宫颈癌免疫治疗的耐药机制及应对措施

宫颈癌严重威胁全球女性的生命健康，晚期宫颈癌治疗手段有限，5年生存率不到20%，是妇科肿瘤的巨大挑战。免疫治疗是晚期宫颈癌患者的重要治疗手段之一，包括免疫检查点抑制剂、治疗性疫苗和过继性T细胞免疫疗法等，但免疫治疗耐药性使部分患者无应答而效果不佳。因此，迫切需要深入研究和探讨免疫耐药的机制从而改善耐药，现归纳总结了近年有关宫颈癌中免疫耐药机制的相关研究，主要分为肿瘤内在因素和外在免疫环境改变等因素，并介绍针对免疫耐药提出的应对措施及进展。     

Cancer Stem Cells and Circulatory Tumor Cells Promote Breast Cancer Metastasis

Breast cancer (BC) is a highly metastatic, pathological cancer that significantly affects women worldwide. The mortality rate of BC is related to its heterogeneity, aggressive phenotype, and metastasis. Recent studies have highlighted that the tumor microenvironment (TME) is critical for the interplay between metastasis mediators in BC. BC stem cells, tumor-derived exosomes, circulatory tumor cells (CTCs), and signaling pathways dynamically remodel the TME and promote metastasis. This review examines the cellular and molecular mechanisms governing the epithelial to mesenchymal transition (EMT) that facilitate metastasis. This review also discusses the role of cancer stem cells (CSCs), tumor-derived exosomes, and CTs in promoting BC metastasis. Furthermore, the review emphasizes major signaling pathways that mediate metastasis in BC. Finally, the interplay among CSCs, exosomes, and CTCs in mediating metastasis have been highlighted. Therefore, understanding the molecular cues that mediate the association of CSCs, exosomes, and CTCs in TME helps to optimize systemic therapy to target metastatic BC.     

脂质体辅助递送CTLA-4 siRNA通过激活系统性抗肿瘤免疫反应抑制肾细胞癌生长

目的:探索携带CTLA-4 siRNA的适配子偶联脂质体颗粒是否可以激活肿瘤部位的抗肿瘤免疫反应，抑制肾细胞癌的生长。方法:采用薄膜水化法制备脂质体；使用透射电子显微镜观察脂质体的形态和结构；用Zetasizer测量Zeta电位；共孵育实验观察靶细胞对Lipo-siRNA的摄取；qPCR检测Lipo-siRNA对CTLA-4基因的沉默；小鼠移植瘤模型检测Lipo-siRNA的体内抑瘤能力；流式细胞术检测肿瘤浸润T细胞的激活状态；免疫荧光法检测肿瘤浸润T细胞的数目。结果:成功制备Lipo-siRNA，电镜结果显示其具有双层球状结构；Zetasizer测得其Zeta电位为(+20.53±2.66)mV；荧光显微镜观察结果表明Lipo-siRNA可以被靶细胞有效摄取，qPCR检测Lipo-siRNA可以显著降低CTLA-4基因的表达（P＜0.001）；小鼠移植瘤模型显示Lipo-siRNA较对照组而言可以显著抑制肿瘤生长（P＜0.001），降低肿瘤细胞中CTLA-4的表达（P＜0.001），提升肿瘤浸润T细胞的数量（P＜0.000 1），并且提高了肿瘤浸润T细胞中IL-2（P＜0.000 1）和IFN-γ（P＜0.000 1）的表达水平。结论:适配子偶联脂质体可以携带CTLA-4 siRNA靶向肿瘤细胞，激活肿瘤部位的抗肿瘤免疫反应，抑制肿瘤的生长，对肾细胞癌的治疗具有潜在的临床应用价值。     

ArgD of Mycobacterium tuberculosis is a functional N-acetylornithine aminotransferase with moonlighting function as an effective immune modulator

