The clinical success of cancer immune checkpoint blockade(ICB)has refocused attention on tumor-infiltrating lymphocytes(TILs)across cancer types.The outcome of immune checkpoint inhibitor therapy in cancer patients ha...The clinical success of cancer immune checkpoint blockade(ICB)has refocused attention on tumor-infiltrating lymphocytes(TILs)across cancer types.The 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 microenvironment.State-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 exhaustion.Many of these states are conserved across tumor types,in line with the broad responses observed clinically.Despite this homology,not all cancer types with similar TIL landscapes respond similarly to immunotherapy,highlighting the complexity of the underlying tumor-immune interactions.This observation is further confounded by the strong prognostic benefit of TILs observed for tumor types that have so far respond poorly to immunotherapy.Thus,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 beginning.Within this review,we discuss recent advances in the understanding of TIL biology,their prognostic benefit,and their predictive value for therapy.展开更多
Background Endometriosis is a controversial and enigmatic disease.Deep infiltrating endometriosis （DIE） is responsible for painful symptoms and is the least understood type of endometriosis.Little work has been devo...Background Endometriosis is a controversial and enigmatic disease.Deep infiltrating endometriosis （DIE） is responsible for painful symptoms and is the least understood type of endometriosis.Little work has been devoted to define the location of DIE lesions and its relationships with pain.The aim of the study was to investigate the relationship between the anatomical distribution of DIE lesions and pain symptoms.Methods Clinical data from 354 patients between May 2003 and December 2007 with laparoscopically diagnosed endometriosis were collected including 177 DIE patients and 177 non-DIE patients.The pain symptoms,including dysmenorrhea （DM）,chronic pelvic pain （CPP,defined as intermittent or permanent pelvic pain,not related to the menstruation and longer than 6 months）,deep dyspareunia （pelvic pain at intercourse） and dyschezia （pelvic pain with defecation）,were recorded for every patient before operation.Endometriotic lesions were recorded by their anatomical distributions,the depth of infiltration and lesion colors.And the relationship between the anatomical distribution of DIE lesions and pain symptoms was analyzed.Pearson＇s chi-square test or Fisher＇s exact test,one-way analysis of variance （ANOVA） and linear regression and binary Logistic regression were used for statistical analysis.Results The duration （（13.79±3.94） years） of pain suffering in DIE patients was much longer than that of non-DIE patients （P 〈0.01）.In DIE patients,60.7% of the uterosacral ligament （USL） nodules were bilateral （P 〈0.01）; 44.6% of the cul-de-sacs were completely blocked.Rectum invasion was observed in 19.9% of DIE patients （P=0.03）; pelvic adhesion was also more common.Up to 98.41% of the deep infiltrative lesions were located in the posterior pelvic compartment.DIE lesions were also found in bladder （1.58%）,USL （67.08%）,cul-de-sac （12.02%）,recto-vaginal septum （12.66%）,rectum and rectosigmoid junction （2.85%） and ureter （3.80%）.The odds ratio of U展开更多
Tumor immune microenvironment is closely related to tumor initiation,prognosis,and response to immunotherapy.The immune landscapes,number of infiltrating immune cells,and the localization of lymphocytes in the tumor v...Tumor immune microenvironment is closely related to tumor initiation,prognosis,and response to immunotherapy.The immune landscapes,number of infiltrating immune cells,and the localization of lymphocytes in the tumor vary in across different types of tumors.The immune contexture in cancer,which is determined by the density,composition,functional state and organization of the leukocyte infiltrate of the tumor,can yield information relevant to the prediction of treatment response and patients’prognosis.Better understanding of the immune atlas in human tumors have been achieved with the development and application of single-cell analysis technology,which has provided a reference for prognosis,and insights on new targets for immunotherapy.In this review,we summarized the different characteristics of immune contexture in cancer defined by a variety of single-cell techniques,which have enhanced our understanding on the pathophysiology of the tumor microenvironment.We believe that there are much more to be uncovered in this rapidly developing field of medicine,and they will predict the prognosis of cancer patients and guide the rational design of immunotherapies for success in cancer eradication.展开更多
Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor imm...Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.展开更多
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 un...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,associated markers of TLS,including peripheral node address(PNAd)in high endothelial venules,CD20 in B cells and CD3 in T cells,were examined in 168 OSCC patients,and survival analysis was performed between TLS-positive and TLS-negative cohorts.We detected the presence of TILs by staining CD8+cytotoxic T cells and CD57+NK cells as well.TLSs appeared as highly organized structures in 45(26.8%)cases.TLSpositive patients had a better 5-year overall survival(OS)rate(88.9%vs.56.1%,P<0.001)and relapse-free survival(RFS)rate(88.9%vs.63.4%,P=0.002).Moreover,the presence of TLS was an independent prognostic factor for both the 5-year OS rate(hazard ratio[HR]=3.784;95%confidence interval[CI],1.498–9.562)and RFS rate(HR=3.296;95%CI,1.279–8.490)in multivariate analysis.Furthermore,a higher density of CD8+T cells and CD57+NK cells was found in TLS-positive sections than in TLS-negative counterparts(P<0.001),and their combination provided a higher predictive accuracy(AUC=0.730;95%CI,0.654–0.805).In conclusion,our results suggest that TLS is an independent positive prognostic factor for OSCC patients.These findings provide a theoretical basis for the future diagnostic and therapeutic value of TLSs in OSCC treatment.展开更多
Tumor-host interaction at the invasive front of colorectal cancer represents a critical interface encompassing a dynamic process of de-differentiation of colorectal carci-noma cells known as epithelial mesenchymal tra...Tumor-host interaction at the invasive front of colorectal cancer represents a critical interface encompassing a dynamic process of de-differentiation of colorectal carci-noma cells known as epithelial mesenchymal transition (EMT). EMT can be identified histologically by the presence of "tumor budding" ,a feature which can be highly specific for tumors showing an inf iltrating tumor growth pattern. Importantly,tumor budding and tumor border configuration have generated considerable interest as additional prognostic factors and are also recognized as such by the International Union Against Cancer. Evidence seems to suggest that the presence of tumor budding or an infiltrating growth pattern is inversely correlated with the presence of immune and inflammatory responses at the invasive tumor front. In fact,several tumor-associated antigens such as CD3,CD4,CD8,CD20,Granzyme B,FOXP3 and other immunological or inflammatory cell types have been identified as poten-tially prognostic in patients with this disease. Evidence seems to suggest that the balance between protumor (including budding and inf iltrating growth pattern) and anti-tumor (immune response or certain inflammatory cell types) factors at the invasive front of colorectal cancer may be decisive in determining tumor progression and the clinical outcome of patients with colorectal cancer. On one hand,the inf iltrating tumor border configuration and tumor budding promote progression and dissemination of tumor cells by penetrating the vascular and lymphatic vessels. On the other,the host attempts to fend off this attack by mounting an immune response to protect vascular and lymphatic channels from invasion by tumor buds. Whereas standard pathology reporting of breast and prostate cancer involves additional prognostic features,such as the BRE and Gleason scores,the ratio of pro-and anti-tumor factors could be a promising approach for the future development of a prognostic score for patients with colorectal cancer which could complement tumor node metastasis stagin展开更多
