Immune response to bacteria induces dissemination of Ras-activated Drosophila hindgut cells

Although pathogenic bacteria are suspected contributors to colorectal cancer progression, cancer-promoting bacteria and their mode of action remain largely unknown. Here we report that sustained infection with the human intestinal colonizer Pseudomonas aeruginosa synergizes with the Ras1V12 oncogene to induce basal invasion and dissemination of hindgut cells to distant sites. Cross-talk between infection and dissemination requires sustained activation by the bacteria of the Imd-dTab2-dTak1 innate immune pathway, which converges with Ras1V12 signalling on JNK pathway activation, culminating in extracellular matrix degradation. Hindgut, but not midgut, cells are amenable to this cooperative dissemination, which is progressive and genetically and pharmacologically inhibitable. Thus, Drosophila hindgut provides a valuable system for the study of intestinal malignancies.     

Toll-like receptors: A pathway alluding to cancer control

Toll-like receptors (TLRs) are usually expressed on immune cells such as macrophages, dendritic cells, mast cells, as well as on eosinophils and some epithelial cells. They play a central role in the recognition of harmful molecules that belong to invading microorganisms or internal damaged tissues, which lead to inflammation. Among the hallmarks of cancer, there is immune evasion and inflammation. Summing this with the discovery that a majority of cancers also seem to express TLRs, made researchers realize these receptors might also be linked with cancer progression. This review will cover some of the effects of TLR engagement in cancer cells that might induce the promotion or inhibition of cancer with mechanisms involved. The differences of TLR expression in cancer progression and its possible relation with patient prognosis, TLR genetic disorders found in cancer, and new strategies to cancer therapy will be discussed to target TLRs in cancer cells.     

Augumentation of splenic antitumor immunity by local immunotherapy in gastric cancer patients

We previously reported that the antitumor effect of OK-432, a streptococcal preparation, was markedly augmented when this agent was injected into tumors together with fibrinogen. In order to elucidate the effect of this treatment on the spleen, we assessed splenic function in gastric cancer patients receiving preoperative local immunotherapy with OK-432 and fibrinogen. Immunohistochemical studies of the spleen at 7 days after intratumoral injection therapy revealed numerous macrophages phagocytizing OK-432 in the splenic sinuses. Phenotypic analysis of splenocytes by flow cytometry revealed an increase in the CD4/CD8 ratio and in the expression of HLA-DR, CD25, and Leu M3 by splenic T cells of the patients treated with OK-432 plus fibrinogen when compared to patients treated with OK-432 alone or untreated patients. Splenic T cells from patients treated with OK-432 plus fibrinogen showed significantly higher cytotoxicity against Daudi and K562 cells than T cells from control patients (p<0.05), and culture of these splenic T cells with recombinant IL-2 induced the expansion of lymphokine-activated killer cells. These results demonstrate that local immunotherapy with a mixture of OK-432 and fibrinogen effectively augumented splenic antitumor immunity in gastric cancer patients.     

The IκB kinase complex in NF-κB regulation and beyond

The IκB kinase (IKK) complex is the signal integration hub for NF-κB activation. Composed of two serine-threonine kinases (IKKα and IKKβ) and the regulatory subunit NEMO (also known as IKKγ), the IKK complex integrates signals from all NF-κB activating stimuli to catalyze the phosphorylation of various IκB and NF-κB proteins, as well as of other substrates. Since the discovery of the IKK complex components about 15 years ago, tremendous progress has been made in the understanding of the IKK architecture and its integration into signaling networks. In addition to the control of NF-κB, IKK subunits mediate the crosstalk with other pathways, thereby extending the complexity of their biological function. This review summarizes recent advances in IKK biology and focuses on emerging aspects of IKK structure, regulation and function.     

Hypoxia-induced autophagy

A major challenge in formulating an effective immunotherapy is to overcome the mechanisms of tumor escape from immunosurveillance. We showed that hypoxia-induced autophagy impairs cytotoxic T-lymphocyte (CTL)-mediated tumor cell lysis by regulating phospho-STAT3 in target cells. Autophagy inhibition in hypoxic cells decreases phospho-STAT3 and restores CTL-mediated tumor cell killing by a mechanism involving the ubiquitin proteasome system and SQSTM1/p62. Simultaneously boosting the CTL-response, using a TRP-peptide vaccination strategy, and targeting autophagy in hypoxic tumors, improves the efficacy of cancer vaccines and promotes tumor regression in vivo. Overall, in addition to its immunosuppressive effect, the hypoxic microenvironment also contributes to immunoresistance and can be detrimental to antitumor effector cell functions.     

