Experimental Immunotherapy - ACIR Journal Articles

Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion

(1) Zhu Y (2) Zhou Z (3) Du X (4) Lin X (5) Liang ZM (6) Chen S (7) Sun Y (8) Wang Y (9) Na Z (10) Wu Z (11) Zhong J (12) Han B (13) Zhu X (14) Fu W (15) Li H (16) Luo ML (17) Hu H

Cancer cell

(1) Zhu Y (2) Zhou Z (3) Du X (4) Lin X (5) Liang ZM (6) Chen S (7) Sun Y (8) Wang Y (9) Na Z (10) Wu Z (11) Zhong J (12) Han B (13) Zhu X (14) Fu W (15) Li H (16) Luo ML (17) Hu H

Cancer cell

ABSTRACT: Arginine metabolism reshapes the tumor microenvironment (TME) into a pro-tumor niche through complex metabolic cross-feeding among various cell types. However, the key intercellular metabolic communication that mediates the collective effects of arginine metabolism within the TME remains unclear. Here, we reveal that the metabolic interplay between cancer cells and macrophages plays a dominant role in arginine-driven breast cancer progression. Within the TME, breast cancer cells serve as the primary source of arginine, which induces a pro-tumor polarization of tumor-associated macrophages (TAMs), thereby suppressing the anti-tumor activity of CD8(+) T cells. Notably, this cancer cell-macrophage interaction overrides the arginine-mediated enhancement of CD8(+) T cell anti-tumor activity. Mechanistically, polyamines derived from arginine metabolism enhance pro-tumor TAM polarization via thymine DNA glycosylase (TDG)-mediated DNA demethylation, regulated by p53 signaling. Importantly, targeting the arginine-polyamine-TDG axis between cancer cells and macrophages significantly suppresses breast cancer growth, highlighting its therapeutic potential.

Author Info: (1) Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Genetic Medicine, Dongguan Children's Hospital Affiliated

Author Info: (1) Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Genetic Medicine, Dongguan Children's Hospital Affiliated to Guangdong Medical University, Dongguan, China. (2) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (3) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (4) Diagnosis and Treatment Center of Breast Diseases, Shantou Central Hospital, Shantou 515031, China. (5) Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (6) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (7) Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310018, China; Experimental Research Center, Zhejiang Cancer Hospital, Hangzhou 310022, China. (8) Experimental Research Center, Zhejiang Cancer Hospital, Hangzhou 310022, China. (9) Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310018, China. (10) Diagnosis and Treatment Center of Breast Diseases, Shantou Central Hospital, Shantou 515031, China. (11) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (12) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (13) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (14) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (15) Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310018, China. Electronic address: lihongde@him.cas.cn. (16) Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. Electronic address: luomli@mail.sysu.edu.cn. (17) Breast Cancer Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou 310022, China. Electronic address: huhai@zjcc.org.cn.

Citation: Cancer Cell 2025 Apr 1 Epub04/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40185095

The local microenvironment suppresses the synergy between irradiation and anti-PD1 therapy in breastto- brain metastasis

(1) Wischnewski V (2) Guerrero Aruffo P (3) Massara M (4) Maas RR (5) Soukup K (6) Joyce JA

Cell reports - Open Access

(1) Wischnewski V (2) Guerrero Aruffo P (3) Massara M (4) Maas RR (5) Soukup K (6) Joyce JA

Cell reports - Open Access

ABSTRACT: The brain environment is uniquely specialized to protect its neuronal tissue from excessive inflammation by tightly regulating adaptive immunity. However, in the context of brain cancer progression, this regulation can lead to a conflict between T cell activation and suppression. Here, we show that, while CD8(+) T cells can infiltrate breast cancer-brain metastases, their anti-tumor cytotoxicity is locally suppressed in the brain. Conversely, CD8(+) T cells exhibited tumoricidal activity in extracranial mammary lesions originating from the same cancer cells. Consequently, combined high-dose irradiation and anti-programmed cell death protein 1 (PD1) therapy was effective in extracranial tumors but not intracranial lesions. Transcriptional analyses and functional studies identified neutrophils and Trem2-expressing macrophages as key sources for local T cell suppression within the brain, providing rational targets for future therapeutic strategies.

