免疫检查点抑制剂治疗口腔鳞癌的研究进展

口腔鳞状细胞癌(Oral squamous cell carcinoma,OSCC)是口腔头颈部肿瘤的常见类型,显著的病理特征为免疫抑制和淋巴细胞的浸润。癌细胞常常通过激活不同的免疫检查点逃避免疫监视,从而躲过机体抗肿瘤免疫反应。目前的治疗方法都有一定的局限性,且毒副作用较大。因此,研究和开发新的治疗手段和给药途径尤为重要。免疫检查点抑制剂(Immune checkpoint inhibitors,ICIs)的引入带动了OSCC临床治疗模式的转变。在这篇综述中,我们讨论了抗细胞程序性死亡受体1(Programmed cell death protein 1,PD-1)治疗OSCC的优势,并综述了目前可用于预测疗效的生物标记物的相关进展。     

肾透明细胞癌联合免疫治疗新策略——有氧糖酵解的研究进展及展望

肾恶性肿瘤的发病率逐年上升,其中肾透明细胞癌约占所有肾恶性肿瘤的80%,肾透明细胞癌独特的遗传背景和突变特征往往涉及以乏氧信号、糖酵解代谢、氨基酸代谢、线粒体氧化磷酸化等通路为代表的肿瘤微环境（tumor microenvironment,TME）内稳态失调。免疫检查点抑制剂（immune checkpoint inhibitor,ICI）联合酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）已经成为晚期肾透明细胞癌患者的一线治疗方案,但是,联合治疗方案的疗效仍有待提高,且缺乏明确诊断、指导用药、评估预后的生物标志物。近年来,多组学研究从不同层次探索肾透明细胞癌分子通路的异常改变。肾透明细胞癌发生代谢重编程,在氧气充足的情况下也以低效能的糖酵解为能量供应来源,促进自身无限生长,并且有氧糖酵解通路展现的显著异常与不良预后相关。肾透明细胞癌异常的糖酵解信号能促进肿瘤生长,并与TME中的免疫细胞相互作用,使促肿瘤免疫和抗肿瘤免疫平衡失调,造成抑制性免疫微环境,介导肿瘤免疫逃逸,从而对免疫治疗产生不利影响。因此,通过阻断异常糖代谢来抑制肿瘤生长,以有氧糖酵解通路和免疫微环境为切入点,可为肾透明细胞癌以及泛肿瘤治疗提供新的研究方向。然而,如何在复杂的肿瘤免疫微环境中最大程度地将肿瘤细胞代谢重编程转化为用药靶点并运用于临床实践仍待探讨。在肾透明细胞癌中,糖酵解抑制剂联合ICI或TKI作为新方案或能协同发挥抗肿瘤效应,逆转治疗抵抗。本文通过对糖酵解代谢途径中的关键限速酶、转运体及其抑制剂与肿瘤免疫微环境之间的关系进行综述,探讨糖酵解抑制剂在肾透明细胞癌中的作用机制和肿瘤免疫微环境的变化,及其与靶向治疗或免疫治疗联合应用的巨大临床转化价值,未来将为肾透明细胞癌的临床诊疗提供新思路,为患者带来临床获益。     