LCK, survivin and PI-3K in the molecular biomarker profiling of oral lichen planus and oral squamous cell carcinoma

T cell signaling is critical in oral lichen planus (OLP) based on the pathogenesis of this chronic inflammatory autoimmune mucocutaneous lesion. Lck plays a key role in T cell signaling; ultimately this signaling affects other targets such as PI-3K. Excessive activity in PI-3K inhibits apoptosis and promotes uncontrolled cell growth. Molecular biomarker profiling in OLP, Chronic Interface Mucosities (CIM), Epithelial Dysplasia (EpD) and Oral Squamous Cell Carcinoma (SCCA) with application of the principle of biomarker voting may represent a new frontier in the diagnosis, assessment and the arguable debate of OLP transformation to cancer. The presence of Lck, PI-3K and Survivin, a cancer specific anti-apoptotic protein was assessed, using immunohistochemistry and tissue micro-array on patient samples, in OLP, SCCA, CIM and EpD. Lck expression was very high in 78.6 % of OLP patients compared to 3.7% in SCCA; PI-3K was high in 63% of SCCA, 100% of EpD, and 35.7% OLP cases. Survivin was high in 64.3% of OLP cases, 96.3% of SCCA, and 100% of EpD. CIM cases may be slightly different molecularly to OLP. Taken together, our data suggest that biomarker protein voting can be effectively used to isolate high-risk OLP cases. Specifically, we show data with four remarkable cases demonstrating that molecular factors are predictive of histopathology. We conclude that it is safer to treat OLP as premalignant lesions, to adopt aggressive treatment measure in histopathologic described well and moderately differentiated SCCA, and to monitor progress of these diseases molecularly using individualized auto-proteomic approach. The use of Lck inhibitors in OLP management needs to be investigated in the future.     

Constitutive expression of functional CD40 on mouse renal cancer cells: induction of Fas and Fas-mediated killing by CD40L

CD40, a member of the TNF receptor superfamily, is expressed on B cells, dendritic cells, and some tumor cells, including melanoma and bladder carcinoma. In this study, we report that both mouse and human renal carcinoma cells (RCC) also constitutively express functional CD40. Treatment of mouse RCC with CD40L induced strong expression of genes and proteins for ICAM-1 and Fas, and this expression was further enhanced by combining CD40L with IFN-gamma. Similar effects were demonstrated using an agonist anti-CD40 antibody. The increased levels of Fas expression on RCC after treatment with CD40L plus IFN-gamma resulted in potent killing by either FasL-positive effector cells or agonistic anti-Fas antibody. The combination of CD40L plus IFN-gamma also significantly enhanced killing of RCC by tumor-specific CTL lines. Our results demonstrate that constitutively expressed CD40 is functionally active and may provide a molecular target for the development of new approaches to the treatment of RCC.     

人乳头瘤病毒16型治疗性疫苗联合免疫效果研究

目的:探索联合免疫策略对人乳头瘤病毒16型(HPV16)治疗疫苗 L2E7E6和 rAdE7E6的免疫效果的影响.方法:用 L2E7E6融合蛋白和重组腺病毒 rAd5E7E6以不同的联合免疫程序分别免疫 C57BL/6小鼠,通过检测其诱发的体液免疫和细胞免疫反应,以及观察其在 HPV16小鼠治疗模型中的抑瘤效果,比较分析联合免疫对小鼠免疫反应及治疗肿瘤效果的影响.结果:异性联合免疫组均可检测到较高水平的体液免疫,该2组针对 E6、E7特异性的 T 细胞免疫反应与同性联合免疫2组相比明显提高,并在小鼠肿瘤治疗模型中能抑制肿瘤生长.结论:异性联合免疫策略可明显提高 HPV16 L2E7E6及 rAd5E7E6疫苗的 T 细胞免疫反应,且有效治疗 HPV16相关肿瘤,为 HPV16 L2E7E6及 rAd5E7E6疫苗的应用提供了实验基础.     