Author Info: (1) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agor

Author Info: (1) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. Electronic address: vladimir.wischnewski@tron-mainz.de. (2) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. (3) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. (4) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland; Neuroscience Research Center, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. (5) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland. (6) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. Electronic address: johanna.joyce@unil.ch.

Citation: Cell Rep 2025 Mar 25 44:115427 Epub03/17/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40106433

Soluble CTLA-4 regulates immune homeostasis and promotes resolution of inflammation by suppressing type 1 but allowing type 2 immunity

(1) Osaki M (2) Sakaguchi S

Immunity

(1) Osaki M (2) Sakaguchi S

Immunity

ABSTRACT: Cytotoxic T-lymphocyte-associated antigen -4 (CTLA-4) is a co-inhibitory receptor that restricts T cell activation. CTLA-4 exists as membrane (mCTLA-4) and soluble (sCTLA-4) forms, but the key producers, kinetics, and functions of sCTLA-4 are unclear. Here, we investigated the roles of sCTLA-4 in immune regulation under non-inflammatory and inflammatory conditions. Effector regulatory T (Treg) cells were the most active sCTLA-4 producers in basal and inflammatory states, with distinct kinetics upon T cell receptor (TCR) stimulation. We generated mice specifically deficient in sCTLA-4 production, which exhibited spontaneous activation of type 1 immune cells and heightened autoantibody/immunoglobulin E (IgE) production. Conversely, mCTLA-4-deficient mice developed severe type 2-skewed autoimmunity. sCTLA-4 blockade of CD80/86 on antigen-presenting cells inhibited T helper (Th)1, but not Th2, differentiation in vitro. In vivo, Treg-produced sCTLA-4, suppressed Th1-mediated experimental colitis, and enhanced wound healing but hampered tumor immunity. Thus, sCTLA-4 is essential for immune homeostasis and controlling type 1 immunity while allowing type 2 immunity to facilitate resolution in inflammatory conditions.

Author Info: (1) Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Experimental Immunology, Institute

Author Info: (1) Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Experimental Immunology, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan. (2) Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Experimental Immunology, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan. Electronic address: shimon@ifrec.osaka-u.ac.jp.

Citation: Immunity 2025 Apr 8 58:889-908.e13 Epub03/31/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40168991

DDX54 downregulation enhances anti-PD1 therapy in immune-desert lung tumors with high tumor mutational burden

(1) Gong JR (2) Lee J (3) Han Y (4) Cho KH

Proceedings of the National Academy of Sciences of the United States of America

(1) Gong JR (2) Lee J (3) Han Y (4) Cho KH

Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT: High tumor mutational burden (TMB-H) is a predictive biomarker for the responsiveness of cancer to immune checkpoint inhibitor (ICI) therapy that indicates whether immune cells can sufficiently recognize cancer cells as nonself. However, about 30% of all cancers from The Cancer Genome Atlas (TCGA) are classified as immune-desert tumors lacking T cell infiltration despite TMB-H. Since the underlying mechanism of these immune-desert tumors has yet to be unraveled, there is a pressing need to transform such immune-desert tumors into immune-inflamed tumors and thereby enhance their responsiveness to anti-PD1 therapy. Here, we present a systems framework for identifying immuno-oncotargets, based on analysis of gene regulatory networks, and validating the effect of these targets in transforming immune-desert into immune-inflamed tumors. In particular, we identify DEAD-box helicases 54 (DDX54) as a master regulator of immune escape in immune-desert lung cancer with TMB-H and show that knockdown of DDX54 can increase immune cell infiltration and lead to improved sensitivity to anti-PD1 therapy.

Author Info: (1) Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. (2) Department of Bio and Brain Engineering, Kore

Author Info: (1) Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. (2) Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. (3) Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. (4) Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.

