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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Prognostic and clinicopathological utility of programmed death-ligand 1 in malignant pleural mesothelioma: A meta-analysis

ObjectiveProgrammed death ligand 1 (PD-L1) has been reported to be connected to prognosis in individuals with malignant pleural mesothelioma (MPM), although there is no consensus based on data from previous studies. Accordingly, this quantitative meta-analysis investigated prognostic and clinicopathological utility of PD-L1 in patients with MPM.MethodsA comprehensive search of the PubMed, Web of Science, Embase, and Cochrane Library databases for articles published up to October 4, 2019 was performed. Studies using immunohistochemical techniques to detect/quantify the expression of PD-L1 in MPM tissue were enrolled in the analysis. The combined hazard ratio (HR) and corresponding 95% confidence interval (CI) was applied to assess the association between PD-L1 expression and overall survival (OS).ResultsA total of 11 studies comprising 1606 patients was included in the present meta-analysis. For OS, pooled data revealed an HR of 1.50 (95% CI 1.32–1.70; p < 0.001), suggesting that patients with PD-L1 overexpression experience inferior OS. Subgroup analysis revealed that elevated PD-L1 remained a significant prognostic indicator for worse OS, irrespective of sample size, cut-off value, ethnicity, and Newcastle-Ottawa Scale score. Moreover, PD-L1 overexpression was associated with non-epithelioid histology (odds ratio 4.30 [95% CI 1.89–9.74]; p < 0.001).ConclusionsResults of this meta-analysis show that elevated expression of PD-L1 could be a factor predicting poorer survival in patients with MPM.     

IL-2激活的TIL对自体肿瘤细胞的杀伤活性及其与LAK细胞活性的比较

肿瘤浸润性淋巴细胞(TIL)经白细胞介素2(IL-2)体外培养后具有很强的体内外抗肿瘤作用,且有一定的靶细胞特异性,其抗肿瘤效果强于淋巴因子激活的杀伤细胞即LAK细胞(P<0.01)。从瘤体中新鲜分离到的TIL对自体肿瘤细胞的杀伤活性极低,经IL-2体外培养后,其杀伤活性逐渐增高,以培养至7～25d的杀伤活性最强,这与IL-2使TIL分泌3种抗癌淋巴因子包括IL-2、IFN-γ、淋巴毒素(LT)增加有关。体外培养25d后,TIL的抗肿瘤活性下降,实验表明这与培养过程中TIL的Lyt-2~+细胞(Tc)减少而L3T4~+细胞(T_H)增多有关。TIL经冻存复苏和IL-2体外培养后仍保持很强的抗肿瘤活性,冻存前后比较未见显著差异(P>0.05),这为间断地运用TIL治疗复发性、晚期肿瘤提供了一条可行的途径。     

人体恶性实体瘤TIL增殖力、表型和杀伤力研究

在建立高活力肿瘤浸润淋巴细胞（ＴＩＬ）分离培养方法的基础上，对８３例恶性实体瘤ＴＩＬ的细胞增殖动力学、部份ＴＩＬ表型与杀伤力等作了较为系统的研究。结果提示，本实验室所建立分离培养的ＴＩＬ增殖能力较强且稳定，有６５％的增殖倍数大于１０００倍；３Ｈ－ＴｄＲ掺入高峰在培养的第４５～７５天；对其自身的原代肿瘤细胞杀伤力可以维持至５６天以上；对５６份经ｒＩＬ２诱导的ＴＩＬ（培养时间１７±５．２天）表型分析：ＣＤ３８０±２１％，ＣＤ４３７±２１％，ＣＤ８４４±１８％，ＨＬＡＤＲ６９±２４％，与ｒＩＬ２诱导前比较，ＣＤ３、ＣＤ４、ＣＤ８和ＨＬＡＤＲ均增多，尤以ＣＤ３与ＣＤ８表型增多明显。     

Separation of tumor-infiltrating lymphocytes from tumor cells in human solid tumors A comparison between velocity sedimentation and discontinuous density gradients

The separation of viable tumor-infiltrating lymphocytes (TIL) from surgical biopsies of human solid tumors was achieved by velocity sedimentation at unit gravity or by discontinuous density gradients. The two methods were adapted to small volumes and cell numbers not exceeding 1 × 10⁸. The recovery, purity and composition of the TIL-enriched fractions were comparable in the two methods. Density gradients were more rapid, simpler and more practical for preparation under sterile conditions of TIL from clinical material than velocity sedimentation. Lymphocytes in the TIL-enriched fractions obtained by either of the methods were poorly responsive to mitogens. This poor responsiveness is a characteristic of the human TIL and seems to be related to effects exerted by tumor cells.     

