journal
https://read.qxmd.com/read/38900485/endoplasmic-reticulum-stress-potentiates-the-immunosuppressive-microenvironment-in-hepatocellular-carcinoma-by-promoting-the-release-of-snhg6-enriched-small-extracellular-vesicles
#1
JOURNAL ARTICLE
Chengdong Liu, Xiaohan Zhou, Hanyi Zeng, Jiaping Yu, Wenwen Li, Wanli Zhang, Yanxia Liao, Haijian Wang, Li Liu
Endoplasmic reticulum (ER) stress leads to hepatocellular carcinoma (HCC) progression. Small extracellular vesicles (sEVs) play a crucial role in modulating the tumor microenvironment (TME) by influencing cellular communication and immune responses. However, it is unclear whether ER stress modulates the TME through sEVs. In the current study, we investigated the effects and underlying mechanisms of ER stress on the HCC TME. In vivo and in vitro experiments showed that overactivated ER stress was a salient attribute of the immunosuppressive HCC TME...
June 20, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38885362/intermittent-mek-inhibition-with-gitr-co-stimulation-rescues-t-cell-function-for-increased-efficacy-with-ctla-4-blockade-in-solid-tumor-models
#2
JOURNAL ARTICLE
Lauren Dong, Hyejin Choi, Sadna Budhu, Isabell Schulze, Svena Verma, Levi Mark Mangarin, Valeria Estrada Navarro, Nezar Mehanna, Jonathan F Khan, Divya Venkatesh, Daniel Thach, Neal Rosen, Jedd D Wolchok, Taha Merghoub
MEK inhibitors (MEKis) have shown limited success as a treatment for MAPK/ERK pathway-dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression on tumor cells and improved T cell-mediated killing. Yet, CKI27 also decreased T-cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T cell-receptor signaling...
June 18, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38885358/rna-encoded-interleukin-2-with-extended-bioavailability-amplifies-rna-vaccine-induced-antitumor-t-cell-immunity
#3
JOURNAL ARTICLE
Daniel Peters, Lena M Kranz, David Eisel, Mustafa Diken, Sebastian Kreiter, Özlem Tureci, Ugur Sahin, Mathias Vormehr
Interleukin-2 (IL-2) is a crucial cytokine in T-cell immunity and a promising combination partner to boost cancer vaccine efficacy. However, therapeutic application of IL-2 is hampered by its short half-life and substantial toxicities. Herein, we report preclinical characterization of a mouse serum albumin-IL-2 fusion protein (Alb-IL2) encoded on nucleoside-modified RNA delivered via a nanoparticle formulation (Alb-IL2 RNA-NP) mediating prolonged cytokine availability. Alb-IL2 RNA-NP was combined with RNA-lipoplex (RNA-LPX) vaccines to evaluate its effect on the expansion of vaccine-induced antigen-specific T-cell immunity...
June 18, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38885356/nivolumab-reaches-brain-lesions-in-patients-with-recurrent-glioblastoma-and-induces-t-cell-activity-and-upregulation-of-checkpoint-pathways
#4
JOURNAL ARTICLE
Signe Koggersbøl Skadborg, Simone Maarup, Arianna Draghi, Annie Borch, Sille Hendriksen, Filip Mundt, Vilde Pedersen, Matthias Mann, Ib Jarle Christensen, Jane Skjøth-Rasmussen, Christina Westmose Yde, Bjarne Winther Kristensen, Hans Skovgaard Poulsen, Benedikte Hasselbalch, Inge Marie Svane, Ulrik Lassen, Sine Reker Hadrup
Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis. Although immunotherapy is being explored as a potential treatment option for patients with GBM, it is unclear whether systemic immunotherapy can reach and modify the tumor microenvironment in the brain. We evaluated immune characteristics in patients receiving the anti-PD1 immune checkpoint inhibitor Nivolumab one week prior to surgery, compared to control patients receiving salvage resection without prior Nivolumab treatment. We observed saturating levels of Nivolumab bound to intratumorally- and tissue-resident T cells in the brain, implicating saturating levels of Nivolumab reaching brain tumors...