Citation: Proc Natl Acad Sci U S A 2025 Apr 8 122:e2412310122 Epub04/02/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40172969

Anti-CTLA4 therapy leads to early expansion of a peripheral Th17 populaton and inducton of Th1 cytokines

(1) Nakazawa M (2) Charmsaz S (3) Hallab E (4) Fang M (5) Kao C (6) Brancati M (7) Munjal K (8) Li HL (9) Leatherman JM (10) Griffin E (11) Thoburn CJ (12) Lipson EJ (13) Ged Y (14) Hoffman-Censits J (15) Baretti M (16) Tang L (17) Bansal S (18) Garonce-Hediger R (19) Guha A (20) Chandler GS (21) Mohindra R (22) Jaffee EM (23) Ho WJ (24) Yarchoan M

Cancer immunology research

ABSTRACT: The systemic immunological effects of combining anti-CTLA4 therapy with PD-(L)1 blockade remain incompletely characterized, despite the widespread use of this combination in treating various solid tumors across multiple stages of disease. Herein, we investigated the additive impact of anti-CTLA4 on peripheral immune signatures in patients undergoing PD-(L)1 blockade, using blood samples from a cohort of patients receiving checkpoint inhibitor therapy for advanced solid tumors. We performed in-parallel analysis of peripheral blood mononuclear cells (PBMC) using Cytometry by Time-of-Flight (CyTOF) and plasma cytokines using Luminex immunoassay. Our study cohort included 104 patients, 54 who received anti-PD(L)1 alone and 50 who received anti-PD(L)1 in combination with anti-CTLA4. As compared to single-agent anti-PD(L)1, combination therapy was associated with a greater expansion of CD4+ T helper cell subsets, including Th17 (adjusted p=0.04) and regulatory T cells (Treg) (adjusted p=0.02), after multivariable and multiple testing adjustment. In patients receiving anti-CTLA4, examination of functional marker expression within the Th17 subset revealed an increase in expression of the Th1-related transcription factor TBET (p=0.003). Assessment of the peripheral cytokine signatures showed an increase in Th1-associated cytokines (p=0.002) in recipients of combination anti-PD(L)1 and anti-CTLA4, particularly the IFN_-inducible cytokines MIG (adjusted p=0.05) and IP-10 (adjusted p=0.05). Our results confirm prior reports that anti-CTLA4 therapy is associated with augmentation of Th17 cell subsets, and they also show that anti-CTLA4 may reshape CD4+ T-cell responses through Th17-to-Th1 plasticity, revealing a potential mechanism for enhanced antitumor immunity with broader implications immune modulation in immunotherapy.

Author Info: (1) Johns Hopkins Medicine, Baltimore, MD, United States. (2) Johns Hopkins Medicine, Baltimore, MD, United States. (3) Johns Hopkins Medicine, United States. (4) Johns Hopkins Med

Author Info: (1) Johns Hopkins Medicine, Baltimore, MD, United States. (2) Johns Hopkins Medicine, Baltimore, MD, United States. (3) Johns Hopkins Medicine, United States. (4) Johns Hopkins Medicine, Baltimore, MD, United States. (5) Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States. (6) Johns Hopkins Medicine, Baltimore, MD, United States. (7) Johns Hopkins Medicine, United States. (8) Johns Hopkins Medicine, United States. (9) Johns Hopkins School of Medicine, Baltimore, MD, United States. (10) Johns Hopkins Medicine, United States. (11) Johns Hopkins Medicine, Baltimore, MD, United States. (12) Johns Hopkins Medicine, BALTIMORE, MD, United States. (13) Johns Hopkins Medicine, Baltimore, United States. (14) Johns Hopkins Medicine, Baltimore, MD, United States. (15) Johns Hopkins Medicine, Baltimore, MD, United States. (16) Genentech, San Francisco, CA, United States. (17) Genentech, San Francisco, CA, United States. (18) Roche (Switzerland), Basel, Switzerland. (19) Genentech, San Francisco, CA, United States. (20) Roche (Switzerland), Basel, Switzerland. (21) Roche (Switzerland), Basel, Switzerland. (22) Johns Hopkins University, Baltimore, MD, United States. (23) Johns Hopkins University, Baltimore, MD, United States. (24) Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.

