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LIM-domain-only 4(LMO4)enhances CD8^(+)T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling

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Signal Transduction and Targeted Therapy 2024年第9期9卷 4066-4078页

作者： Roland C.Schelker Jessica Fioravanti Fabio Mastrogiovanni Jeremy G.Baldwin Nisha Rana Peng Li Ping Chen Timea Vadász Rosanne Spolski Christoph Heuser-Loy Dragana Slavkovic-Lukic Pedro Noronha Giuseppe Damiano Laura Raccosta Daniela Maggioni Sree Pullugula Jian-Xin Lin Jangsuk Oh Patrick Grandinetti Mario Lecce Leo Hesse Emilia Kocks Azucena Martín-Santos Claudia Gebhard William G.Telford Yun Ji Nicholas P.Restifo Vincenzo Russo Michael Rehli Wolfgang Herr Warren J.Leonard Luca Gattinoni Division of Functional Immune Cell Modulation Leibniz Institute for ImmunotherapyRegensburgGermany Center for Cancer Research National Cancer InstituteNational Institutes of HealthBethesdaMDUSA Laboratory of Molecular Immunology and the Immunology Center National HeartLung and Blood InstituteNational Institutes of HealthBethesdaMDUSA department of Internal MedicineⅢ University Hospital RegensburgRegensburgGermany Next Generation Sequencing Core Leibniz Institute for ImmunotherapyRegensburgGermany Immuno-Biotherapy of melanoma and Solid Tumors Unit Division of Experimental OncologyIRCCS Scientific Institute San RaffaeleMilanItaly Vita-Salute San Raffaele University MilanItaly University of Regensburg RegensburgGermany National Center for Tumor Diseases WERA SiteWürzburg-Erlangen-Regensburg-AugsburgGermany Center for Immunomedicine in Transplantation and oncology University Hospital RegensburgRegensburgGermany

High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy ***,we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8^(+)T *** IFN-γproduction as a proxy for CD8^(+)T cell terminal differentiation,LMO4 emerged among the top hits inhibiting the development of effectors ***,we found that Lmo4 was downregulated upon CD8^(+)T cell activation but maintained under culture conditions facilitating the formation of stem-like T *** employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8^(+)T cells,we enabled selective expansion and enhanced persistence of transduced cells,while limiting their terminal differentiation and ***4 overexpression promoted transcriptional programs regulating stemness,increasing the numbers of stem-like CD8^(+)memory T cells and enhancing their polyfunctionality and recall *** tested in syngeneic and xenograft tumor models,LMO4 overexpression boosted CD8^(+)T cell antitumor immunity,resulting in enhanced tumor *** than directly modulating gene transcription,LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21,inducing the expression of target genes(Tcf7,Socs3,Junb,and Zfp36)crucial for memory ***/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4,thereby abrogating the therapeutic benefit of LMO4 *** results establish LMO4 overexpression as an effective strategy to boost CD8^(+)T cell stemness,providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies.

关键词： STAT3 immunity LMO4

Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis

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World Journal of Gastroenterology 2017年第11期23卷 2023-2028页

作者： Animesh Jain Evan J Lipson William H Sharfman Steven R Brant Mark G Lazarev Division of Gastroenterology and Hepatology Department of Internal MedicineUniversity of North Carolina Chapel Hill department of oncology Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center Division of Gastroenterology and Hepatology Department of Internal MedicineJohns Hopkins University School of Medicine

AIM To investigate management of patients who develop ipilimumab-mediated enterocolitis, including association of endoscopic findings with steroid-refractory symptoms and utility of infliximab as second-line *** We retrospectively reviewed all patients at our centerwith metastatic melanoma who were treated with ipilimumab between March 2011 and May 2014. All patients received a standard regimen of intravenous ipilimumab 3 mg/kg every 3 wk for four doses or until therapy was stopped due to toxicity or disease progression. Basic demographic and clinical data were collected on all patients. For patients who developed grade 2 or worse diarrhea(increase of 4 bowel movements per day), additional data were collected regarding details of gastrointestinal symptoms, endoscopic findings and treatment course. Descriptive statistics were *** A total of 114 patients were treated with ipilimumab during the study period and all were included. Sixteen patients(14%) developed ≥ grade 2 diarrhea. All patients were treated with high-dose corticosteroids(1-2 mg/kg prednisone daily or equivalent). Nine of 16 patients(56%) had ongoing diarrhea despite highdose steroids. Steroid-refractory patients received one dose of intravenous infliximab at 5 mg/kg, and all but one had brisk resolution of diarrhea. Fourteen of the patients underwent either colonoscopy or sigmoidoscopy with variable endoscopic findings, ranging from mild erythema to colonic ulcers. Among 8 patients with ulcers demonstrated by sigmoidoscopy or colonoscopy, 7 patients(88%) developed steroidrefractory symptoms requiring infliximab. With a median follow-up of 264 d, no major adverse events associated with prednisone or infliximab were *** In patients with ipilimumab-mediated enterocolitis, the presence of colonic ulcers on endoscopy was associated with a steroid-refractory course.

