Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy

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Atypical cutaneous γδ T cell proliferation with morphologic features of lymphoma but with clinical features and course of PLEVA or lymphomatoid papulosis

Reactive lymphoid infiltrates of the skin composed predominantly of gamma‐delta (γδ) T cells are not well described in the literature. Herein we report a case of an otherwise healthy 4‐year‐old male who presented with a waxing and waning papular rash characterized by small, discrete crusted papules spread across his trunk, face and extremities. Clinical evaluation revealed no evidence of systemic disease. Microscopic examination revealed a dermal, perivascular infiltrate of highly atypical lymphocytes with a γδ T cell phenotype, worrisome for primary cutaneous γδ T cell lymphoma. The clinical course, however, was that of a reactive condition and prompted consideration of a diagnosis of pityriasis lichenoides et varioliformis acuta (PLEVA) and lymphomatoid papulosis (LyP). In many ways, this case defies current classification schemes and seems to expand the spectrum of reactive γδ T cell infiltrates of the skin.     

抗PD-(L)1、抗CTLA-4免疫治疗标志物研究进展

免疫检查点抑制剂已经改变了包括肺癌、黑色素瘤等许多肿瘤的治疗情况，并且在一些难治性肿瘤中表现出持久的应答率，然而在部分接受治疗的患者中表现出无反应及严重免疫相关副作用。为了优化免疫疗法的使用，可能需要多种临床应答的预测性标志物。本研究回顾了几种潜在有效生物标志物的可用数据，通过免疫组化检测肿瘤细胞和免疫细胞中PD-L1的表达，提示其是一种临床疗效的良好预测标志物;且PD-L1表达阴性者经免疫治疗后仍可获益。PD-L1表达在肿瘤内是动态和异质性的:在原发性灶和转移灶之间或在穿刺标本和大体标本之间表达不一致。肿瘤突变负荷与新抗原的高比率可获得持久获益。外周血标志物也可作为潜在标志物，增加的绝对淋巴细胞计数（ALC）与疾病控制和生存显著相关。在这篇综述中，我们旨在讨论抗PD-（L）1与抗CTLA-4 免疫治疗相关标志物研究现状，为临床运用提供指导，以便能够准确筛选出从这些治疗中获益更多的患者。     

The prognostic role of tumour‐infiltrating lymphocytes in oral squamous cell carcinoma: A meta‐analysis

It has been suggested that tumour‐infiltrating lymphocytes (TILs) are associated with the progression of oral squamous cell carcinoma (OSCC). However, the prognostic value of TILs is inconclusive due to the heterogeneity of immune cells within the tumour microenvironment. In this meta‐analysis, we aimed to assess the prognostic value of TILs in OSCC. The PubMed, Cochrane, Embase, Scopus and Web of Science databases were searched up to April 20, 2019, and 33 studies were ultimately included in this meta‐analysis. Our pooled meta‐analysis showed that high infiltration of CD8⁺ TILs, CD45RO⁺ TILs and CD57⁺ TILs favoured better overall survival (OS). However, high infiltration of CD68⁺ macrophages and CD163⁺ macrophages was associated with poor prognosis in OSCC. These findings suggest that CD8⁺ TILs, CD45RO⁺ TILs, CD57⁺ TILs, CD68⁺ macrophages and CD163⁺ macrophages might serve as novel prognostic factors and therapeutic targets in OSCC.     

脑肿瘤患者手术前后T细胞亚群及NK细胞活性的变化

目的 探讨脑肿瘤患者手术前后细胞免疫功能的变化及其临床意义。方法 采用单克隆抗体酶标法对22例脑肿瘤和12例脑内血肿患者手术前后不同时期的T细胞亚群及NK细胞活性进行动态监测。结果 脑肿瘤CD3^ 、CD4^ ,CD10^16 56和CD4^ /CD8^ 比值较对照组均有不同程度降低。而胶质瘤组较其余两组明显下降。34例患者术后4期CD3^ ,CD4^ ,CD16 56^ 比值均发生变化。胶质瘤组在术后1至2周明显低于其余两组。术后3至4周才逐渐恢复至正常水平。结论 脑肿瘤患者细胞免疫功能被抑制。且恶性胶质瘤较良性肿瘤更为明显，手术应激能导致T细胞亚群及NK细胞活性变化。脑肿瘤切除术后细胞免疫功能呈现暂时抑制至逐渐恢复的过程。     

树突状细胞激活的肿瘤浸润性淋巴细胞体外对自体肝癌细胞杀伤活性的研究

目的探讨树突状细胞(DC)激活的肿瘤浸润性淋巴细胞(TIL)体外对自体肝癌细胞杀伤活性.方法从肝癌患者外周血获取DC,应用粒/巨噬细胞集落刺激因子(GM-CSF)、白细胞介素-4(IL-4)和肿瘤抗原激活DC,然后用DC来激活TIL,观察TIL在体外对自体肝癌细胞的杀伤活性.结果DC激活的TIL具有很高的对自体肝癌细胞杀伤活性,杀伤率为(89.39±3.05)%,明显高于未经DC激活的TIL、CD激活的T淋巴细胞和未经DC激活的T淋巴细胞对自体肝癌细胞的杀伤率.结论肝癌患者外周血DC能诱导TIL产生高效而特异的抗肝癌免疫.     