Deep infiltrating endometriosis is an often-painful disorder affecting women during their reproductive years that usually involves the structures of the pelvis and frequently the gastrointestinal tract.We present the ...Deep infiltrating endometriosis is an often-painful disorder affecting women during their reproductive years that usually involves the structures of the pelvis and frequently the gastrointestinal tract.We present the case of a 37-year-old female patient with an endometrial growth on the sigmoid colon wall causing pain,diarrhea and the presence of blood in the feces.The histology of the removed specimen also revealed the involvement of the utero-vesical fold,the recto-vaginal septum and a pericolic lymph node,which are all quite uncommon findings.To identify the endometrial cells,we performed immunohistochemical staining for CD10and the estrogen and progesterone receptors.展开更多
BACKGROUND The complexity of the immune microenvironment has an impact on the treatment of colorectal cancer(CRC),one of the most prevalent malignancies worldwide.In this study,multi-omics and single-cell sequencing t...BACKGROUND The complexity of the immune microenvironment has an impact on the treatment of colorectal cancer(CRC),one of the most prevalent malignancies worldwide.In this study,multi-omics and single-cell sequencing techniques were used to investigate the mechanism of action of circulating and infiltrating B cells in CRC.By revealing the heterogeneity and functional differences of B cells in cancer immunity,we aim to deepen our understanding of immune regulation and provide a scientific basis for the development of more effective cancer treatment strategies.AIM To explore the role of circulating and infiltrating B cell subsets in the immune microenvironment of CRC,explore the potential driving mechanism of B cell development,analyze the interaction between B cells and other immune cells in the immune microenvironment and the functions of communication molecules,and search for possible regulatory pathways to promote the anti-tumor effects of B cells.METHODS A total of 69 paracancer(normal),tumor and peripheral blood samples were collected from 23 patients with CRC from The Cancer Genome Atlas database(https://portal.gdc.cancer.gov/).After the immune cells were sorted by multicolor flow cytometry,the single cell transcriptome and B cell receptor group library were sequenced using the 10X Genomics platform,and the data were analyzed using bioinformatics tools such as Seurat.The differences in the number and function of B cell infiltration between tumor and normal tissue,the interaction between B cell subsets and T cells and myeloid cell subsets,and the transcription factor regulatory network of B cell subsets were explored and analyzed.RESULTS Compared with normal tissue,the infiltrating number of CD20+B cell subsets in tumor tissue increased significantly.Among them,germinal center B cells(GCB)played the most prominent role,with positive clone expansion and heavy chain mutation level increasing,and the trend of differentiation into memory B cells increased.However,the number of plasma cells in the tumor microenviro展开更多
文摘The clinical success of cancer immune checkpoint blockade(ICB)has refocused attention on tumor-infiltrating lymphocytes(TILs)across cancer types.The 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 microenvironment.State-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 exhaustion.Many of these states are conserved across tumor types,in line with the broad responses observed clinically.Despite this homology,not all cancer types with similar TIL landscapes respond similarly to immunotherapy,highlighting the complexity of the underlying tumor-immune interactions.This observation is further confounded by the strong prognostic benefit of TILs observed for tumor types that have so far respond poorly to immunotherapy.Thus,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 beginning.Within this review,we discuss recent advances in the understanding of TIL biology,their prognostic benefit,and their predictive value for therapy.
