外泌体在肿瘤细胞与TAMs之间相互作用中“桥梁”和调控作用的研究进展北大核心

外泌体是一类直径为30~100 nm的圆盘囊泡,其内包含许多组分,诸如复杂RNA和蛋白质等,主要参与细胞间的信号转导。肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)是肿瘤微环境中普遍存在的巨噬细胞,通过对肿瘤生长、免疫逃逸、侵袭和转移、耐药性等多方面的作用影响肿瘤进程。外泌体在肿瘤相关巨噬细胞的招募、极化及抗肿瘤免疫调控等方面发挥着重要的调节功能。同时,TAMs以外泌体为媒介作用于肿瘤细胞,从而构成了外泌体、TAMs与肿瘤细胞之间相互作用的调控通路。综上所述,本文旨在阐明肿瘤细胞与TAMs之间,以外泌体为“桥梁”相互影响的潜在机制,以及靶向肿瘤细胞和TAMs来源的外泌体在恶性肿瘤治疗中的展望。     

顺铂诱导铁死亡促进肿瘤相关巨噬细胞极化抑制宫颈癌细胞耐药性北大核心

目的:探究顺铂通过引起宫颈癌细胞铁死亡进而诱导肿瘤相关巨噬细胞极化从而抑制宫颈癌细胞耐药性的机制。方法:使用5μmol/L顺铂处理顺铂耐药宫颈癌细胞Hela/R一定时间后,采用qRT-PCR法检测铁死亡相关基因的mRNA表达变化情况;使用ELISA试剂盒和荧光染色法测定铁死亡后的Hela/R细胞释放高迁移率族蛋白1(high mobility group box 1,HMGB1)的情况。将顺铂处理过的Hela/R细胞和M2型小鼠骨髓来源巨噬细胞共培养一定时间后,采用流式细胞术检测巨噬细胞激活情况。将共培养后的巨噬细胞和Hela/R细胞共孵育,采用CCK8法和流式细胞术分别检测肿瘤细胞的存活率和凋亡情况。结果:实验数据显示,顺铂可引起Hela/R细胞的铁死亡,抑制其铁死亡抑制基因Slc40a1、Slc7a11、Slc3a2、Gpx4、Fth1、Blvrb的mRNA表达(P<0.05),上调铁死亡诱发基因Slc5a1、Tfrc的mRNA表达(P<0.01)。铁死亡Hela/R细胞释放损伤相关模式分子HMGB1,诱导M2型肿瘤相关巨噬细胞的CD80、CD86和CD40平均荧光强度提升,增强了肿瘤相关巨噬细胞对Hela/R细胞的杀伤能力。结论:顺铂通过引起宫颈癌细胞的铁死亡激活肿瘤相关巨噬细胞进而达到有效杀伤肿瘤细胞的效果。     

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.     

Tumor-associated Macrophage-derived Interleukin-23 Interlinks Kidney Cancer Glutamine Addiction with Immune Evasion

Background

Glutamine addiction is a hallmark of clear cell renal cell carcinoma (ccRCC); yet whether glutamine metabolism impacts local immune surveillance is unclear. This knowledge may yield novel immunotherapeutic opportunities.

Cryo-thermal therapy inducing MI macrophage polarization created CXCL10 and IL-6-rich pro-inflammatory environment for CD4+ T cell-mediated anti-tumor immunity

Purpose: We previously developed a novel cryo-thermal therapy to treat malignant mammary carcinoma and melanoma in a mouse model; long-term survival and CD4⁺ T cell orchestrating anti-tumor immune memory response were achieved. Moreover, cryo-thermal-induced CD4⁺ T cell differentiation into Th1 and CD4⁺CTL sub-lineages, in which M1 macrophage polarization played a direct, important role. In particular, cryo-thermal therapy triggered M1 macrophage polarization with up-regulated expression of C–X–C motif ligand 10 (CXCL10) and Interleukin 6 (IL-6). But whether CXCL10 and IL-6 contribute to CD4⁺ T cell-mediated anti-tumor immunity remains unclear. In this study, the role of cryo-thermal-induced CXCL10 and IL-6 in anti-tumor immunity was determined.

Methods: The level of CXCL10 and IL-6 in spleen and serum was determined by RT-PCR and ELISA on day 14 after cryo-thermal therapy. Splenic dendritic cells (DCs) and macrophages were isolated from cryo-thermal-treated mice on day 5 and 14, and the level of CXCL10 and IL-6 in macrophages and DCs was determined by ELISA. The transwell migration assay was performed to study immune cell migration. In vivo neutralization of CXCL10 or IL-6 was performed to investigate the phenotypic changes of immune cells.

Results: Cryo-thermal therapy induced M1 macrophage polarization with up-regulation of CXCL10 and IL-6 expression in spleen. CXCL10 and IL-6 promoted DCs migration and maturation, and subsequently promoted CD4⁺ T cell migration and differentiation into Th1 and CD4⁺ CTL, moreover, reduced myeloid-derived suppressor cells (MDSCs) accumulation.

Conclusions: Cryo-thermal-induced CXCL10 and IL-6 created acute inflammatory environment to initiate a systemically cascading innate and adaptive anti-tumor immunity, which was more permissive for tumor eradication.     

Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver

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