On the Role of Proteasomes in Cell Biology and Proteasome Inhibition as a Novel Frontier in the Development of Immunosuppressants

The proteasome, a large protease complex in cells, is the major machinery for protein degradation. It was previously considered a humble garbage collector, performing housekeeping duties to remove misfolded or spent proteins. Until recently, the interests of immunologists in proteasomes were focused largely on its role in antigen processing. Its real importance in cell biology has only been revealed contemporarily due to the availability of relatively specific inhibitors. It has now become increasingly clear that many aspects of immune responses highly depend on proper proteasome activity. Recently, a proteasome inhibitor has been successfully used to prevent acute as well as ongoing heart allograft rejection in mice. Such inhibitors are also efficacious in treating several autoimmune diseases, such as arthritis, psoriasis, and probably type I diabetes, in animal models. Phase II and III clinical trials of proteasome inhibitors in treating various tumors have shown promising results, and the side-effects of these drugs are tolerable. Therefore, proteasome inhibition represents a new and promising frontier in immunosuppressant development.     

慢性乙型病毒性肝炎患者外周血T淋巴细胞亚群CD27和CD28的表达

目的分析慢性乙型病毒性肝炎患者外周血T淋巴细胞亚群CD27和CD28的表达,初步探讨其分化表型。方法采集分离健康人和慢性乙型病毒性肝炎患者外周血单个核细胞(PBMC),利用多种荧光标记抗体标记细胞表面分子,再用流式细胞仪检测CD8 和CD4 T淋巴细胞表面CD27和CD28分子的表达。结果31例慢性乙型病毒性肝炎患者CD8 CD27 CD28 T细胞占CD8 T细胞(41.13±24.89)%,低于28例健康对照组的(71.93±14.47)%(P<0.05)。而CD8 CD27-CD28-T细胞占CD8 T细胞(42.16±10.98)%,显著高于健康对照组的(9.16±5.24)%(P<0.01)。慢性乙型病毒性肝炎患者CD4 CD27 CD28 T细胞(80.89±7.93)%和健康对照组(83.17±8.31)%比较,差异无统计学意义。结论健康人外周血T淋巴细胞以CD27 CD28 早期分化表型为主。而慢性乙型病毒性肝炎患者外周血中不同的亚群分化特征又有所不同,CD4 T淋巴细胞的分化表型仍然以CD27 CD28 早期分化表型为主,而CD8 T淋巴细胞中早期分化表型明显减少,晚期分化表型(CD27-CD28-)显著增加。     

正常人外周血淋巴细胞 IL—2受体免疫放射测定

采用~(125)I 标记小鼠抗人IL—2受体(P55)的抗Tac(CD_(25))单克隆抗体,成功地建立了人IL—2受体的免疫放射分析法,动态观察了人外周血淋巴细胞经PHA 刺激24、48和72h 后IL—2受体表达的时间曲线,通过Scatchard 作图分析表明~(125)I—抗Tac 单克隆抗体与PHA 活化的上述三个时间点的T 淋巴细胞的最大结合容量(B_(max))分别为43000位点/细胞、54000位点/细胞和61000位点/细胞。本研究为临床IL—2受体检测提供一种简便的免疫放射测定法。     

Surface activation markers of T lymphocytes: role in the detection of infection in neonates

Diagnosis of perinatal infection in the newborn is difficult; there may be few clinical signs and current tests are slow or non-specific. Detection of organisms, antigen or specific antibody to common pathogens often requires repeat samples and does not give immediate results. Haematological parameters, although relied upon frequently to diagnose infection in the neonate prior to a positive bacterial isolation, are unreliable and insensitive. Indicators such as an increase in neutrophil band cell counts are highly variable between morphologists. Infection induces the expression of a number of T lymphocyte surface markers, including CD45RA/CD45RO and CD45RO. The use of changed expression of surface markers as a laboratory test for detection of infection in neonates was evaluated. We used multiparameter flow cytometry to detect expression of early (CD45RA/CD45RO) and late (CD45RO) activation markers. In the respective groups of 50 full term (including 25 normal vaginal deliveries and 25 caesarean deliveries) and 30 premature, i.e. < 36 weeks gestation (born by either normal vaginal delivery or caesarean delivery) the CD45RA isoform was brightly expressed on newborn ‘naive’ CD4⁺ T cells, whereas the CD45RO isoform (including both ‘bright’ and ‘dim’ populations) was present on < 19% of CD4⁺ T cells from these newborn infants. In a group of 37 infants, tested to evaluate possible effects of non-infective parameters such as respiratory distress and iso-immunization, no significant changes in surface marker expression were found and specificity of the test was confirmed. In 14 neonates with documented sepsis, up-regulation of dual staining CD45RA/CD45RO isoforms on CD4⁺ T cells was detected early in the infection. In addition, we found that CD45RO expression persisted for several weeks after bacterial infection, and up to several months in viral infection. In conclusion, detection of T cell activation by flow cytometry for the early diagnosis of neonatal infection is an easy test to carry out on small volumes of blood, is inexpensive, and may be a specific indicator of infection.