关键词： Ipilimumab melanoma Enterocolitis Colitis Infliximab Corticosteroid Colonic ulcer

Metabolic reprogramming in inflammaging and aging in T cells

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Life Metabolism 2023年第5期2卷 17-24页

作者： Alessio Bevilacqua Ping-Chih Ho Fabien Franco department of Fundamental oncology University of Lausanne1007 LausanneSwitzerland Ludwig Institute for Cancer Research University of Lausanne1066 EpalingesSwitzerland

Aging represents an emerging challenge for public health due to the declined immune responses against pathogens, weakened vaccination efficacy, and disturbed tissue homeostasis. Metabolic alterations in cellular and systemic levels are also known to be cardinal features of aging. Moreover, cellular metabolism has emerged to provide regulations to guide immune cell behavior via modulations on signaling cascades and epigenetic landscape, and the aberrant aging process in immune cells can lead to inflammaging, a chronic and low-grade inflammation that facilitates aging by perturbing homeostasis in tissues and organs. Here, we review how the metabolic program in T cells is influenced by the aging process and how aged T cells modulate inflammaging. In addition, we discuss the potential approaches to reverse or ameliorate aging by rewiring the metabolic programming of immune cells.

关键词： immunometabolism inflammaging T cells

Tracking in vivo migration and distribution of antigen-specific cytotoxic T lymphocytes by 5,6-carboxyfluorescein diacetate succinimidyl ester staining during cancer immunotherapy

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Chinese Medical Journal 2013年第16期126卷 3019-3025页

作者： XU Wei-li LI Suo-lin WEN Ming WEN Jun-ye HAN Jie ZHANG Hong-zhen GAO Fei CAI Jian-hui department of Pediatric Surgery the Second Hospital of HebeiMedical University Shijiazhuang Hebei 050000 China department of Surgical oncology the Affiliated Hospital of HebeiUniversity Baoding Hebei 071000 China department of oncology & Immunotherapy of Hebei GeneralHospital Shijiazhuang Hebei 050051 China

Background Killing of targeted tumors during adoptive cell transfer therapy is associated with cytotoxic T lymphocyte （CTL） numbers,immunophenotype,tumor-specificity,and in vivo residence time,migration,and ***,tracing in vivo persistence,migration,and distribution of CTLs is important for cancer *** Optimal staining concentration for CTL proliferation was determined by cell counting kit-8 （CCK-8） assay and killing efficiencies of CTLs or carboxyfluorescein diacetate succinimidyl ester （CFSE）-labeled melanoma antigen-specific cytotoxic T lymphocytes （CFSE-CTLs） for malignant melanoma cells in vitro were ***,CFSE-CTLs were intravenously transfused to mice receiving B16 melanoma,and their residence time,migration,and distribution in vivo were observed by measuring fluorescence intensities of CFSE-CTLs per gram of tissue （％FI/g） in various tissues and analyzing tumor/non-tumor （T/NT） ***-tumor effects of transferred CTLs and correlation between ％FI/g and D-value of tumor size were *** Five-micromolar CFSE was optimal for labeling CTLs with minimal *** significant difference occurred between CTLs and CFSE-CTLs for tumor cell killing （P=0.849） or interleukin-2 （P=0.318） and interferon-y （P=0.201）*** of CTLs in vivo varied with time.A negative correlation between ％FI/g in tumors and D-value of tumor sizes by Spearman correlation analysis was *** were recruited to and killed tumors from 6 hours to 3 days after cell *** were observed up to three weeks later in the tumor,liver,kidneys,and spleen; this was related to the abundant blood supply or the nature of immune *** CCK-8 assay is a novel method to select optimal CFSE staining *** intensity of transferred CTLs reflects their killing efficiency of *** fluorescent markers can trace in vivo CTL persistence,migration,and distribution because of its stability

关键词： cytotoxic T lymphocyte migration and distribution carboxyfluorescein diacetate succinimidyl ester adoptive cell transfer melanoma