Citation: Cancer Immunol Res 2025 Mar 27 Epub03/27/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40145982

Spatial transcriptomics reveals tryptophan metabolism restricting maturation of intratumoral tertiary lymphoid structures

(1) Tang Z (2) Bai Y (3) Fang Q (4) Yuan Y (5) Zeng Q (6) Chen S (7) Xu T (8) Chen J (9) Tan L (10) Wang C (11) Li Q (12) Lin J (13) Yang Z (14) Wu X (15) Shi G (16) Wang J (17) Yin C (18) Guo J (19) Liu S (20) Peng S (21) Kuang M

Cancer cell

ABSTRACT: Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates found in numerous cancers, often linked to enhanced immunotherapy responses and better clinical outcomes. However, the factors driving TLS maturation are not fully understood. Using near single-cell spatial transcriptomic mapping, we comprehensively profile TLSs under various maturation stages and their microenvironment in hepatocellular carcinoma (HCC). Based on their developmental trajectories, we classify immature TLSs into two groups: conforming and deviating TLSs. Our findings indicate that conforming TLSs, similar to mature TLSs, possess a niche function for immunotherapy responses, while deviating TLSs do not. We discover that the tryptophan-enriched metabolic microenvironment shaped by malignant cells contributes to the deviation of TLS maturation. Inhibiting tryptophan metabolism promotes intratumoral TLS maturation and enhances tumor control, synergizing with anti-PD-1 treatments. Therefore, promoting TLS maturation represents a potential strategy to improve antitumor responses and immunotherapy outcomes.

Author Info: (1) Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Zhongshan School of Medicine,

Author Info: (1) Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: tangzhh99@mail.sysu.edu.cn. (2) BGI Research, Sanya 572025, China; BGI Research, Hangzhou 310030, China. (3) BGI Research, Hangzhou 310030, China. (4) Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. (5) Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (6) Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (7) Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (8) Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (9) Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (10) BGI Research, Chongqing 401329, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. (11) BGI Research, Sanya 572025, China; BGI Research, Hangzhou 310030, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. (12) BGI Research, Sanya 572025, China; BGI Research, Hangzhou 310030, China; BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450000, China. (13) BGI Research, Sanya 572025, China; BGI Research, Hangzhou 310030, China. (14) Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. (15) Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. (16) Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (17) Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, 80336 Munich, Germany. (18) Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (19) BGI Research, Hangzhou 310030, China; Shenzhen Bay Laboratory, Shenzhen 518000, China; Shenzhen Key Laboratory of Single-Cell Omics, BGI-Shenzhen, Shenzhen 518120, China; The Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, Guangzhou 510000, China. Electronic address: liushiping@genomics.cn. (20) Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Clinical Trial Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: pengsui@mail.sysu.edu.cn. (21) Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: kuangm@mail.sysu.edu.cn.

Citation: Cancer Cell 2025 Apr 1 Epub04/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40185093

The response to antiÐPD-1 and antiÐLAG-3 checkpoint blockade is associated with regulatory T cell reprogramming

(1) Rolig AS (2) Peng X (3) Sturgill ER (4) Holay N (5) Kasiewicz M (6) Mick C (7) Mcgee GH (8) Miller W (9) Koguchi Y (10) Kaufmann J (11) Yanamandra N (12) Griffin S (13) Smothers J (14) Adamow M (15) Lee J (16) Shen R (17) Callahan MK (18) Redmond WL

Science translational medicine

ABSTRACT: Immune checkpoint blockade (ICB) has revolutionized cancer treatment; however, many patients develop therapeutic resistance. We previously identified and validated a pretreatment peripheral blood biomarker, characterized by a high frequency of LAG-3(+) lymphocytes, that predicts resistance in patients receiving anti-PD-1 (aPD-1) ICB. To better understand the mechanism of aPD-1 resistance, we identified murine tumor models with a high LAG-3(+) lymphocyte frequency (LAG-3(hi)), which were resistant to aPD-1 therapy, and LAG-3(lo) murine tumor models that were aPD-1 sensitive, recapitulating the predictive biomarker we previously described in patients. LAG-3(hi) tumor-bearing mice were sensitive to aPD-1 + anti-LAG-3 (aLAG-3) therapy, and this benefit was CD8(+) T cell dependent. The efficacy of combination therapy was enhanced in LAG-3(hi) (but not LAG-3(lo)) mice with depletion of CD4(+) T cells. Furthermore, responses to aPD-1 + aLAG-3 correlated with regulatory T cell (T(reg)) phenotypic plasticity in LAG-3(hi) mice, suggesting a specific role for T(regs) in response to aPD-1 + aLAG-3 treatment. Using T(reg) fate-tracking Foxp3(GFP-Cre-ERT2) _ ROSA(YFP) reporter mice, we demonstrated that expanded populations of unstable T(regs) correlated with improved response to combination therapy in LAG-3(hi) mice. Complementing these preclinical data, an increased proportion of unstable T(regs) also correlated with higher response rate and improved survival after aPD-1 + aLAG-3 therapy in a cohort of patients with metastatic melanoma (n = 117). These data indicate that T(reg) phenotypic plasticity affects aPD-1 + aLAG-3 responsiveness, which may represent a biomarker to aid patient selection and a rational therapeutic target for a subset of PD-1-refractory patients.