June 18, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38874583/plexinb1-inactivation-reprograms-immune-cells-in-the-tumor-microenvironment-inhibiting-breast-cancer-growth-and-metastatic-dissemination
#5
JOURNAL ARTICLE
Giulia Franzolin, Serena Brundu, Carina Florina Cojocaru, Aurora Curatolo, Matteo Ponzo, Roberta Mastrantonio, Emiko Mihara, Atsushi Kumanogoh, Hiroaki Suga, Junichi Takagi, Luca Tamagnone, Enrico Giraudo
Semaphorin-Plexin signaling plays a major role in the tumor microenvironment (TME). In particular, Semaphorin 4D (SEMA4D) has been shown to promote tumor growth and metastasis; however, the role of its high-affinity receptor Plexin-B1 (PLXNB1), which is expressed in the TME, is poorly understood. In this study, we directly targeted PLXNB1 in the TME of triple-negative murine breast carcinoma to elucidate its relevance in cancer progression. We found that primary tumor growth, and metastatic dissemination were strongly reduced in PLXNB1-deficient mice, which showed longer survival...
June 14, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38874582/knocking-out-cd70-rescues-cd70-specific-nanocar-t-cells-from-antigen-induced-exhaustion
#6
JOURNAL ARTICLE
Stijn De Munter, Juliane L Buhl, Laurenz De Cock, Alexander Van Parys, Willem Daneels, Eva Pascal, Lucas Deseins, Joline Ingels, Glenn Goetgeluk, Hanne Jansen, Lore Billiet, Melissa Pille, Julie Van Duyse, Sarah Bonte, Niels Vandamme, Jo Van Dorpe, Fritz Offner, Georges Leclerq, Tom Taghon, Erik Depla, Jan Tavernier, Tessa Kerre, Jarno Drost, Bart Vandekerckhove
CD70 is an attractive target for chimeric antigen receptor (CAR) T-cell therapy for the treatment of both solid and liquid malignancies. However, the functionality of CD70-specific CAR T cells is modest. We optimized a CD70-specific VHH-based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant models in vitro, using co-cultures of CD70-specific nanoCAR T cells with malignant rhabdoid tumor organoids, and in vivo, using a diffuse large B-cell lymphoma (DLBCL) patient-derived xenograft (PDX) model...
June 14, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38869428/identification-of-core-techniques-that-enhance-genome-editing-of-human-t-cells-expressing-synthetic-antigen-receptors
#7
JOURNAL ARTICLE
Ju-Fang Chang, Nils Wellhausen, Nils Wolfgang Engel, Jack H Landmann, Caitlin R Hopkins, January Salas-McKee, Adham S Bear, Mehmet Emrah Selli, Sangya Agarwal, Julie Jadlowsky, Gerald P Linette, Saar Gill, Carl H June, Joseph A Fraietta, Nathan Singh
Genome editing technologies have seen remarkable progress in recent years, enabling precise regulation of exogenous and endogenous genes. These advances have been extensively applied to the engineering of human T lymphocytes, leading to the development of practice changing therapies for patients with cancer and the promise of synthetic immune cell therapies for a variety of non-malignant diseases. Many distinct conceptual and technical approaches have been used to edit T-cell genomes, however targeted assessments of which techniques are most effective for manufacturing, gene editing and transgene expression are rarely reported...
June 13, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38869181/intracellular-osteopontin-promotes-the-release-of-tnf%C3%AF-by-mast-cells-to-restrain-neuroendocrine-prostate-cancer
#8
JOURNAL ARTICLE
Roberta Sulsenti, Giuseppina Beatrice Scialpi, Barbara Frossi, Laura Botti, Renata Ferri, Irene Tripodi, Annamaria Piva, Sabina Sangaletti, Davide Pernici, Valeria Cancila, Francesco Romeo, Claudia Chiodoni, Daniele Lecis, Francesca Bianchi, Irene Fischetti, Claudia Enriquez, Filippo Crivelli, Marco Bregni, Giuseppe Renne, Salvatore Pece, Claudio Tripodo, Carlo E Pucillo, Mario P Colombo, Elena Jachetti
Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer that emerges as tumors become resistant to hormone therapies or, rarely, arises de novo in treatment-naïve patients. The urgent need for effective therapies against NEPC is hampered by the limited knowledge of the biology governing this lethal disease. Based on our prior observations in the TRAMP spontaneous prostate cancer model, in which the genetic depletion of either mast cells (MCs) or the matricellular protein osteopontin (OPN) increases NEPC frequency, we tested the hypothesis that MCs can restrain NEPC through OPN production, using in vitro co-cultures between murine or human tumor cell lines and MCs, and in vivo experiments...