共刺激分子与宫颈癌相关性的研究进展

共刺激分子是T细胞激活的第二信号,有促进T细胞生长、分化和细胞因子产生的正调控分子,也包括诱导和维持T细胞免疫耐受以至凋亡的负调控分子。将从这两方面对共刺激分子在肿瘤免疫,尤其在宫颈癌中的相关研究方面进行综述。     

BCL-3的研究进展

bcl-3基因最初发现于B细胞慢性淋巴细胞白血病（B-CLL）的一个亚型,并被认为是其分子特征。研究显示BCL-3蛋白含七个锚蛋白样重复序列,属于IκB家族蛋白,在NF-κB途径中有着重要的调控作用。此后的研究显示,BCL-3在血液肿瘤及实体肿瘤中均可见过度或失控表达,发挥着促进肿瘤形成的作用,而其正常水平的表达对于正常免疫反应的形成和防止过度的炎症反应也是极其重要的。同时BCL-3也可对促进肿瘤形成的基因进行调控。本文现就BCL-3在这些方面的研究进展作一综述。     

Oncoimmunology: Some fundamental problems of cancer immunotherapy

The review briefly discusses several central problems of modern oncoimmunology. The controversies surrounding the concept of immunological surveillance, as well as the problem of immunological tolerance to tumors, are considered. The discovery of tumor antigens is a great advance towards the identification of possible therapeutic targets. However, antigen-specific vaccinations against cancer have, so far, a very limited use, mainly for prevention of virus-associated cancers, which is essentially based on the antiviral immune response. On the other hand, antibodies to cancer antigens are widely used in cancer diagnosis, and there are remarkable examples of their therapeutic applications. The future opportunities in both theoretical and applied oncoimmunology will directly depend on further advances in basic science.     

宫颈癌患者阴道微生态变化及其与细胞免疫的相关性探讨

目的探讨宫颈癌患者阴道微生态变化及其与细胞免疫的相关性。方法回顾性分析2018年1月-2020年5月本院收治的且经病理确诊的73例宫颈癌患者(宫颈癌组)和同期65例体检筛查宫颈正常者(正常宫颈组)的临床病例资料。两组均采用直接涂片法、革兰染色法检测阴道分泌物中乳酸杆菌、滴虫、支原体、衣原体、细菌性阴道病、霉菌、淋菌、假丝酵母菌、人乳头瘤病毒(HPV)及阴道唾液酸甘酶活性、白细胞酯酶、过氧化氢等。另采用流式细胞仪检测外周血T淋巴细胞(CD3⁺、CD4⁺、CD8⁺、CD4⁺/CD8⁺)及自然杀伤细胞(CD16⁺CD56⁺)水平。观察各组阴道微生态变化情况及外周血CD3⁺、CD4⁺、CD8⁺、CD4⁺/CD8⁺、CD16⁺CD56⁺水平。另对比宫颈癌组中感染致病微生物者、阴道微生态失调者与未感染致病微生物者、阴道微环境正常者的CD3⁺、CD4⁺、CD8⁺、CD4⁺/CD8⁺、CD16⁺CD56⁺水平,采用Pearson相关性分析法分析宫颈癌组阴道乳酸杆菌定植密度与细胞免疫的相关性。结果宫颈癌组滴虫、支原体、衣原体、霉菌、细菌性阴道病、HPV感染检出率及阴道微生态失调率均高于正常宫颈组,宫颈癌组乳酸杆菌定植密度低于正常宫颈组,差异均有统计学意义(P<0.05),宫颈癌组淋菌、假丝酵母菌感染检出率与正常宫颈组比较差异均无统计学意义(P>0.05)；宫颈癌组CD3⁺、CD4⁺、CD4⁺/CD8⁺、CD16⁺CD56⁺水平均低于正常宫颈组,CD8⁺水平高于正常宫颈组,差异均有统计学意义(P<0.05)；宫颈癌组中滴虫、支原体、衣原体、霉菌、细菌性阴道病、HPV感染者及阴道微生态失调者CD3⁺、CD4⁺、CD4⁺/CD8⁺、CD16⁺CD56⁺均低于未感染者、阴道微环境正常者,CD8⁺高于未感染者、阴道微环境正常者,差异均有统计学意义(P<0.05)；宫颈癌患者乳酸杆菌定植密度与CD3⁺、CD4⁺、CD4⁺/CD8⁺、CD16⁺CD56⁺呈正相关性(P<0.05),与CD8⁺呈负相关性(P<0.05)。结论宫颈癌患者阴道致病微生物感染率较健康人群高,同时细胞免疫功能降低,增加罹患宫颈癌的风险。     

