目前,恶性肿瘤仍是全球范围内人类疾病死亡的主要原因之一。越来越多的研究揭示,恶性肿瘤的发生进展与基因表达密切相关。因此,通过转录组学研究寻找恶性肿瘤相关的生物标志物已成为癌症研究的热门领域。白细胞免疫球蛋白样受体B家族成...目前,恶性肿瘤仍是全球范围内人类疾病死亡的主要原因之一。越来越多的研究揭示,恶性肿瘤的发生进展与基因表达密切相关。因此,通过转录组学研究寻找恶性肿瘤相关的生物标志物已成为癌症研究的热门领域。白细胞免疫球蛋白样受体B家族成员3 (Leukocyte immunoglobulin-like receptor subfamily B member 3, LILRB3)是LILR家族的一员,在免疫细胞中广泛表达,主要抑制免疫反应并介导耐受。LILRB3的异常表达与一系列病理学过程相关,包括感染和肿瘤进展过程中的免疫功能抑制,这表明LILRB3可能是免疫疗法的潜在候选靶点。本综述将概述这一广泛的免疫受体的免疫学功能和肿瘤相关性,总结了其在急性髓系白血病白血病、结直肠癌、神经胶质瘤等肿瘤中的研究进展,希望能够为靶向LILR治疗从癌症到自身免疫等多种疾病研究提供新的思路。Currently, malignant tumors remain one of the principal causes of mortality from human diseases globally. An increasing body of research has unveiled that the genesis and progression of malignant tumors are intimately associated with gene expression. Consequently, the quest for biomarkers related to malignant tumors through transcriptomic studies has emerged as a fervent area of cancer research. The Leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3), a constituent of the LILR family, is ubiquitously expressed in immune cells, primarily inhibiting immune responses and mediating tolerance. The aberrant expression of LILRB3 is linked with a spectrum of pathological processes, including the suppression of immune function during infections and tumor progression, suggesting LILRB3 as a potential target for immunotherapy. This review aims to encapsulate the immunological functions and tumor relevance of this expansive immune receptor, summarizing its research progress in malignancies such as acute myeloid leukemia, colorectal cancer, and glioma, in hopes of furnishing novel insights for targeted LILR therapy in a wide array of diseases ranging from cancer to autoimmunity.展开更多
We recently demonstrated that leukocyte Ig-like receptor 4(LILRB4)expressed by monocytic acute myeloid leukemia(AML)cells mediates T-cell inhibition and leukemia cell infiltration via its intracellular domain.The cyto...We recently demonstrated that leukocyte Ig-like receptor 4(LILRB4)expressed by monocytic acute myeloid leukemia(AML)cells mediates T-cell inhibition and leukemia cell infiltration via its intracellular domain.The cytoplasmic domain of LILRB4 contains three immunoreceptor tyrosine-based inhibitory motifs(ITIMs);the tyrosines at positions 360,412,and 442 are phosphorylation sites.Here,we analyzed how the ITIMs of LILRB4 in AML cells mediate its function.Our in vitro and in vivo data show that Y412 and Y442,but not Y360,of LILRB4 are required for T-cell inhibition,and all three ITIMs are needed for leukemia cell infiltration.We constructed chimeric proteins containing the extracellular domain of LILRB4 and the intracellular domain of LILRB1 and vice versa.The intracellular domain of LILRB4,but not that of LILRB1,mediates T-cell suppression and AML cell migration.Our studies thus defined the unique signaling roles of LILRB4 ITIMs in AML cells.展开更多
Leukocyte immunoglobulin-like receptor B4(LILRB4)is an inhibitory receptor in the LILR family mainly expressed on normal and malignant human cells of myeloid origin.By binding to ligands,LILRB4 is activated and subseq...Leukocyte immunoglobulin-like receptor B4(LILRB4)is an inhibitory receptor in the LILR family mainly expressed on normal and malignant human cells of myeloid origin.By binding to ligands,LILRB4 is activated and subsequently recruits adaptors to cytoplasmic immunoreceptor tyrosine inhibitory motifs to initiate different signaling cascades,thus playing an important role in physiological and pathological conditions,including autoimmune diseases,microbial infections,and cancers.In normal myeloid cells,LILRB4 regulates intrinsic cell activation and differentiation.In disease-associated or malignant myeloid cells,LILRB4 is significantly correlated with disease severity or patient survival and suppresses T cells,thereby participating in the pathogenesis of various diseases.In summary,LILRB4 functions as an immune checkpoint on myeloid cells and may be a promising therapeutic target for various human immune diseases,especially for cancer immunotherapy.展开更多