June 13, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38842383/pancreatic-epithelial-il-17-il-17ra-signaling-drives-b7-h4-expression-to-promote-tumorigenesis
#9
JOURNAL ARTICLE
Susana Castro-Pando, Rian M Howell, Le Li, Marilina Mascaro, Erika Y Faraoni, Olivereen Le Roux, David Romanin, Virginia Tahan, Erick Riquelme, Yu Zhang, Jay K Kolls, James P Allison, Guillermina Lozano, Seyed Javad Moghaddam, Florencia McAllister
IL-17 is required for the initiation and progression of pancreatic cancer, particularly in the context of inflammation, as previously shown by genetic and pharmacological approaches. The cellular compartment and downstream molecular mediators of IL-17-mediated pancreatic tumorigenesis have not been fully identified. We interrogated the cellular compartment required by generating transgenic animals with Interleukin 17 receptor A (IL-17RA) genetically deleted from the pancreatic epithelial compartment vs. the hematopoietic compartment via generation of IL-17RA-deficient (IL17-RA-/-) bone marrow chimeras, in the context of embryonically activated or inducible Kras...
June 6, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38842347/cln-617-retains-il-2-and-il-12-in-injected-tumors-to-drive-robust-and-systemic-immune-mediated-antitumor-activity
#10
JOURNAL ARTICLE
Naveen K Mehta, Kavya Rakhra, Kristan A Meetze, Bochong Li, Noor Momin, Jason Yh Chang, K Dane Wittrup, Patrick A Baeuerle, Jennifer S Michaelson
Despite clinical evidence of antitumor activity, the development of cytokine therapies has been hampered by a narrow therapeutic window and limited response rates. Two cytokines of high interest for clinical development are interleukin 2 (IL-2) and interleukin 12 (IL-12), which potently synergize to promote the activation and proliferation of T cells and natural killer (NK) cells. However, the only approved human IL-2 therapy, Proleukin, is rarely used in the clinic due to systemic toxicities, and no IL-12 product has been approved to date due to severe dose-limiting toxicities...
June 6, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38833270/overexpression-of-an-engineered-serpinb9-enhances-allogeneic-t-cell-persistence-and-efficacy
#11
JOURNAL ARTICLE
Pei Yun Teo, Youngrock Jung, David H Quach, Joanna Koh, Richard Weijie Ong, Angeline Goh, Alrina Tan, Chee Hoe Ng, Cheah Chen Seh, Kar Wai Tan, Ivan D Horak, Lionel Low
Allogeneic chimeric antigen receptor (CAR)-expressing T cells offer many advantages over autologous therapies, but their benefits are curtailed by graft-versus-host disease (GvHD) and elimination by recipient immune cells. Moreover, just as with autologous therapies, allogeneic CAR T cells are susceptible to activation-induced cell death (AICD) caused by chronic antigen exposure (CAE). Granzyme B (GzmB) and Fas/FasL-initiated, caspase-mediated apoptosis are key mechanisms of T-cell death caused by T/NK cell-mediated allorejection or CAE...
June 4, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38819256/impact-of-scfv-on-functionality-and-safety-of-third-generation-cd123-car-t-cells
#12
JOURNAL ARTICLE
Maxime Fredon, Margaux Poussard, Sabeha Biichlé, Francis Bonnefoy, Charles-Frédéric Mantion, Evan Seffar, Florian Renosi, Elodie Bôle-Richard, Romain Boidot, Sandy Chevrier, François Anna, Maria Loustau, Julien Caumartin, Mathieu Gonçalves-Venturelli, Eric Robinet, Philippe Saas, Eric Deconinck, Etienne Daguindau, Xavier Roussel, Yann Godet, Olivier Adotévi, Fanny Angelot-Delettre, Jeanne Galaine, Francine Garnache-Ottou
Chimeric antigen receptor (CAR) T cells express an extracellular domain consisting of a single-chain fragment variable (scFv) targeting a surface tumor-associated antigen. scFv selection should involve safety profiling with evaluation of the efficacy/toxicity balance, especially when the target antigen also is expressed on healthy cells. Here, to assess differences in terms of efficacy and on-target/off-tumor effects, we five different CARs targeting CD123 by substituting only the scFv. In in vitro models, T cells engineered to express three of these five CD123 CARs were effectively cytotoxic on leukemic cells without increasing lysis of monocytes or endothelial cells...