Author Info: (1) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (2) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (3) Earle A. Chil

Author Info: (1) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (2) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (3) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (4) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (5) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (6) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (7) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (8) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (9) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA. (10) Deck Bio, Cambridge, MA 02139 USA. (11) Immuno-Oncology & Combinations Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA. (12) Immuno-Oncology & Combinations Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA. (13) Immuno-Oncology & Combinations Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA. (14) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (15) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (16) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (17) University of Connecticut School of Medicine, Farmington, CT 06030, USA. (18) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA.

Citation: Sci Transl Med 2025 Apr 9 17:eadk3702 Epub04/09/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40203085

New soluble CSF-1R-dimeric mutein with enhanced trapping of both CSF-1 and IL-34 reduces suppressive tumor-associated macrophages in pleural mesothelioma Spotlight

(1) Joalland N (2) Quéméner A (3) Deshayes S (4) Humeau R (5) Maillasson M (6) LeBihan H (7) Salama A (8) Fresquet J (9) Remy S (10) Mortier E (11) Blanquart C (12) Guillonneau C (13) Anegon I

Journal for immunotherapy of cancer - Open Access | Free PMC Article

To inhibit interactions of CSF-1 with CSF-1R and IL-34 with CSF-1R, PTPζ, SDC-1 and TREM2, Joalland et al. generated a soluble fusion protein comprising a mutein (M149K) of the human CSF-1R extracellular domain dimerized by a silenced human IgG1Fc. Mutein CSF-1R-Fc had higher affinity for CSF-1 and IL-34 than wild-type CSF-1R-Fc; inhibited CSF-1R signaling, monocyte viability, and induction of suppressive TAMs by CSF-1/IL-34-expressing pleural mesothelioma cells better than anti-IL-34 and/or anti-CSF-1 mAbs; and induced lysis of mesothelioma cells by a tumor-specific CD8+ T cell clone in mesothelioma/macrophage spheroids in vitro and in vivo.

Contributed by Paula Hochman

(1) Joalland N (2) Quéméner A (3) Deshayes S (4) Humeau R (5) Maillasson M (6) LeBihan H (7) Salama A (8) Fresquet J (9) Remy S (10) Mortier E (11) Blanquart C (12) Guillonneau C (13) Anegon I