Objective Chronic myelomonocytic leukemia(CMML) has been categorized as an uncommon hematological malignancy with overlapping features of myelodysplastic syndromes(MDS) and myeloproliferative neoplasms that have an in...Objective Chronic myelomonocytic leukemia(CMML) has been categorized as an uncommon hematological malignancy with overlapping features of myelodysplastic syndromes(MDS) and myeloproliferative neoplasms that have an inherent risk of progressing to acute myeloid leukemia(AML). Methods This study presents a case of confirmed CMML combined with M protein, in which the molecular changes upon progression to AML and under decitabine(DAC) plus bortezomib therapy were reported by tracking variant allele frequency(VAF) of mutations in a series of bone marrow samples. Results First, variable sensitivity of clones was observed during DAC treatment, and incomplete mutation clearance may be associated with low overall response rate and unsustained response. Secondly, DAC cannot prevent the new genetic alterations and accumulation of genetic progression on treatment, leading to acute transformation. Finally, autoimmunity was found to have acted as an important pathogenetic factor, increasing the additive mutations that further drive the clonal evolution in CMML. Conclusion Overall, changes in mutations and clonal architecture during CMML progression or treatment are predictive of an early evaluation of therapeutic strategies in CMML.展开更多
Inhibitory leukocyte immunoglobulin-like receptors(LILRB1-5) signal through immunoreceptor tyrosine-based inhibitory motifs(ITIMs) in their intracellular domains and recruit phosphatases protein tyrosine phosphatase, ...Inhibitory leukocyte immunoglobulin-like receptors(LILRB1-5) signal through immunoreceptor tyrosine-based inhibitory motifs(ITIMs) in their intracellular domains and recruit phosphatases protein tyrosine phosphatase, non-receptor type 6(PTPN6, SHP-1), protein tyrosine phosphatase, non-receptor type 6(PTPN6, SHP-2), or Src homology 2 domain containing inositol phosphatase(SHIP) to negatively regulate immune cell activation. These receptors are known to play important regulatory roles in immune and neuronal functions. Recent studies demonstrated that several of these receptors are expressed by cancer cells. Importantly, they may directly regulate development, drug resistance, and relapse of cancer, and the activity of cancer stem cells. Although counterintuitive, these findings are consistent with the generally immune-suppressive and thus tumor-promoting roles of the inhibitory receptors in the immune system. This review focuses on the ligands, expression pattern, signaling, and function of LILRB family in the context of cancer development. Because inhibition of the signaling of certain LILRBs directly blocks cancer growth and stimulates immunity that may suppress tumorigenesis, but does not disturb normal development, LILRB signaling pathways may represent ideal targets for treating hematological malignancies and perhaps other tumors.展开更多
文摘目前,恶性肿瘤仍是全球范围内人类疾病死亡的主要原因之一。越来越多的研究揭示,恶性肿瘤的发生进展与基因表达密切相关。因此,通过转录组学研究寻找恶性肿瘤相关的生物标志物已成为癌症研究的热门领域。白细胞免疫球蛋白样受体B家族成员3 (Leukocyte immunoglobulin-like receptor subfamily B member 3, LILRB3)是LILR家族的一员,在免疫细胞中广泛表达,主要抑制免疫反应并介导耐受。LILRB3的异常表达与一系列病理学过程相关,包括感染和肿瘤进展过程中的免疫功能抑制,这表明LILRB3可能是免疫疗法的潜在候选靶点。本综述将概述这一广泛的免疫受体的免疫学功能和肿瘤相关性,总结了其在急性髓系白血病白血病、结直肠癌、神经胶质瘤等肿瘤中的研究进展,希望能够为靶向LILR治疗从癌症到自身免疫等多种疾病研究提供新的思路。Currently, malignant tumors remain one of the principal causes of mortality from human diseases globally. An increasing body of research has unveiled that the genesis and progression of malignant tumors are intimately associated with gene expression. Consequently, the quest for biomarkers related to malignant tumors through transcriptomic studies has emerged as a fervent area of cancer research. The Leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3), a constituent of the LILR family, is ubiquitously expressed in immune cells, primarily inhibiting immune responses and mediating tolerance. The aberrant expression of LILRB3 is linked with a spectrum of pathological processes, including the suppression of immune function during infections and tumor progression, suggesting LILRB3 as a potential target for immunotherapy. This review aims to encapsulate the immunological functions and tumor relevance of this expansive immune receptor, summarizing its research progress in malignancies such as acute myeloid leukemia, colorectal cancer, and glioma, in hopes of furnishing novel insights for targeted LILR therapy in a wide array of diseases ranging from cancer to autoimmunity.
基金We thank the National Cancer Institute(1R01CA172268)the Cancer Prevention and Research Institute of Texas(RP180435)+3 种基金the Robert A.Welch Foundation(I-1834)China Natural Science Foundation(81872332)Shandong Natural Science Foundation(2018GSF118201)Yantai Science and Technology Development Plan(2018ZHGY070)for generous support.