May 31, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38819238/multifunctional-bispecific-nanovesicles-targeting-slamf7-trigger-potent-antitumor-immunity
#13
JOURNAL ARTICLE
Manman Zhu, Yongjian Wu, Tianchuan Zhu, Jian Chen, Zhenxing Chen, Hanxi Ding, Siyi Tan, Jianzhong He, Qi Zeng, Xi Huang
The effectiveness of immune checkpoint inhibitor (ICI) therapy is hindered by the ineffective infiltration and functioning of cytotoxic T cells and the immunosuppressive tumor microenvironment (TME). Signaling lymphocytic activation molecule family member 7 (SLAMF7) is a pivotal co-stimulatory receptor thought to simultaneously trigger natural killer (NK)-cell, T-cell, and macrophage antitumor cytotoxicity. However, the potential of this collaborative immune stimulation in antitumor immunity for solid tumors is under-explored due to the exclusive expression of SLAMF7 by hematopoietic cells...
May 31, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38810242/venetoclax-induces-bcl-2-dependent-treg-to-th17-plasticity-to-enhance-the-antitumor-efficacy-of-anti-pd-1-checkpoint-blockade
#14
JOURNAL ARTICLE
Rosy Liao, Jocelyn Y Hsu, Nada S Aboelella, Joshua A McKeever, Anika T Thomas-Toth, Andrew S Koh, James L LaBelle
The specific BCL-2 small molecule inhibitor venetoclax induces apoptosis in a wide range of malignancies, which has led to rapid clinical expansion in its use alone and in combination with chemotherapy and immune-based therapies against a myriad of cancer types. While lymphocytes, and T cells in particular, rely heavily on BCL-2 for survival and function, the effects of small molecule blockade of the BCL-2 family on surviving immune cells is not fully understood. We aimed to better understand the effect of systemic treatment with venetoclax on regulatory T (Treg) cells, which are relatively resistant to cell death induced by specific drugging of BCL-2 compared to other T cells...
May 29, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38768394/molecular-pathways-and-cellular-subsets-associated-with-adverse-clinical-outcomes-in-overlapping-immune-related-myocarditis-and-myositis
#15
JOURNAL ARTICLE
Bilal A Siddiqui, Nicolas L Palaskas, Sreyashi Basu, Yibo Dai, Zhong He, Shalini S Yadav, James P Allison, Rahul A Sheth, Sudhakar Tummala, Maximilian Buja, Meena B Bhattacharjee, Cezar Iliescu, Anishia Rawther-Karedath, Anita Deswal, Linghua Wang, Padmanee Sharma, Sumit K Subudhi
Immune checkpoint therapies (ICTs) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we obtained heart and skeletal muscle biopsies for single-cell RNA sequencing in living patients with cancers treated with ICTs admitted to the hospital with myocarditis and/or myositis (overlapping myocarditis plus myositis, n=10; myocarditis-only, n=1) compared to ICT-exposed patients ruled out for toxicity utilized as controls (n=9) within 96 hours of clinical presentation...
May 20, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38768391/improvement-of-tumor-neoantigen-detection-by-high-field-asymmetric-waveform-ion-mobility-mass-spectrometry
#16
JOURNAL ARTICLE
Wei Meng, Yoshiko Takeuchi, Jeffrey P Ward, Hussein Sultan, Cora D Arthur, Elaine R Mardis, Maxim N Artyomov, Cheryl F Lichti, Robert D Schreiber
Cancer neoantigens have been shown to elicit cancer-specific T-cell responses and have garnered much attention for their roles in both spontaneous and therapeutically induced antitumor responses. Mass spectrometry (MS) profiling of tumor immunopeptidomes has been used, in part, to identify MHC-bound mutant neoantigen ligands. However, under standard conditions, MS-based detection of such rare but clinically relevant neoantigens is relatively insensitive, requiring 300 million cells or more. Here, to quantitatively define the minimum detectable amounts of therapeutically relevant MHC-I and MHC-II neoantigen peptides, we analyzed different dilutions of immunopeptidomes isolated from the well-characterized T3 mouse methylcholanthrene (MCA)-induced cell line by MS...