Journal for immunotherapy of cancer - Open Access | Free PMC Article

BACKGROUND: Colony stimulating factor-1 receptor (CSF-1R) and its ligands CSF-1 and interleukin (IL)-34 have tumorigenic effects through both induction of suppressive macrophages, and survival/proliferation of tumor cells. In addition, the IL-34 tumorigenic effect can also be mediated by its other receptors, protein-tyrosine phosphatase zeta, Syndecan-1 (CD138) and triggering receptor expressed on myeloid cells 2. Small tyrosine kinase inhibitors are used to block CSF-1R signaling but lack specificity. Neutralizing anti-CSF-1 and/or IL-34 antibodies have been proposed, but their effects are limited. Thus, there is a need for a more specific and yet integrative approach. METHODS: A human mutated form of the extracellular portion of CSF-1R was in silico modelized to trap both IL-34 and CSF-1 with higher affinity than the wild-type CSF-1R by replacing the methionine residue at position 149 with a Lysine ((M149K)). The extracellular portion of the mutated CSF-1R M149K was dimerized using the immunoglobulin Fc sequence of a silenced human IgG1 (sCSF-1R(M149K)-Fc). Signaling through CSF-1R, survival of monocytes and differentiation of suppressive macrophages were analyzed using pleural mesothelioma patient's samples and mesothelioma/macrophage spheroids in vitro and in vivo in the presence of sCSF-1R(M149K)-Fc or sCSF-1R-Fc wild type control (sCSF-1R(WT)-Fc). RESULTS: We defined that the D1 to D5 domains of the extracellular portion of CSF-1R were required for efficient binding to IL-34 and CSF-1. The mutein sCSF-1R(M149K)-Fc trapped with higher affinity than sCSF-1R(WT)-Fc both CSF-1 and IL-34 added in culture and naturally produced in mesothelioma pleural effusions. sCSF-1R(M149K)-Fc inhibited CSF-1R signaling, survival and differentiation of human suppressive macrophage in vitro and in vivo induced by pleural mesothelioma cells. Neutralization of IL-34 and CSF-1 by sCSF-1R(M149K)-Fc also resulted in higher killing of pleural mesothelioma cells by a tumor-specific CD8(+) T cell clone in mesothelioma/macrophage spheroids. CONCLUSIONS: sCSF-1R(M149K)-Fc efficiently traps both CSF-1 and IL-34 and inhibits CSF-1R signaling, monocyte survival and suppressive macrophage differentiation induced by pleural mesothelioma cells producing CSF-1 and IL-34, as well as restores cytotoxic T-cell responses. sCSF-1R(M149K)-Fc has therapeutic potential vs other therapies under development targeting single components of this complex cytokine pathway involved in cancer.

Author Info: (1) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes Universit, Nantes, France. (2) LabE

Author Info: (1) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes Universit, Nantes, France. (2) LabEx IGO, Nantes Universit, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, Universit d'Angers, CRCI2NA, University of Nantes, Nantes, France. (3) LabEx IGO, Nantes Universit, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, Universit d'Angers, CRCI2NA, University of Nantes, Nantes, France. (4) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes Universit, Nantes, France. (5) LabEx IGO, Nantes Universit, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, Universit d'Angers, CRCI2NA, University of Nantes, Nantes, France. INSERM, CNRS, SFR Bonamy, UMS BioCore, Imp@ct Platform, Nantes Universit, Centre Hospitalo-Universitaire (CHU) Nantes, Nantes, France. (6) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes Universit, Nantes, France. (7) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes Universit, Nantes, France. (8) LabEx IGO, Nantes Universit, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, Universit d'Angers, CRCI2NA, University of Nantes, Nantes, France. (9) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. (10) LabEx IGO, Nantes Universit, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, Universit d'Angers, CRCI2NA, University of Nantes, Nantes, France. INSERM, CNRS, SFR Bonamy, UMS BioCore, Imp@ct Platform, Nantes Universit, Centre Hospitalo-Universitaire (CHU) Nantes, Nantes, France. (11) LabEx IGO, Nantes Universit, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, Universit d'Angers, CRCI2NA, University of Nantes, Nantes, France. (12) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France ianegon@nantes.inserm.fr carole.guillonneau@univ-nantes.fr. LabEx IGO, Nantes Universit, Nantes, France. (13) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France ianegon@nantes.inserm.fr carole.guillonneau@univ-nantes.fr. LabEx IGO, Nantes Universit, Nantes, France.

Citation: J Immunother Cancer 2025 Mar 17 13: Epub03/17/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40101804

Embryonic reprogramming of the tumor vasculature reveals targets for cancer therapy Spotlight

(1) Huijbers EJM (2) van Beijnum JR (3) van Loon K (4) Griffioen CJ (5) Volckmann R (6) Bassez A (7) Lambrechts D (8) Nunes Monteiro M (9) Jimenez CR (10) Hogendoorn PCW (11) Koster J (12) Griffioen AW

Proceedings of the National Academy of Sciences of the United States of America

Hypothesizing that tumor endothelial cells (TECs) re-express fetal genes in tumor tissues, Huijbers et al. identified target genes selectively expressed in mouse embryos and in sorted TECs, but not in adult mice. Identified TEC self-antigens (Fbn2, Emilin2, Lox and Pai-1) were validated in in vitro angiogenesis assays and were used to generate fusion protein vaccines (with bacterial thioredoxin) that induced highly specific polyclonal Abs and inhibited tumor growth in preclinical models, without affecting healthy vasculature (Fbn2 and Emilin2 vaccines). High levels of FBN2 and EMILIN2 correlated with elevated levels of ECs in human CRC and melanoma.