文摘Background Endometriosis is a controversial and enigmatic disease.Deep infiltrating endometriosis （DIE） is responsible for painful symptoms and is the least understood type of endometriosis.Little work has been devoted to define the location of DIE lesions and its relationships with pain.The aim of the study was to investigate the relationship between the anatomical distribution of DIE lesions and pain symptoms.Methods Clinical data from 354 patients between May 2003 and December 2007 with laparoscopically diagnosed endometriosis were collected including 177 DIE patients and 177 non-DIE patients.The pain symptoms,including dysmenorrhea （DM）,chronic pelvic pain （CPP,defined as intermittent or permanent pelvic pain,not related to the menstruation and longer than 6 months）,deep dyspareunia （pelvic pain at intercourse） and dyschezia （pelvic pain with defecation）,were recorded for every patient before operation.Endometriotic lesions were recorded by their anatomical distributions,the depth of infiltration and lesion colors.And the relationship between the anatomical distribution of DIE lesions and pain symptoms was analyzed.Pearson＇s chi-square test or Fisher＇s exact test,one-way analysis of variance （ANOVA） and linear regression and binary Logistic regression were used for statistical analysis.Results The duration （（13.79±3.94） years） of pain suffering in DIE patients was much longer than that of non-DIE patients （P 〈0.01）.In DIE patients,60.7% of the uterosacral ligament （USL） nodules were bilateral （P 〈0.01）; 44.6% of the cul-de-sacs were completely blocked.Rectum invasion was observed in 19.9% of DIE patients （P=0.03）; pelvic adhesion was also more common.Up to 98.41% of the deep infiltrative lesions were located in the posterior pelvic compartment.DIE lesions were also found in bladder （1.58%）,USL （67.08%）,cul-de-sac （12.02%）,recto-vaginal septum （12.66%）,rectum and rectosigmoid junction （2.85%） and ureter （3.80%）.The odds ratio of U
基金This work was supported by the State Key Project for Liver Cancer(2018ZX10732202-001)the National Research Program of China(2017YFA0505803,2017YFC0908100)+1 种基金National Natural Science Foundation of China(81790633,91729303,81672860,81702298 and 81422032)National Natural Science Foundation of Shanghai(17ZR143800)
文摘Tumor immune microenvironment is closely related to tumor initiation,prognosis,and response to immunotherapy.The immune landscapes,number of infiltrating immune cells,and the localization of lymphocytes in the tumor vary in across different types of tumors.The immune contexture in cancer,which is determined by the density,composition,functional state and organization of the leukocyte infiltrate of the tumor,can yield information relevant to the prediction of treatment response and patients’prognosis.Better understanding of the immune atlas in human tumors have been achieved with the development and application of single-cell analysis technology,which has provided a reference for prognosis,and insights on new targets for immunotherapy.In this review,we summarized the different characteristics of immune contexture in cancer defined by a variety of single-cell techniques,which have enhanced our understanding on the pathophysiology of the tumor microenvironment.We believe that there are much more to be uncovered in this rapidly developing field of medicine,and they will predict the prognosis of cancer patients and guide the rational design of immunotherapies for success in cancer eradication.
基金Supported by(in part)Research Programs on the Innovative Development and Application for New Drugs for Hepatitis B(No.17fk0310116h0001) from the Japan Agency for Medical Research and Development(AMED)Extramural Collaborative Research Grant of Cancer Research Institute,Kanazawa University
文摘Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.
基金This work was supported by the National Natural Science Foundations of China(Nos.81972532,81772896,81602383 and 81472524)the Science and Technology Planning Project of Guangzhou City of China(No.2017004020102).
文摘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,associated markers of TLS,including peripheral node address(PNAd)in high endothelial venules,CD20 in B cells and CD3 in T cells,were examined in 168 OSCC patients,and survival analysis was performed between TLS-positive and TLS-negative cohorts.We detected the presence of TILs by staining CD8+cytotoxic T cells and CD57+NK cells as well.TLSs appeared as highly organized structures in 45(26.8%)cases.TLSpositive patients had a better 5-year overall survival(OS)rate(88.9%vs.56.1%,P<0.001)and relapse-free survival(RFS)rate(88.9%vs.63.4%,P=0.002).Moreover,the presence of TLS was an independent prognostic factor for both the 5-year OS rate(hazard ratio[HR]=3.784;95%confidence interval[CI],1.498–9.562)and RFS rate(HR=3.296;95%CI,1.279–8.490)in multivariate analysis.Furthermore,a higher density of CD8+T cells and CD57+NK cells was found in TLS-positive sections than in TLS-negative counterparts(P<0.001),and their combination provided a higher predictive accuracy(AUC=0.730;95%CI,0.654–0.805).In conclusion,our results suggest that TLS is an independent positive prognostic factor for OSCC patients.These findings provide a theoretical basis for the future diagnostic and therapeutic value of TLSs in OSCC treatment.