一氧化氮合酶与浸润性乳腺癌血管形成的关系及临床意义

目的:探讨一氧化氮合酶(nitrioxide synthase,NOS)与浸润性乳腺癌新生血管形成的关系及其临床意义。方法:采用分光光度法检测30例浸润性乳腺癌及其相应癌旁乳腺组织和30例良性乳腺病变组织的 NOS活性,应用免疫组织化学SP法,以抗第8因子相关抗原(ⅧRAg)抗体标记血管内皮细胞,根据ⅧRAg阳性的血管内皮细胞计数来测定微血管密度(microvessel density, MVD)。结果:1)浸润性乳腺癌 NOS活性(2. 22±1 .39)显著高于相应癌旁乳腺组织(1. 29±0 .48)及良性乳腺病变组织(0 .50±0. 14),P=0 .004,P=0. 000;相应癌旁乳腺组织NOS活性高于良性乳腺病变组织,P=0 .000。2)乳腺癌 MVD计数(40. 53±8. 29)明显高于相应癌旁乳腺组织(18. 07±4. 90),P=0 000。3)有腋淋巴结转移者 NOS活性(2 .60±1 .66)高于无淋巴结转移者(1 .72±0 .41),P=0 .048,且明显形成更多的微血管,P=0 000。4)乳腺肿瘤组织NOS活性和MVD与肿瘤大小、分化程度和ER、PR表达状况无关。5)浸润性乳腺癌NOS活性与肿瘤 MVD呈正相关,r=0 .494,P=0 .014。结论:1)浸润性乳腺癌NOS活性、MVD与其淋巴结转移密切相关,一氧化氮(nitric oxide, NO)生成可促肿瘤新生血管形成,并促其生长、发展和侵袭转移。2)肿瘤微环境中 NO合成增加可能促肿瘤生长。3)NOS活性增加可作     

The diagnostic and prognostic value of MRP8/MRP14 in intrahepatic cholangiocarcinoma

Myeloid-related protein 8 (MRP8) and 14 (MRP14) are abundantly expressed in several kinds of benign and malignant tumors. However, little is known about their clinicopathological significance in intrahepatic cholangiocarcinoma (ICC), biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of bile duct (IPNB), or inflammatory hepatic biliary ducts epithelium (IHBD). This study aimed to investigate the diagnostic and prognostic values of MRP8 and MRP14 as new biomarkers for ICC. We examined MRP8 and MRP14 expression levels by immunohistochemistry in IHBD (n = 15), BilIN (BilIN1 = 24, BilIN2 = 9, BilIN3 = 5), IPNB (n = 18) and ICC (n = 416). The differential diagnostic and prognosis values were also evaluated. The results showed that the ratio of tumor-infiltrating MRP8 and MRP14 positive immune cells, relative to biliary epithelial cells, was significantly increased in ICC tissues compared with nonmalignant tissues, including IHBD, BilIN1, BilIN2, BilIN3, and IPNB (P value < 0.05). In addition, over-expression levels of MRP8 and MRP14 were correlated with overall survival (OS) and time to recurrence (TTR) by univariate analysis; MRP8/MRP14 combination was an independent prognostic factor for OS and TTR. MRP8 and MRP14 expression might help to identify the benign bile duct diseases from ICC, as high expression of MRP8 and MRP14 suggests a poor prognosis after surgical resection.     

Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors

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Innovation in Chemistry,Manufacturing, and Controls—A Regulatory Perspective From Industry

This review describes the landscape of novel modalities such as cell and gene therapies, viruses, other novel biologics, oligomers, and emerging technologies, including modern analytics. We summarize the regulatory history and recent landmark developments in some major markets and examine specific chemistry, manufacturing, and controls (CMC) challenges, including suggestions for exploration of potential science-based approaches in support of regulatory strategy development from an industry perspective. In addition, we evaluate the economic factors contributing to patient access to innovation and discuss the impact of regulation. There is a desperate need for a consistent form of regulation where global approaches to regulatory strategies can be harmonized, and specific CMC challenges can be dealt with using the appropriate science and risk-based tools. Although these tools are well described in current guidance documents, the specifics of applicability to complex novel modalities can still result in differing regulatory advice and outcomes. The future goals for efficiently regulating innovative modalities and technologies could be aided by more regulatory harmonization, regulatory education, and industry cooperation through consortia, enabling industry to supply key information to regulators in a transparent yet well-defined manner, and utilizing mutually understood risk-benefit analyses to produce drugs with appropriate safety, efficacy, and quality characteristics.     

B cell and B cell-related pathways for novel cancer treatments

B cells are recognized as the main effector cells of humoral immunity which suppress tumor progression by secreting immunoglobulins, promoting T cell response, and killing cancer cells directly. Given these properties, their anti-tumor immune response in the tumor micro-environment (TME) is of great interest. Although T cell-related immune responses have become a therapeutic target with the introduction of immune checkpoint inhibitors, not all patients benefit from these treatments. B cell and B cell-related pathways (CCL19, −21/CCR7 axis and CXCL13/CXCR5 axis) play key roles in activating immune response through humoral immunity and local immune activation via tertiary lymphoid structure (TLS) formation. However they have some protumorigenic works in the TME. Thus, a better understanding of B cell and B cell-related pathways is necessary to develop effective cancer control. In this review, we summarize recent evidences regarding the roles of B cell and B cell-related pathways in the TME and immune response and discuss their potential roles for novel cancer treatment strategies.