Contributed by Katherine Turner

Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT: A sustained blood supply is critical for tumor growth, as it delivers the nutrients and oxygen required for development. Targeting of blood vessel formation via immunotherapies is an area of great importance. Knowing that certain embryonic genes, such as carcinoembryonic antigens (CEA) and oncofetal fibronectin, become reexpressed in malignant transformation, we hypothesized that a similar phenomenon holds true for tumor endothelial cells (TECs) as well. An approach for identification of highly selective tumor endothelial markers was conducted to develop targeted antiangiogenic immunotherapies. We first queried the transcriptome that is present during embryo development. We then performed a systematic search for genes selectively expressed in the mouse embryo at days E11 and E18, as compared to the transcriptome of the adult mouse. Subsequently, we queried for expression of these embryonic genes in sorted murine TECs. This approach identified among others the tumor endothelial antigens fibrillin-2 (Fbn2), elastin microfibril interface-located protein 2 (Emilin2) as well as the tumor endothelial antigens lysyl oxidase (Lox) and serine/cysteine protease inhibitor, clade E, member 1 (Serpine1; Pai-1). For these selected genes, functional involvement in angiogenesis was confirmed in in vitro bioassays. We subsequently used iBoost conjugate vaccine technology to develop vaccines against the selected targets. For all four targets, vaccination readily induced target-specific antibody responses in mice, resulting in inhibition of tumor growth. Access to highly specific tumor endothelial markers provides opportunities for direct targeting of the tumor vasculature with high specificity, without affecting healthy vasculature.

Author Info: (1) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. CimCure Besloten Venn

Author Info: (1) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. CimCure Besloten Vennootschap, Amsterdam 1066 CX, The Netherlands. (2) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. (3) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. (4) Laboratory of Experimental Oncology and Radiobiology, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1105 AZ, The Netherlands. (5) Laboratory of Experimental Oncology and Radiobiology, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1105 AZ, The Netherlands. (6) Vlaams Instituut voor Biotechnologie-Katolieke Universiteit Leuven Center for Cancer Biology, Leuven 3000, Belgium. (7) Vlaams Instituut voor Biotechnologie-Katolieke Universiteit Leuven Center for Cancer Biology, Leuven 3000, Belgium. (8) Department of Medical Oncology, Oncoproteomics Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. (9) Department of Medical Oncology, Oncoproteomics Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. (10) Department of Pathology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands. (11) Laboratory of Experimental Oncology and Radiobiology, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1105 AZ, The Netherlands. (12) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. CimCure Besloten Vennootschap, Amsterdam 1066 CX, The Netherlands.

Citation: Proc Natl Acad Sci U S A 2025 Mar 25 122:e2424730122 Epub03/17/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40096611

A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells Spotlight

(1) Chen X (2) Tang X (3) Xie Y (4) Cuffari BJ (5) Tang C (6) Cao F (7) Gao X (8) Meng Z (9) Noble PW (10) Young MR (11) Turk OM (12) Shirali A (13) Gera J (14) Nishimura RN (15) Zhou J (16) Hansen JE

Science signaling

Chen et al. found that the guanosine binding autoantibody 4H2 uses nucleoside transporter-2 (ENT-2)-mediated nucleoside transport to penetrate into and localize in the cytoplasm of live cells, thus avoiding endosomes and lysosomes. 4H2 activated and promoted cGAS signaling and cGAS-dependent cytotoxicity in a nucleic acid-dependent interaction, but did not interfere with protein translation. In orthotropic GBM mouse models, systemically administered 4H2 localized to areas of necrotic tumor cells, increased T cell infiltration, and prolonged survival in a T cell-dependent manner. When injected locally, 4H2 delivered functional mRNA to cells.

