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第十四届全国免疫学学术大会

作者： Jiangping Li Department of Oncological Radiotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital Sichuan University

Background: A major current challenge is to exploit tertiary lymphoid structures(TLSs) to promote the lymphocyte-infiltration, activation and differentiation by tumor antigens to increase anti-tumor immune responses. The mechanisms that underlie the role of TLSs formation in the adaptive immune responses against nasopharyngeal carcinoma(NPC) remain largely ***: Cell populations and the corresponding markers were identified by single-cell RNA sequencing(scRNA-seq) and fluorescence-activated cell sorting(FACS) analysis. In vitro differentiation experiments were used to simulate the generation, regulation and function of the Th-CXCL13 cell subset in the tumor microenvironment of NPC. These were followed by histological evaluation of the co-localization of tumor-associated B cells(TABs) and Th-CXCL13 cells within TLSs, and statistical analysis of the relationship between the cells in TLSs and overall ***: A PD-1CXCR5-CD4 Th-CXCL13 cell subset was identified in NPC. This subset was a major source of CXCL13, representing the majority of the CD4 T cells at levels comparable with Th1 and Tfh cells present in the TLSs. Monocytes activated by toll-like receptor 4(TLR4) agonists served as the antigen-presenting cells(APCs) that most efficiently triggered the expansion of Th-CXCL13 cells. TGF-β1 stimulation and activation of Sox4 was critical for the induction and polarization of Th-CXCL13 cells in this process. The potential functional contributions of TABs recruited by Th-CXCL13 cells which induced plasma cell differentiation and immunoglobulin production via IL-21 and CD84 interactions in the TLSs demonstrated improved ***: Induction of Th-CXCL13 cells links innate inflammation to immune privilege in tumor-associated TLSs, and might predict better survival.

关键词： Nasopharyngeal carcinoma CXCL13 tertiary lymphoid structures TLSs Immune response

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Tumor-infiltrating lymphocytes in the immunotherapy era

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Cellular & Molecular Immunology 2021年第4期18卷 842-859页

作者： Sterre T.Paijens Annege Vledder Marco de Bruyn Hans W.Nijman Department of Obstetrics and Gynecology University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands

The clinical success of cancer immune checkpoint blockade(ICB)has refocused attention on tumor-infiltrating lymphocytes(TILs)across cancer *** outcome of immune checkpoint inhibitor therapy in cancer patients has been linked to the quality and magnitude of T cell,NK cell,and more recently,B cell responses within the tumor ***-of-the-art single-cell analysis of TIL gene expression profiles and clonality has revealed a remarkable degree of cellular heterogeneity and distinct patterns of immune activation and *** of these states are conserved across tumor types,in line with the broad responses observed *** this homology,not all cancer types with similar TIL landscapes respond similarly to immunotherapy,highlighting the complexity of the underlying tumor-immune *** observation is further confounded by the strong prognostic benefit of TILs observed for tumor types that have so far respond poorly to ***,while a holistic view of lymphocyte infiltration and dysfunction on a single-cell level is emerging,the search for response and prognostic biomarkers is just *** this review,we discuss recent advances in the understanding of TIL biology,their prognostic benefit,and their predictive value for therapy.

关键词： Tumor infiltrating lymphocytes B cells T cells tertiary lymphoid structures immunotherapy

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B cells in pancreatic cancer stroma

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World Journal of Gastroenterology 2022年第11期28卷 1088-1101页

作者： Francesca Romana Delvecchio Michelle R Goulart Rachel Elizabeth Ann Fincham Michele Bombadieri Hemant M Kocher William Harvey Research Institute Queen Mary University of LondonLondon EC1M 6BQUnited Kingdom Barts Cancer Institute Queen Mary University of LondonLondon EC1M 6BQUnited Kingdom Barts and the London HPB Centre Barts Health NHS TrustLondon E11BBUnited Kingdom

Pancreatic cancer is a disease with high unmet clinical *** cancer is also characterised by an intense fibrotic stroma,which harbours many immune *** in both human and animal models have demonstrated that the immune system plays a crucial role in modulating tumour onset and *** human pancreatic ductal adenocarcinoma,high B-cell infiltration correlates with better patient ***,B cells have received recent interest in pancreatic cancer as potential therapeutic ***,the data on the role of B cells in murine models is unclear as it is dependent on the pancreatic cancer model used to ***,it appears that B cells do organise along with other immune cells such as a network of follicular dendritic cells(DCs),surrounded by T cells and DCs to form tertiary lymphoid structures(TLS).TLS are increasingly recognised as sites for antigen presentation,T-cell activation,Bcell maturation and differentiation in plasma *** this review we dissect the role of B cells and provide directions for future studies to harness the role of B cells in treatment of human pancreatic cancer.