Strange attractors: DAMPs and autophagy link tumor cell death and immunity

Resistance to ‘apoptotic'' cell death is one of the major hallmarks of cancer, contributing to tumor development and therapeutic resistance. Damage-associated molecular patterns (DAMPs) are molecules released or exposed by dead, dying, injured, or stressed non-apoptotic cells, with multiple roles in inflammation and immunity. Release of DAMPs not only contributes to tumor growth and progression but also mediates skewing of antitumor immunity during so-called immunogenic tumor cell death (ICD). Autophagy is a lysosome-mediated homeostatic degradation process in which cells digest their own effete organelles and macromolecules to meet bioenergetic needs and enable protein synthesis. For tumor cells, autophagy is a double-edged sword. Autophagy, in balance with apoptosis, can function as a tumor suppressor; autophagy deficiency, associated with alterations in apoptosis, initiates tumorigenesis in many settings. In contrast, autophagy-related stress tolerance generally promotes cell survival, which enables tumor growth and promotes therapeutic resistance. Most anticancer therapies promote DAMP release and enhance autophagy. Autophagy not only regulates DAMP release and degradation, but also is triggered and regulated by DAMPs. This interplay between autophagy and DAMPs, serving as ‘strange attractors'' in the dynamic system that emerges in cancer, regulates the effectiveness of antitumor treatment. This interplay also shapes the immune response to dying cells upon ICD, culling the least fit tumor cells and promoting survival of others. Thus, DAMPs and autophagy are suitable emergent targets for cancer therapy, considering their more nuanced role in tumor progression.     

Construction of an immune-related LncRNA signature with prognostic significance for bladder cancer

Bladder cancer (BLCA) is one of the most common urological cancer with increasing cases and deaths every year. In the present study, we aim to construct an immune-related prognostic lncRNA signature (IRPLS) in bladder cancer (BLCA) patients and explore its immunogenomic implications in pan-cancers. First, the immune-related differentially expressed lncRNAs (IRDELs) were identified by ‘limma’ R package and the score of IRPLS in every patient were evaluated by Cox regression. The dysregulation of IRDELs expression between cancer and para-cancer normal tissues was validated through RT-qPCR. Then, we further explore the biological functions of a novel lncRNA from IRPLS, RP11-89 in BLCA using CCK8 assay, Transwell assay and Apoptosis analysis, which indicated that RP11-89 was able to promote cell proliferation and invasive capacity while inhibits cell apoptosis in BLCA. In addition, we performed bioinformatic methods and RIP to investigate and validate the RP11-89/miR-27a-3p/PPARγ pathway in order to explore the mechanism. Next, CIBERSORT and ESTIMATE algorithm were used to evaluate abundance of tumour-infiltrating immune cells and scores of tumour environment elements in BLCA with different level of IRPLS risk scores. Finally, multiple bioinformatic methods were performed to show us the immune landscape of these four lncRNAs for pan-cancers. In conclusion, this study first constructed an immune-related prognostic lncRNA signature, which consists of RP11-89, PSORS1C3, LINC02672 and MIR100HG and might shed lights on novel targets for individualized immunotherapy for BLCA patients.     

X‐chromosome‐located microRNAs in immunity: Might they explain male/female differences?

In this paper, we hypothesize that X chromosome-associated mechanisms, which affect X-linked genes and are behind the immunological advantage of females, may also affect X-linked microRNAs. The human X chromosome contains 10% of all microRNAs detected so far in the human genome. Although the role of most of them has not yet been described, several X chromosome-located microRNAs have important functions in immunity and cancer. We therefore provide a detailed map of all described microRNAs located on human and mouse X chromosomes, and highlight the ones involved in immune functions and oncogenesis. The unique mode of inheritance of the X chromosome is ultimately the cause of the immune disadvantage of males and the enhanced survival of females following immunological challenges. How these aspects influence X-linked microRNAs will be a challenge for researchers in the coming years, not only from an evolutionary point of view, but also from the perspective of disease etiology.