Contributed by Ute Burkhardt

Science signaling

ABSTRACT: Nucleic acid-mediated signaling triggers an immune response that is believed to be central to the pathophysiology of autoimmunity in systemic lupus erythematosus (SLE). Here, we found that a cell-penetrating, SLE-associated antiguanosine autoantibody may present therapeutic opportunities for cancer treatment. The autoantibody entered cells through a nucleoside salvage-linked pathway of membrane transit that avoids endosomes and lysosomes and bound to endogenous RNA in live cells. In orthotopic models of glioblastoma, the antibody localized to areas adjacent to necrotic tumor cells and promoted animal survival in a manner that depended on T cells. Mechanistic studies revealed that antibody binding to nucleic acids activated the cytoplasmic pattern recognition receptor cyclic GMP-AMP synthase (cGAS), thereby stimulating immune signaling and cGAS-dependent cytotoxicity. Moreover, the autoantibody could carry and deliver functional RNA into tumor, brain, and muscle tissues in live mice when administered locally. The findings establish a collaborative autoantibody-nucleic acid interaction that is translatable to strategies for nonviral gene delivery and immunotherapy.

Author Info: (1) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (2) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (3) D

Author Info: (1) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (2) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (3) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (4) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (5) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (6) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (7) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (8) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (9) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (10) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA. (11) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (12) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (13) Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Johnson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA. Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA. Department of Research & Development, Veterans Affairs Greater Los Angeles Healthcare System, North Hills, CA 91343, USA. (14) Department of Research & Development, Veterans Affairs Greater Los Angeles Healthcare System, North Hills, CA 91343, USA. Department of Neurology, David Geffen School of Medicine at UCLA Los Angeles, CA 90095, USA. (15) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA. (16) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA.

Citation: Sci Signal 2025 Mar 25 18:eadk3320 Epub03/25/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40132052

Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion

Tags:

The local microenvironment suppresses the synergy between irradiation and anti-PD1 therapy in breastto- brain metastasis

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Soluble CTLA-4 regulates immune homeostasis and promotes resolution of inflammation by suppressing type 1 but allowing type 2 immunity

Tags:

DDX54 downregulation enhances anti-PD1 therapy in immune-desert lung tumors with high tumor mutational burden

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Anti-CTLA4 therapy leads to early expansion of a peripheral Th17 populaton and inducton of Th1 cytokines

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Spatial transcriptomics reveals tryptophan metabolism restricting maturation of intratumoral tertiary lymphoid structures

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The response to antiÐPD-1 and antiÐLAG-3 checkpoint blockade is associated with regulatory T cell reprogramming

Tags:

New soluble CSF-1R-dimeric mutein with enhanced trapping of both CSF-1 and IL-34 reduces suppressive tumor-associated macrophages in pleural mesothelioma Spotlight

Tags:

Embryonic reprogramming of the tumor vasculature reveals targets for cancer therapy Spotlight

Tags:

A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells Spotlight

Tags:

Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion

Tags:

The local microenvironment suppresses the synergy between irradiation and anti-PD1 therapy in breastto- brain metastasis

Tags:

Soluble CTLA-4 regulates immune homeostasis and promotes resolution of inflammation by suppressing type 1 but allowing type 2 immunity

Tags:

DDX54 downregulation enhances anti-PD1 therapy in immune-desert lung tumors with high tumor mutational burden

Tags:

Anti-CTLA4 therapy leads to early expansion of a peripheral Th17 populaton and inducton of Th1 cytokines

Tags:

Spatial transcriptomics reveals tryptophan metabolism restricting maturation of intratumoral tertiary lymphoid structures

Tags:

The response to antiÐPD-1 and antiÐLAG-3 checkpoint blockade is associated with regulatory T cell reprogramming

Tags:

New soluble CSF-1R-dimeric mutein with enhanced trapping of both CSF-1 and IL-34 reduces suppressive tumor-associated macrophages in pleural mesothelioma Spotlight

Tags:

Embryonic reprogramming of the tumor vasculature reveals targets for cancer therapy Spotlight

Tags:

A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells Spotlight

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