May 20, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38752667/low-serum-apolipoprotein-a1-impairs-antitumor-immunity-of-cd8-t-cells-via-the-hif-1%C3%AE-glycolysis-pathway
#17
JOURNAL ARTICLE
Qiaoying Lv, Tong Su, Wei Liu, Lulu Wang, Jiali Hu, Yali Cheng, Chengcheng Ning, Weiwei Shan, Xuezhen Luo, Xiaojun Chen
An immunosuppressive microenvironment promotes the occurrence and development of tumors. Low apolipoprotein A1 (ApoA1) is closely related to tumor development, but the underlying mechanisms are unclear. This study investigated the association between serum ApoA1 levels and the immune microenvironment in endometrial, ovarian, and lung cancers. The serum ApoA1 level was decreased significantly in patients with endometrial and ovarian cancers compared with healthy controls. In endometrial cancer tissues, the low serum ApoA1 group showed increased CD163+ macrophage infiltration and decreased CD8+ T-cell infiltration compared with the normal serum ApoA1 group...
May 16, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38752503/pvrig-is-expressed-on-stem-like-t-cells-in-dendritic-cell-rich-niches-in-tumors-and-its-blockade-may-induce-immune-infiltration-in-non-inflamed-tumors
#18
JOURNAL ARTICLE
Zoya Alteber, Gady Cojocaru, Roy Z Granit, Inbal Barbiro, Assaf Wool, Masha Frenkel, Amit Novik, Adi Shuchami, Yu Liang, Vered Daniel Carmi, Niv Sabath, Rob Foreman, Natalia Petrenko, Jieng He, Yossef Kliger, Adva Levy-Barda, Ram Eitan, Oded Raban, Eran Sadot, Omri Sulimani, Abraham Avi Nathan, Henry Adewoye, Pierre Ferre, Zurit Levine, Eran Ophir
Cancers that are poorly immune infiltrated pose a substantial challenge, with current immunotherapies yielding limited clinical success. Stem-like memory T cells (TSCM) have been identified as a subgroup of T cells that possess strong proliferative capacity and that can expand and differentiate following interactions with dendritic cells (DCs). In this study, we explored the pattern of expression of a recently discovered inhibitory receptor PVRIG and its ligand, PVRL2, in the human tumor microenvironment. Using spatial and single-cell RNA transcriptomics data across diverse cancer indications, we found that among the T-cell checkpoints, PVRIG is uniquely expressed on TSCM and PVRL2 is expressed on DCs in immune aggregate niches in tumors...
May 16, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38739030/il-3-driven-t-cell-basophil-crosstalk-enhances-antitumor-immunity
#19
JOURNAL ARTICLE
Jian Wei, Colleen L Mayberry, Xiaoting Lv, Fangyan Hu, Taushif Khan, Natalie A Logan, John J Wilson, John D Sears, Damien Chaussabel, Chih-Hao Chang
Cytotoxic T lymphocytes (CTLs) are pivotal in combating cancer, yet their efficacy is often hindered by the immunosuppressive tumor microenvironment, resulting in exhaustion. This study investigates the role of interleukin (IL)-3 in orchestrating anti-tumor immunity through CTL modulation. Intratumoral CTLs undergo a progressive decline in IL-3 production, which is correlated with impaired cytotoxic function. Augmenting IL-3 supplementation, through intraperitoneal administration of recombinant IL-3, IL-3-expressing tumor cells, or IL-3-engineered CD8+ T cells, confers protection against tumor progression, concomitant with increased CTL activity...
May 13, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38701369/metabolic-reprogramming-of-tumor-associated-macrophages-using-glutamine-antagonist-jhu083-drives-tumor-immunity-in-myeloid-rich-prostate-and-bladder-cancer-tumors
#20
JOURNAL ARTICLE
Monali Praharaj, Fan Shen, Alex J Lee, Liang Zhao, Thomas R Nirschl, Debebe Theodros, Alok K Singh, Xiaoxu Wang, Kenneth M Adusei, Kara A Lombardo, Raekwon A Williams, Laura A Sena, Elizabeth A Thompson, Ada Tam, Srinivasan Yegnasubramanian, Edward J Pearce, Robert D Leone, Jesse Alt, Rana Rais, Barbara S Slusher, Drew M Pardoll, Jonathan D Powell, Jelani C Zarif
Glutamine metabolism in tumor microenvironments critically regulates anti-tumor immunity. Using glutamine-antagonist prodrug JHU083, we report potent tumor growth inhibition in urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes (TIMs). We show JHU083-mediated glutamine antagonism in tumor microenvironments induces TNF, pro-inflammatory, and mTORC1 signaling in intratumoral TAM clusters. JHU083-reprogrammed TAMs also exhibit increased tumor cell phagocytosis and diminished pro-angiogenic capacities...
May 3, 2024: Cancer Immunology Research
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