Mycobacterium tuberculosis (M. tuberculosis) encodes an essential enzyme acetyl ornithine aminotransferase ArgD (Rv1655) of arginine biosynthetic pathway which plays crucial role in M. tuberculosis growth and survival. ArgD catalyzes the reversible conversion of N-acetylornithine and 2 oxoglutarate into glutamate-5-semialdehyde and L-glutamate. It also possesses succinyl diaminopimelate aminotransferase activity and can thus carry out the corresponding step in lysine biosynthesis. These essential roles played by ArgD in amino acid biosynthetic pathways highlight it as an important metabolic chokepoint thus an important drug target. We showed that M. tuberculosis ArgD rescues the growth of ΔargD E. coli grown in minimal media validating its functional importance. Phylogenetic analysis of M. tuberculosis ArgD showed homology with proteins in gram positive bacteria, pathogenic and non-pathogenic mycobacteria suggesting the essentiality of this protein. ArgD is a secretory protein that could be utilized by M. tuberculosis to modulate host innate immunity as its moonlighting function. In-silico analysis predicted it to be a highly antigenic protein. The recombinant ArgD protein when exposed to macrophage cells induced enhanced production of pro-inflammatory cytokines TNF, IL6 and IL12 in a dose dependent manner. ArgD also induced the increased production of innate immune effector molecule NOS2 and NO in macrophages. We also demonstrated ArgD mediated activation of the canonical NFkB pathway. Notably, we also show that ArgD is a specific TLR4 agonist involved in the activation of pro-inflammatory signaling for sustained production of effector cytokines. Intriguingly, ArgD protein treatment activated macrophages to acquire the M1 phenotype through the increased surface expression of MHCII and costimulatory molecules CD80 and CD86. ArgD induced robust B-cell response in immunized mice, validating its antigenicity potential as predicted by the in-silico analysis. These properties of M. tuberculosis ArgD signify its functional plasticity that could be exploited as a possible drug target to combat tuberculosis.     

Motivational interviewing for maternal Immunizations: Intervention development

Background and ObjectiveVaccine uptake during pregnancy remains low. Our objectives were to describe 1) development and adaptation of a clinician communication training intervention for maternal immunizations and 2) obstetrics and gynecology (ob-gyn) clinician and staff perspectives on the intervention and fit for the prenatal care context.MethodsDesign of the Motivational Interviewing for Maternal Immunizations (MI4MI) intervention was based on similar communication training interventions for pediatric settings and included presumptive initiation of vaccine recommendations (“You’re due for two vaccines today”) combined with motivational interviewing (MI) for hesitant patients. Interviews and focus group discussions were conducted with ob-gyn clinicians and staff in five Colorado clinics including settings with obstetric physicians, certified nurse midwives (CNMs), and clinician-trainees. Participants were asked about adapting training to the ob-gyn setting and their implementation experiences. Feedback was incorporated through iterative changes to training components.ResultsInterview and focus group discussion results from participants before (n = 3), during (n = 11) and after (n = 25) implementation guided intervention development and adaptation. Three virtual, asynchronous training components were created: a video and two interactive modules. This virtual format was favored due to challenges attending group meetings; however, participants noted opportunities to practice skills through role-play were lacking. Training modules were adapted to include common challenging vaccine conversations and live-action videos. Participants liked interactive training components and use of adult learning strategies. Some participants initially resisted the presumptive approach but later found it useful after applying it in their practices. Overall, participants reported that MI4MI training fit well with the prenatal context and recommended more inclusion of non-clinician staff.ConclusionsMI4MI training was viewed as relevant and useful for ob-gyn clinicians and staff. Suggestions included making training more interactive, and including more complex scenarios and non-clinician staff.     

The impact of preoperative immune checkpoint inhibitors on kidney and bladder cancer surgeries: a systematic review☆

Therapies based on the use of immune checkpoint inhibitors (ICIs), such as nivolumab, pembrolizumab, ipilimumab, atezolizumab, avelumab, and durvalumab, have proven effective in the treatment of metastatic urological neoplasms. Recently, it has been hypothesized that the use of this type of treatment prior to surgery could lead to an increased difficulty in renal and bladder surgeries. The literature concerning this topic, however, is still scarce and non-consensual. In our systematic review, we used the PRISMA guidelines methodology to search the pertinent literature available up to June 18, 2020 in PubMed. Additionally, we searched the related grey literature in the abstracts of the meetings of the American Society of Clinical Oncology (ASCO), American Society of Clinical Oncology Genitourinary (ASCO-GU), European Society of Medical Oncology (ESMO), and American Urological Association (AUA) from 2015 to 2020. We were able to find only 16 publications that addressed the use of ICIs prior to surgery in kidney and bladder neoplasms. The results were conflicting, and usually the issue of surgical difficulties after the use of ICIs was not directly approached. We hope that our publication may raise the awareness towards the need to further investigate the effects of neoadjuvant ICIs on surgical outcomes in urologic cancers.