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FtY720,Sphingosine 1-Phosphate Receptor Modulator,Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibition of t cell infiltration

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cellular & Molecular Immunology 2005年第6期2卷 439-448页

作者： Hirotoshi Kataoka Kunio Sugaharal Kyoko Shimano Koji teshima Mamoru Koyama Atsyshi Fukunari Kenji Chiba Research Laboratory Ⅲ(Immunology) Pharmaceutical Research UnitResearch and Development DivisionMitsubishi Pharma CorporationYokohamaJapan Research Laboratory 1(CNS) Pharmaceutical Research UnitResearch and Development DivisionMitsubishi Pharma CorporationYokohamaJapan Discovery technology Laboratory Ⅰ Pharmaceutical Research UnitResearch and Development DivisionMitsubishi Pharma CorporationYokohamaJapan Research Laboratory Ⅲ(Immunology) Pharmaceutical Research UnitResearch and Development DivisionMitsubishi Pharma Corporation1000 Kamoshida-choAoba-kuYokohama 227-0033.Japan.

FtY720, a sphingosine 1-phosphate receptor modulator, induces a marked decrease in the number of peripheral blood lymphocytes and exerts immunomodulating activity in various experimental allograft and autoimmune disease models. In this study, we evaluated the effect of FtY720 and its active metabolite, （S）-enantiomer of FtY720-phosphate [（S）-FtY720-P] on experimental autoimmune encephalomyelitis （EAE） in rats and mice. Prophylactic administration of FtY720 at 0.1 to 1 mg/kg almost completely prevented the development of EAE, and therapeutic treatment with FtY720 significantly inhibited the progression of EAE and EAE-associated histological change in the spinal cords of LEW rats induced by immunization with myelin basic protein. Consistent with rat EAE, the development of proteolipid protein-induced EAE in SJL/J mice was almost completely prevented and infiltration of CD4^＋ t cells into spinal cord was decreased by prophylactic treatment with FtY720 and （S）-FtY720-P. When FtY720 or （S）-FtY720-P was given after establishment of EAE in SJL/J mice, the relapse of EAE was markedly inhibited as compared with interferon-β, and the area of demyelination and the infiltration of CD4^＋ t cells were decreased in spinal cords of EAE mice. Similar therapeutic effect by FtY720 was obtained in myelin oligodendrocyte glycoprotein-induced EAE in C57BL/6 mice. these results indicate that FtY720 exhibits not only a prophylactic but also a therapeutic effect on EAE in rats and mice, and that the effect of FtY720 on EAE appears to be due to a reduction of the infiltration of myelin antigen-specific CD4^＋ t cells into the inflammation site. cellular ＆ Molecular Immunology. 2005;2（6）：439-448.

关键词： FtY720 S1P receptor modulator lymphopenia EAE t cell infiltration

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Nanoparticles (NPs)-mediated Siglec15 silencing and macrophage repolarization for enhanced cancer immunotherapy

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Acta Pharmaceutica Sinica B 2023年第12期13卷 5048-5059页

作者： Xiaodi Liu Qi Zhang Yixia Liang Shiyu Xiong Yan Cai Jincheng Cao Yanni Xu Xiaolin Xu Ye Wu Qiang Lu Xiaoding Xu Baoming Luo Department of Ultrasound Laboratory of Ultrasound Imaging and DrugWest China HospitalSichuan UniversityChengdu 610041China Department of Ultrasound Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Guangdong Provincial Key Laboratory of Malignant tumor Epigenetics and Gene Regulation Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Department of Ultrasound Central People's Hospital of ZhanjiangZhanjiang 524045China

cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer *** evidence has shown that interferon-gamma(IFN)could enhance CXCL9 secretion from macrophages to recruit t cells,but Siglec15 expressed on tAMs can attenuate t cell ***,targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of t cells in tumor *** herein developed reductionresponsive nanoparticles(NPs)made with poly(disulfide amide)(PDSA)and lipid-poly(ethylene glycol)(lipid-PEG)for systemic delivery of Siglec15 siRNA(siSiglec15)and IFN for enhanced cancer *** intravenous administration,these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages(tAMs).With the highly concentrated glutathione(GSH)in the cytoplasm to destroy the nanostructure,the loaded IFN and si-Siglec15 could be rapidly released,which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for t cell infiltration and silence Siglec15 expression to promote t cell proliferation,leading to significant inhibition of hepatocellular carcinoma(HCC)growth when combining with the immune checkpoint *** strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.

关键词： Nanoparticles tumor-associated macrophages Macrophage repolarization t cell infiltration t cell proliferation Cancer immunotherapy Siglec15 Hepatocellular carcinoma

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An integrative approach of digital image analysis and transcriptome profiling to explore potential predictive biomarkers for tGFβblockade therapy

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3594-3601页

作者： Robert Pomponio Qi tang Anthony Mei Anne Caron Bema Coulibaly Joachim theilhaber Maximilian Rogers-Grazado Michele Sanicola-Nadel Souad Naimi Reza Olfati-Saber Cecile Combeau Jack Pollard tun tun Lin Rui Wang Sanofi translational Medicine Early Development Cambridge MA 02142USA Sanofi Artificial Intelligence and Deep Analytics Data and Data Sciences CambridgeMA 02142USA Sanofi translational Science Vitry sur Seine 94403France Sanofi Precision Oncology Cambridge MA 02142USA Sanofi Oncology Early Development Cambridge MA 02142USA

Increasing evidence suggests that the presence and spatial localization and distribution pattern of tumor infiltrating lymphocytes(tILs)is associate with response to *** studies have identified tGFβactivity and signaling as a determinant of t cell exclusion in the tumor microenvironment and poor response to PD-1/PD-L1 *** we coupled the artificial intelligence(AI)-powered digital image analysis and gene expression profiling as an integrative approach to quantify distribution of tILs and characterize the associated tGFβpathway *** of t cell spatial distribution in the solid tumor biopsies revealed substantial differences in the distribution *** digital image analysis approach achieves 74%concordance with the pathologist assessment for tumor-immune *** transcriptomic profiling suggests that the tIL score was negatively correlated with tGFβpathway activation,together with elevated tGFβsignaling activity observed in excluded and desert tumor *** present results demonstrate that the automated digital pathology algorithm for quantitative analysis of CD8 immunohistochemistry image can successfully assign the tumor into one of three infiltration phenotypes:immune desert,immune excluded or immune *** association between“cold”tumor-immune phenotypes and tGFβsignature further demonstrates their potential as predictive biomarkers to identify appropriate patients that may benefit from tGFβblockade.

关键词： Digital pathology Artificial intelligence tGFβ Predictive biomarker tumor topography t cell infiltration transcriptomic profiling Machine learning

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