文摘We recently demonstrated that leukocyte Ig-like receptor 4(LILRB4)expressed by monocytic acute myeloid leukemia(AML)cells mediates T-cell inhibition and leukemia cell infiltration via its intracellular domain.The cytoplasmic domain of LILRB4 contains three immunoreceptor tyrosine-based inhibitory motifs(ITIMs);the tyrosines at positions 360,412,and 442 are phosphorylation sites.Here,we analyzed how the ITIMs of LILRB4 in AML cells mediate its function.Our in vitro and in vivo data show that Y412 and Y442,but not Y360,of LILRB4 are required for T-cell inhibition,and all three ITIMs are needed for leukemia cell infiltration.We constructed chimeric proteins containing the extracellular domain of LILRB4 and the intracellular domain of LILRB1 and vice versa.The intracellular domain of LILRB4,but not that of LILRB1,mediates T-cell suppression and AML cell migration.Our studies thus defined the unique signaling roles of LILRB4 ITIMs in AML cells.
基金This work was supported by the Imported Scholar Project and Startup from Peking University Health Science Center(68263Y1056 to MD).
文摘Leukocyte immunoglobulin-like receptor B4(LILRB4)is an inhibitory receptor in the LILR family mainly expressed on normal and malignant human cells of myeloid origin.By binding to ligands,LILRB4 is activated and subsequently recruits adaptors to cytoplasmic immunoreceptor tyrosine inhibitory motifs to initiate different signaling cascades,thus playing an important role in physiological and pathological conditions,including autoimmune diseases,microbial infections,and cancers.In normal myeloid cells,LILRB4 regulates intrinsic cell activation and differentiation.In disease-associated or malignant myeloid cells,LILRB4 is significantly correlated with disease severity or patient survival and suppresses T cells,thereby participating in the pathogenesis of various diseases.In summary,LILRB4 functions as an immune checkpoint on myeloid cells and may be a promising therapeutic target for various human immune diseases,especially for cancer immunotherapy.
基金Supported by a grant from the Foundation of Ruijin Hospital North Affiliated with Shanghai Jiao Tong University School of Medicine(No.2018ZY03)
文摘Objective Chronic myelomonocytic leukemia(CMML) has been categorized as an uncommon hematological malignancy with overlapping features of myelodysplastic syndromes(MDS) and myeloproliferative neoplasms that have an inherent risk of progressing to acute myeloid leukemia(AML). Methods This study presents a case of confirmed CMML combined with M protein, in which the molecular changes upon progression to AML and under decitabine(DAC) plus bortezomib therapy were reported by tracking variant allele frequency(VAF) of mutations in a series of bone marrow samples. Results First, variable sensitivity of clones was observed during DAC treatment, and incomplete mutation clearance may be associated with low overall response rate and unsustained response. Secondly, DAC cannot prevent the new genetic alterations and accumulation of genetic progression on treatment, leading to acute transformation. Finally, autoimmunity was found to have acted as an important pathogenetic factor, increasing the additive mutations that further drive the clonal evolution in CMML. Conclusion Overall, changes in mutations and clonal architecture during CMML progression or treatment are predictive of an early evaluation of therapeutic strategies in CMML.
基金supported b y the Na tional In stitu te o f Health(1R01CA172268)the Leukemia&Lymphoma Society(1024-14+7 种基金TRP-6024-14)the Robert A.Welch Foundation(I-1834)the Cancer Prevention and Research Institute of Texas(RP140402 and DP150056)the Innovation Program of Shanghai Municipal Education Commission(13G20)the Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learningthe National Natural Science Foundation of China(813706548142200181471524)
文摘Inhibitory leukocyte immunoglobulin-like receptors(LILRB1-5) signal through immunoreceptor tyrosine-based inhibitory motifs(ITIMs) in their intracellular domains and recruit phosphatases protein tyrosine phosphatase, non-receptor type 6(PTPN6, SHP-1), protein tyrosine phosphatase, non-receptor type 6(PTPN6, SHP-2), or Src homology 2 domain containing inositol phosphatase(SHIP) to negatively regulate immune cell activation. These receptors are known to play important regulatory roles in immune and neuronal functions. Recent studies demonstrated that several of these receptors are expressed by cancer cells. Importantly, they may directly regulate development, drug resistance, and relapse of cancer, and the activity of cancer stem cells. Although counterintuitive, these findings are consistent with the generally immune-suppressive and thus tumor-promoting roles of the inhibitory receptors in the immune system. This review focuses on the ligands, expression pattern, signaling, and function of LILRB family in the context of cancer development. Because inhibition of the signaling of certain LILRBs directly blocks cancer growth and stimulates immunity that may suppress tumorigenesis, but does not disturb normal development, LILRB signaling pathways may represent ideal targets for treating hematological malignancies and perhaps other tumors.