关键词： B cells Pancreatic cancer Cancer immunology tertiary lymphoid structures Anti-tumour immunoglobulins Plasma cells

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tertiary lymphoid structure patterns predicted anti-PD1 therapeutic responses in gastric cancer

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Chinese Journal of Cancer Research 2022年第4期34卷 365-382页

作者： Quan Jiang Chenyu Tian Hao Wu Lingqiang Min Hao Chen Lingli Chen Fenglin Liu Yihong Sun Department of General Surgery Zhongshan HospitalFudan UniversityShanghai 200032China Cancer Center Zhongshan HospitalFudan UniversityShanghai 200032China Gastric Cancer Center Zhongshan HospitalFudan UniversityShanghai 200032China Department of Laboratory Medicine Zhongshan HospitalFudan UniversityShanghai 200032China Department of Pathology Zhongshan HospitalFudan UniversityShanghai 200032China

Objective:Recent studies have highlighted the distinct value of tertiary lymphoid structure(TLS)for immunotherapeutic response ***,it remains unclear whether TLS could play such roles in gastric cancer(GC).Methods:In this study,tumor tissue slices from 292 GC patients from Zhongshan Hospital were firstly reviewed to explore the correlation between TLS and clinical ***,we curated 38 reported genes that may function as triggers of TLS and performed consensus molecular subtyping in public RNA-seq datasets to determine TLS patterns in *** on the differentially expressed genes acquired from two TLS patterns,we quantified TLS-related genes on the principal component analysis(PCA)algorithm to develop TLS score.A Zhongshan immunotherapy cohort including 13 patients who received programmed cell death 1(PD1)blockade therapy was established to conduct RNA sequencing analysis and multiplex immunohistochemistry(mIHC)tests using formalin-fixed and paraffin-embedded(FFPE)*** corresponding TLS score and immune cell counts were further compared based on therapeutic response ***:Mature TLS was revealed as an independent prognostic factor in 292 GC *** with higher TLS score was characterized by prolonged survival time and superior response to *** score was correlated with immunotherapy-related characters,such as microsatellite instability(MSI)and tumor mutation burden(TMB).In addition,RNA-seq data analysis in the Zhongshan immunotherapy cohort indicated that a higher TLS score was correlated with a superior response to PD1 blockade *** tests also revealed that PD1+CD8+T cell counts were significantly increased in the high-TLS score ***:This study highlighted that TLS was significantly associated with immune landscape diversity and *** evaluating TLS patterns of individual tumor will strengthen our understanding of TME characteristics and promote

关键词： Gastric cancer tertiary lymphoid structures immune landscape immunotherapy

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Prognostic value of tertiary lymphoid structure and tumour infiltrating lymphocytes in oral squamous cell carcinoma

Prognostic value of tertiary lymphoid structure and tumour i...

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2020年全国口腔颌面-头颈肿瘤学术大会暨中华口腔医学会口腔颌面-头颈肿瘤专业委员会学术年会——创新超越、共赢未来

作者： Qunxing Li Xiangqi Liu Dikan Wang Zhi Wang Jinsong Li Sun Yat-sen Memorial Hospital of Sun Yat-sen University Hospital of Stomatology Guanghua School of Stomatology Sun Yat-Sen University

Purpose/Background:tertiary lymphoid structures(TLS) are ectopic lymphoid structures in cancers that are largely associated with favourable prognosis. However, the prognostic value of TLSs in oral squamous cell carcinoma(OSCC) is largely unknown, and the association between tumour infiltrating lymphocytes(TILs) and TLSs has been rarely explored in OSCC. In this study, we investigated the clinical significance of TLS in OSCC.

关键词： tertiary lymphoid structures Oral cancer detection Prognostic markers Cancer microenvironment

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Novel oncolytic adenovirus mediates vascular normalization and tertiary lymphoid structure formation by activating the STING pathway of DCs

Novel oncolytic adenovirus mediates vascular normalization a...

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第十四届全国免疫学学术大会

作者： Teng He Zhixing Hao Mingjie Lin Zhongwei Xin Yongyuan Chen Feng Xu Ping Wu The Second Affiliated Hospital Zhejiang University school of Medicine

Background: Immunotherapy has become an important treatment for tumor patients. However, the structural abnormalities, dysfunction of tumor blood vessels and the formation of hypoxic microenvironment hinder the infiltration of immune cells. In this study, we report the construction and evaluation of a novel oncolytic adenovirus, which can play an antitumor role by promoting tumor vascular normalization(VN) and the formation of tertiary lymphatic structure(TLS).Methods: E1ACR2-deleted oncolytic adenovirus was specifically activated by human telomerase reverse transcriptase(hTERT) and armed with mIL-15 to produce Ad-IL15. The antitumor efficacy of Ad-IL15 was characterized in vitro and in vivo. The effects of Ad-IL15 on tumor vessels and TLS formation were analyzed by polychromatic immunofluorescence and qPCR, and the role and specific mechanism of dendric cells(DCs) were explored by ***: Compared with non-infected cells, Ad-IL15 showed the ability to kill tumor cells efficiently in vitro. Intratumoral injection of Ad-IL15 can exert antitumor effect by increasing tumor infiltrating lymphocytes(TILs). Moreover, intratumoral treatment with Ad-IL15 resulted in vascular normalization(VN) in tumor microenvironment(TME)(i.e., reduced vascular leakage and intratumoral hypoxia and increased PDGFRβ and VCAM-1 vessels), and promoted the local formation of TLS. Concomitantly, Ad-IL15-activated mCD11cDCs exhibited upregulated expression of vascular maturity and TLS promoting factors, and activation of STING-TBK1-IRF3 pathway in ***: Our findings supported the notion that this novel mIL-15-armed oncolytic adenovirus increases the activation and infiltration of immune cells, which supports VN improvement and TLS formation. The mechanism might be related to the activation of STING(interferon gene stimulating factor) pathway in DCs. This discovery provided a theoretical basis for the development and treatment of oncolytic virus.

关键词： Oncolytic Adenovirus dendritic cells CD8-positive T-lymphocytes tertiary lymphoid structures vascular normalization

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