文摘Tumor-host interaction at the invasive front of colorectal cancer represents a critical interface encompassing a dynamic process of de-differentiation of colorectal carci-noma cells known as epithelial mesenchymal transition (EMT). EMT can be identified histologically by the presence of "tumor budding" ,a feature which can be highly specific for tumors showing an inf iltrating tumor growth pattern. Importantly,tumor budding and tumor border configuration have generated considerable interest as additional prognostic factors and are also recognized as such by the International Union Against Cancer. Evidence seems to suggest that the presence of tumor budding or an infiltrating growth pattern is inversely correlated with the presence of immune and inflammatory responses at the invasive tumor front. In fact,several tumor-associated antigens such as CD3,CD4,CD8,CD20,Granzyme B,FOXP3 and other immunological or inflammatory cell types have been identified as poten-tially prognostic in patients with this disease. Evidence seems to suggest that the balance between protumor (including budding and inf iltrating growth pattern) and anti-tumor (immune response or certain inflammatory cell types) factors at the invasive front of colorectal cancer may be decisive in determining tumor progression and the clinical outcome of patients with colorectal cancer. On one hand,the inf iltrating tumor border configuration and tumor budding promote progression and dissemination of tumor cells by penetrating the vascular and lymphatic vessels. On the other,the host attempts to fend off this attack by mounting an immune response to protect vascular and lymphatic channels from invasion by tumor buds. Whereas standard pathology reporting of breast and prostate cancer involves additional prognostic features,such as the BRE and Gleason scores,the ratio of pro-and anti-tumor factors could be a promising approach for the future development of a prognostic score for patients with colorectal cancer which could complement tumor node metastasis stagin
文摘Deep infiltrating endometriosis is an often-painful disorder affecting women during their reproductive years that usually involves the structures of the pelvis and frequently the gastrointestinal tract.We present the case of a 37-year-old female patient with an endometrial growth on the sigmoid colon wall causing pain,diarrhea and the presence of blood in the feces.The histology of the removed specimen also revealed the involvement of the utero-vesical fold,the recto-vaginal septum and a pericolic lymph node,which are all quite uncommon findings.To identify the endometrial cells,we performed immunohistochemical staining for CD10and the estrogen and progesterone receptors.
文摘BACKGROUND The complexity of the immune microenvironment has an impact on the treatment of colorectal cancer(CRC),one of the most prevalent malignancies worldwide.In this study,multi-omics and single-cell sequencing techniques were used to investigate the mechanism of action of circulating and infiltrating B cells in CRC.By revealing the heterogeneity and functional differences of B cells in cancer immunity,we aim to deepen our understanding of immune regulation and provide a scientific basis for the development of more effective cancer treatment strategies.AIM To explore the role of circulating and infiltrating B cell subsets in the immune microenvironment of CRC,explore the potential driving mechanism of B cell development,analyze the interaction between B cells and other immune cells in the immune microenvironment and the functions of communication molecules,and search for possible regulatory pathways to promote the anti-tumor effects of B cells.METHODS A total of 69 paracancer(normal),tumor and peripheral blood samples were collected from 23 patients with CRC from The Cancer Genome Atlas database(https://portal.gdc.cancer.gov/).After the immune cells were sorted by multicolor flow cytometry,the single cell transcriptome and B cell receptor group library were sequenced using the 10X Genomics platform,and the data were analyzed using bioinformatics tools such as Seurat.The differences in the number and function of B cell infiltration between tumor and normal tissue,the interaction between B cell subsets and T cells and myeloid cell subsets,and the transcription factor regulatory network of B cell subsets were explored and analyzed.RESULTS Compared with normal tissue,the infiltrating number of CD20+B cell subsets in tumor tissue increased significantly.Among them,germinal center B cells(GCB)played the most prominent role,with positive clone expansion and heavy chain mutation level increasing,and the trend of differentiation into memory B cells increased.However,the number of plasma cells in the tumor microenviro
