeling of the homozygous to a heterozygous HLA genotype revealed normalized peptide repertoires. Transcriptome sequencing showed imbalanced expression of HLA-I alleles in 75% of heterozygous patients. Out of these, 33% showed complete loss of heterozygosity, whereas 66% had altered expression of only one or two HLA-I molecules. In a FluoroSpot assay, we determined that peptide-specific T-cell responses against NY-ESO-1 are derived from multiple peptides, which often exclusively bind only one HLA-I allele. Conclusion The high frequency of germline homozygosity in EGA patients suggests reduced cancer immunosurveillance leading to an increased cancer risk. Therapeutic targeting of allelic imbalance of HLA-I molecules should be considered in EGA.
Monoclonal antibodies and aptamers: The future therapeutics for Alzheimer's disease
Authors: Alvaro Barrera-Ocampo
Journal: Acta Pharmaceutica Sinica B (2024)

Alzheimer's disease (AD) is considered the most common and prevalent form of dementia of adult-onset with characteristic progressive impairment in cognition and memory. The cure for AD has not been found yet and the treatments available until recently were only symptomatic. Regardless of multidisciplinary approaches and efforts made by pharmaceutical companies, it was only in the past two years that new drugs were approved for the treatment of the disease. Amyloid beta (A
Tumor-targeted therapy with BRAF-inhibitor recruits activated dendritic cells to promote tumor immunity in melanoma
Authors: Florian Hornsteiner, Janine Vierthaler, Helen Strandt, Antonia Resag, Zhe Fu, Markus Ausserhofer, Christoph H Tripp, Sophie Dieckmann, Markus Kanduth, Kathryn Farrand, Sarah Bregar, Niloofar Nemati, Natascha Hermann-Kleiter, Athanasios Seretis, Sudhir Morla, David Mullins, Francesca Finotello, Zlatko Trajanoski, Guido Wollmann, Franca Ronchese, Marc Schmitz, Ian F Hermans, Patrizia Stoitzner
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Tumor-targeted therapy causes impressive tumor regression, but the emergence of resistance limits long-term survival benefits in patients. Little information is available on the role of the myeloid cell network, especially dendritic cells (DC) during tumor-targeted therapy. Methods Here, we investigated therapy-mediated immunological alterations in the tumor microenvironment (TME) and tumor-draining lymph nodes (LN) in the D4M.3A preclinical melanoma mouse model (harboring the V-Raf murine sarcoma viral oncogene homolog B (BRAF) V600E mutation) by using high-dimensional multicolor flow cytometry in combination with multiplex immunohistochemistry. This was complemented with RNA sequencing and cytokine quantification to characterize the immune status of the tumors. The importance of T cells during tumor-targeted therapy was investigated by depleting CD4 + or CD8 + T cells in tumor-bearing mice. Tumor antigen-specific T-cell responses were characterized by performing in vivo T-cell proliferation assays and the contribution of conventional type 1 DC (cDC1) to T-cell immunity during tumor-targeted therapy was assessed using Batf3 −/− mice lacking cDC1. Results Our findings reveal that BRAF-inhibitor therapy increased tumor immunogenicity, reflected by an upregulation of genes associated with immune activation. The T cell-inflamed TME contained higher numbers of activated cDC1 and cDC2 but also inflammatory CCR2-expressing monocytes. At the same time, tumor-targeted therapy enhanced the frequency of migratory, activated DC subsets in tumor-draining LN. Even more, we identified a cDC2 population expressing the Fc gamma receptor I (FcγRI)/CD64 in tumors and LN that displayed high levels of CD40 and CCR7 indicating involvement in T cell-mediated tumor immunity. The importance of cDC2 is underlined by just a partial loss of therapy response in a cDC1-deficient mouse model. Both CD4 + and CD8 + T cells were essential for therapy response as their respective depletion impaired therapy success. On resistance development, the tumors reverted to an immunologically inert state with a loss of DC and inflammatory monocytes together with the accumulation of regulatory T cells. Moreover, tumor antigen-specific CD8 + T cells were compromised in proliferation and interferon-γ-production. Conclusion Our results give novel insights into the remodeling of the myeloid landscape by tumor-targeted therapy. We demonstrate that the transient immunogenic tumor milieu contains more activated DC. This knowledge has important implications for the development of future combinatorial therapies.
Bis-2′-F-cGSASMP isomers encapsulated in cytidinyl/cationic lipids act as potent in situ autologous tumor vaccines
Authors: Jing Yu, Xiaotong Yu, Xudong Sun, Quanxin Wang, Sijie Long, Runan Ren, Zhu Guan, Zhenjun Yang
Journal: Molecular Therapy (2024)
The Associations of Prenatal Exposure to Fine Particulate Matter and Its Chemical Components with Allergic Rhinitis in Children and the Modification Effect of Polyunsaturated Fatty Acids: A Birth Cohort Study
Authors: Yujing Chen, Cuihua Guo, Ming Kei Chung, Quanying Yi, Xin Wang, Yuxuan Wang, Bibo Jiang, Yu Liu, Minyan Lan, Lizi Lin, Li Cai
Journal: Environmental Health Perspectives (2024)

Polyunsaturated fatty acids (PUFAs) have been shown to protect against fine particulate matter <2.5μm in aerodynamic diameter (PM2.5)-induced hazards. However, limited evidence is available for respiratory health, particularly in pregnant women and their offspring.
Evaluation of Lipids and Lipid-Related Transcripts in Human and Ovine Theca Cells and an <i>in Vitro</i> Mouse Model Exposed to the Obesogen Chemical Tributyltin
Authors: Natalia Pascuali, Yong Pu, Anita A. Waye, Sarah Pearl, Denny Martin, Allison Sutton, Ariella Shikanov, Almudena Veiga-Lopez
Journal: Environmental Health Perspectives (2024)

Exposure to obesogenic chemicals has been reported to result in enhanced adipogenesis, higher adipose tissue accumulation, and reduced ovarian hormonal synthesis and follicular function. We have reported that organotins [tributyltin (TBT) and triphenyltin (TPT)] dysregulate cholesterol trafficking in ovarian theca cells, but, whether organotins also exert lipogenic effects on ovarian cells remains unexplored.