Management of Post-Mastectomy Radio-Necrotic Ulcers &Osteoradionecrosis

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Journal of Cancer Therapy 2019年第6期10卷 433-441页

作者： Alaadin Hussein Rimoun Boutros Amani Saber Surgical oncology department National Cancer Institute Cairo University Cairo Egypt Radiotherapy department National Cancer Institute Cairo University Cairo Egypt Clinical oncology department Minia Oncology Center Minia University Minia Egypt

Background: Breast cancer is still the most common indication for chest wall irradiation, despite the advances in RTH techniques complications still occur, and the time of its occurrence vary and could take few months to many years. ORN usually manifests with pain, exposed bone, fistulae and pathological fracture and the proper management needs proper debridement and coverage by thick musculocutaneous flaps. Objective: To evaluate different techniques of surgical management of post-irradiation persistent radio-necrotic ulcer & ORN with emphasis on the outcome of each technique. Patients and methods: A retrospective study from 2010 to 2015 reviewed 20 patients subjected to post-mastectomy radiotherapy as a treatment for breast cancer inNCICairo, and Minia oncology center Hospital, Egypt. Cases were biopsied to exclude local recurrence. The age, sex, type of ulcer, dose of radiotherapy received and the management done for these cases were recorded. Results: Only 4 patients responded to conservative treatment in the form of repeated dressings, and 16 patients needed surgical treatment;5 of them were treated with debridement and coverage with split thickness graft with high rate of complications reaching 80%, the other 11 patients were reconstructed with musculocutanoeus flaps, of these 7 patients were reconstructed with LD flaps with 57.14% success rate and minor complications only, the other 4 cases were reconstructed with TRAM flap with 50% success and major loss of the flap in one case that needed salvage by LD flap. Pre-operative comorbidity was found in 6 patients and all of them experienced complications while only 3 of the other 14 who had no comorbidity had postoperative complications. Conclusion: Pedicled flaps provide a good choice for reconstruction and provide chest wall support without the use of synthetic mesh.

关键词： Radionecrotic Ulcer Osteoradionecrosis Pedicled Myo-cutaneous Flaps Breast Cancer

Current diagnosis and management of cardiac melanoma: a case series and review

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Journal of Cancer Metastasis and Treatment 2023年第1期9卷 556-564页

作者： Aaron S.Long Jungsoo Chang Joshua Z.Glahn Kelly Olino Thuy T.Tran James Clune Division of Plastic Surgery Department of SurgeryYale School of MedicineNew HavenCT 06510USA Division of Surgical oncology Department of SurgeryYale School of MedicineNew HavenCT 06510USA Yale Cancer Center Section of Medical OncologyYale UniversityNew HavenCT 06510USA

Malignant melanoma is believed to have the highest rate of cardiac metastasis of any cancer based on autopsy studies,but descriptions of clinical findings,diagnosis,and treatment remain *** particular,the use of immunotherapy has been only sparingly *** present eight cases of malignant melanoma treated at our *** patients displayed symptoms,three were diagnosed on routine surveillance imaging,and one was diagnosed *** of cardiac tumors varied with all four chambers and septum involved between the *** patients underwent genetic profiling:two patients had a CDKN2A variant detected in their cardiac tumor,one patient had a BRAF mutation,and one patient had an NRAS *** patients underwent immunotherapy with either anti-PD-1 and/or anti-CTLA-4 *** report highlights the importance of considering cardiac melanoma in surveillance imaging and the use of immunotherapy for management.

关键词： melanoma metastasis cardiac tumor

Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity

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Cellular & Molecular Immunology 2021年第7期18卷 1761-1771页

作者： Nina Dumauthioz Benjamin Tschumi Mathias Wenes Bastien Marti Haiping Wang Fabien Franco Wenhui Li Isabel CLopez-Mejia Lluis Fajas Ping-Chih Ho Alena Donda Pedro Romero Lianjun Zhang Translational Tumor Immunology Group Ludwig Cancer ResearchUniversity of LausanneEpalingesSwitzerland department of Fundamental oncology University of LausanneEpalingesSwitzerland department of Fundamental oncology University of LausanneEpalingesSwitzerland Ludwig Cancer Research Institute Lausanne BranchEpalingesSwitzerland Center for Systems Medicine Institute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical College100005BeijingChina Suzhou Institute of Systems Medicine SuzhouJiangsu215123China Center for Integrative Genomics University of LausanneLausanneSwitzerland

