FTY720,Sphingosine 1-Phosphate Receptor Modulator,Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibition of T Cell Infiltration

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.

TMB相关免疫浸润调控评分(MOTIF)预测免疫治疗响应并指导联合增效

Patients with high tumor mutational burden(TMB)levels do not consistently respond to immune checkpoint inhibitors(ICIs),possibly because a high TMB level does not necessarily result in adequate infiltration of CD8^(+)T cells.Using bulk ribonucleic acid sequencing(RNA-seq)data from 9311 tumor samples across 30 cancer types,we developed a novel tool called the modulator of TMB-associated immune infiltration(MOTIF),which comprises genes that can determine the extent of CD8^(+)T cell infiltration prompted by a certain TMB level.We confirmed that MOTIF can accurately reflect the integrity and defects of the cancer-immunity cycle.By analyzing 84 human single-cell RNA-seq datasets from 32 types of solid tumors,we revealed that MOTIF can provide insights into the diverse roles of various cell types in the modulation of CD8^(+)T cell infiltration.Using pretreatment RNA-seq data from 13 ICI-treated cohorts,we validated the use of MOTIF in predicting CD8^(+)T cell infiltration and ICI efficacy.Among the components of MOTIF,we identified EMC3 as a negative regulator of CD8^(+)T cell infiltration,which was validated via in vivo studies.Additionally,MOTIF provided guidance for the potential combinations of programmed death 1 blockade with certain immunostimulatory drugs to facilitate CD8^(+)T cell infiltration and improve ICI efficacy.

SOX17-mediated immune evasion in early colorectal cancer:From pre-malignant adaptation to tumor progression

One of the hallmarks of cancer is its inherently immunosuppressive microenvironment,which strategically manipulates surrounding immune cells,signaling molecules,and structural components to shield cancer cells from immune attacks and foster tumor progression1.Such tumor microenvironment is characterized by the presence of immunosuppressive entities such as tumor-associated macrophages,T cells,tumor-associated neutrophils,and myeloid-derived suppressor cells(MDSCs),as well as metabolic alterations like hypoxia2 and elevated lactate levels3.

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

cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy.Emerging 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 proliferation.Therefore,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 tissues.We 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 immunotherapy.After 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 inhibitor.The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.

Single cell RNA-seqrevealed landscape of infiltrating T cells in HBV+ liver cancer

Subject Code:H16With the support by the National Natural Science Foundation of China,a collaborative study by the research groups led by Prof.Zhang Zemin(张泽民)from the Biodynamic Optical Imaging Center(BIOPIC),Peking University,Prof.Peng Jirun(彭吉润)from Beijing Shijitan Hospital,Capital

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

Increasing evidence suggests that the presence and spatial localization and distribution pattern of tumor infiltrating lymphocytes(TILs)is associate with response to immunotherapies.Recent 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 blockade.Here 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 activity.Analysis of T cell spatial distribution in the solid tumor biopsies revealed substantial differences in the distribution patterns.The digital image analysis approach achieves 74%concordance with the pathologist assessment for tumor-immune phenotypes.The transcriptomic profiling suggests that the TIL score was negatively correlated with TGFβpathway activation,together with elevated TGFβsignaling activity observed in excluded and desert tumor phenotypes.The 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 inflamed.The association between“cold”tumor-immune phenotypes and TGFβsignature further demonstrates their potential as predictive biomarkers to identify appropriate patients that may benefit from TGFβblockade.