Memory CD8 T cells can provide long-term protection against tumors,which depends on their enhanced proliferative capacity,self-renewal and unique metabolic rewiring to sustain cellular ***,memory CD8 T cells engage oxidative phosphorylation and fatty acid oxidation to fulfill their metabolic *** contrast,tumor-infiltrating lymphocytes(TILs)display severe metabolic defects,which may underlie their functional ***,we show that overexpression of proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α),the master regulator of mitochondrial biogenesis(MB),favors CD8 T cell central memory formation rather than resident memory ***-1α-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide ***,CD8 T cells with enhanced PGC-1αexpression provide stronger antitumor immunity in a mouse melanoma ***,TILs overexpressing PGC-1αmaintain higher mitochondrial activity and improved expansion when rechallenged in a tumor-free ***,our findings indicate that enforcing mitochondrial biogenesis promotes CD8 T cell memory formation,metabolic fitness,and antitumor immunity in vivo.

关键词： PGC-1α Mitochondria CD8 Memory Anti-tumor immunity

Management of pembrolizumab-induced steroid refractory mucositis with infliximab:A case report

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World Journal of Clinical Cases 2020年第18期8卷 4100-4108页

作者： Harry Dang Jiyuan Sun Guoliang Wang Gregory Renner Lester Layfield Jaffar Hilli department of Medicine University of MissouriColumbiaMO 65212United States department of Hematology-oncology University of MissouriColumbiaMO 65212United States department of Pathology University of MissouriColumbiaMO 65212United States department of Otolaryngology-Head and Neck Surgery University of MissouriColumbiaMO 65212United States

BACKGROUND Pembrolizumab is an anti-programmed death receptor 1(PD-1)that was shown to have a tolerable safety profile with 17%of grade 3-4 drug-related adverse events,notable response rate of 16%with median duration of response of 8 mo,and median overall survival of 8 *** mucositis is a very rare complication with only two cases of grade 4 mucositis reported,and both cases had good response to intravenous methylprednisolone and subsequent oral prednisone *** report the first case of pembrolizumab-induced severe mucositis that was refractory to steroid *** SUMMARY An 80-year-old woman with a past medical history of recurrent right cheek nodular melanoma status post resection and new right lung metastatic melanoma on immunotherapy presented with dysphagia and odynophagia for 2 *** initially received 2 doses of ipilimumab 1 year ago with good outcome,but treatment was discontinued after developing severe diarrhea and *** was then initiated 4 mo after disease *** improvement was noted after 3 ***,after 6 cycles of pembrolizumab,patient developed odynophagia and *** of symptoms was noted after discontinuation of pembrolizumab and initiation of steroids.3 mo later,patient developed pharyngeal swelling with hoarseness and new oxygen requirement due to impending airway obstruction while being on prednisone tapering regimen,finally ended up with intubation and *** analysis of left laryngeal and epiglottis tissue showed granulation tissue with acute on chronic inflammation,negative for malignancy and *** achieved marked improvement after 2 doses of infliximab of 5 mg/kg every 2 wk while continuing on prednisone tapering *** We report the first case of pembrolizumab-induced grade 4 mucositis that had limited recovery with prolonged steroid course but had rapid response with addition of *** patient had recurrent mucositis symp

关键词： Pembrolizumab Infliximab Mucositis melanoma Immunotherapy Refractory Case report

Primary malignant melanoma of uterine cervix: a suggestion of new scheme of treatment combination

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Chinese Journal of Cancer Research 2014年第3期26卷 351-354页

作者： Kyung-Jin Min Yeun-Sun Kim Jin-Hwa Hong Jae-Kwan Lee Dae-Sik Yang department of Obstetrics and Gynaecology Korea University Medical Centre department of Radiation oncology Korea University Medical Centre

Historically, the lack of melanocytes in the vaginal and cervical mucus membranes has deterred the findings of primary melanomas. Mainly due to its rarity, difficulty to diagnose, and poor prognosis, there has been no absolute agreement on comprehensive treatment so far. In this case report, we present a case of a 46-year-old woman with primary malignant melanoma of uterine cervix. She underwent neo-adjuvant chemotherapy initially followed by a radical hysterectomy. After adjuvant concurrent chemo-radiation, the patient has been followed up for 24 months. So far, she has not shown any symptoms or signs of recurrence. Further studies with more cases based on variable combinations of treatment regimen have been on the way.

关键词： Malignant melanoma uterine cervix neo-adjuvant chemotherapy chemo-radiation