Update on the treatment of metastatic renal cell carcinoma

Metastatic renal cell cancer (mRCC) management has undergone a paradigm shift in recent decades. The first revolution came with the emergence of vascular endothelial growth factor inhibitors; there was a second wave with the unprecedented success of checkpoint inhibitors, and then the latest approach, which is becoming the new care standard in mRCC, of combining these two strategies in different ways. Updated results of Checkmate-214 after 42 mo of follow-up were consistent with previously published results showing the superiority of nivolumab/ipilimumab over sunitinib in progression free survival (PFS), overall survival (OS), and objective response rate (ORR) in intermediate and high-risk patients. However, several studies presented at the American Society of Clinical Oncology 2020 suggested that the best place, and so far, the only one for nivolumab/ipilimumab is the frontline setting. The update on Keynote-426 after 23 mo of follow-up showed no superiority of pembroli-zumab/axitinib over sunitinib in favorable-risk mRCC, suggesting that it should no longer be the first line of choice in low-risk patients. Finally, the phase III Checkmate 9ER trial results revealed the superiority of nivolumab/cabozantinib vs sunitinib in PFS, OS, and ORR, providing a new first-line option among all International Metastatic RCC Database Consortium risk patients. Some phase II clinical trials also presented this year showed promising results with new combination therapies such as nivolumab/sitravatinib, cabozantinib/atezolizumab, and lenvatinib/pembrolizumab, providing promising grounds upon which to start phase III studies. In addition, other works are using novel therapeutic agents with different mechanisms of action, including telaglenastat (a glutaminase inhibitor), entinostat [an inhibitor of histone deacetylases (HDACs)], and olaparib and talazoparib, poly(ADP-ribose) polymerase inhibitors widely used in other tumors. However, some questions regarding mRCC management still need to be addressed, such as head-to-head comparisons between the current options, treatment sequencing, non-clear cell mRCC, and the role of biomarkers to ascertain the best treatment choice.     

Adjuvant therapy in renal cell carcinoma

Several drugs have demonstrated clinical activity in metastatic renal cell carcinoma (mRCC). The identification of key metabolic pathways has led to the development of novel targeted therapies which have drastically changed the treatment paradigm of mRCC. Moreover, immune-checkpoint inhibitors have recently shown significant activity in advanced disease. Despite these advancements, the role of adjuvant therapy in localized, non-metastatic RCC remains unclear. The utility of many of these agents in the adjuvant setting is currently being actively explored. In this review, we will summarize the main clinical trials investigating adjuvant therapy in renal cell carcinoma, focusing primarily on immunotherapy and targeted agents.     

Frontline immunotherapy treatment with nivolumab and ipilimumab in metastatic renal cell cancer: a new standard of care

Nivolumab is a programmed death 1 (PD-1) inhibitor currently approved as second-line treatment for advanced renal cell carcinomas (RCC) after failure of standard antiangiogenic treatment. Motzer et al. have recently published in the New England Journal of Medicine the findings of CheckMate 214 trial, using nivolumab and ipilimumab, a cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor, versus sunitinib in previously untreated advanced RCC. The combination demonstrated a higher 18-month overall survival rate of 75% versus 60%, and a higher objective response rate of 42% versus 27%, for the combination in favor over sunitinib monotherapy. These results herald the rapidly changing role of immune checkpoint inhibitor therapy as first-line treatment for metastatic RCC.     

Radiation therapy in the treatment of metastatic renal cell carcinoma

Adenocarcinoma of the kidney is an unusual tumor, both in its biological behavior and in its response to radiation treatment. Historically, these tumors have been considered to be radioresistant, and the role of radiation therapy remains questionable in the primary management of this disease. However, radiation treatment is routinely used in the palliation of metastatic lesions for relief of symptoms. Therefore we have undertaken a review of our experience in the treatment of this disease to determine the effectiveness of radiation in its palliation. From 1956 to 1981, 125 patients with metastatic lesions from hypernephroma have been treated in the Department of Radiation Therapy at Thomas Jefferson University Hospital. Most patients were referred for relief of bone pain (86), brain metastasis (12), spinal cord compression (9), and soft tissue masses (18). Total doses varied from 2000 rad to a maximum of 6000 rad. Response to treatment was evaluated on the basis of relief of symptoms, either complete, partial or no change. Our results indicate a significantly higher response rate of 65% for total doses equal to or greater than a TDF of 70, as compared to 25% for doses lower than a TDF of 70. No difference in response was observed either for bone or soft tissue metastasis or visceral disease. This leads us to believe that metastatic lesions from adenocarcinomas of the kidney should be treated to higher doses to obtain maximum response rates. Analysis of these results are presented in detail.     

抗PD-L1药物在晚期肿瘤治疗中的应用

程序性死亡分子1(PD-1)及其配体1(PD-L1)在肿瘤细胞逃避宿主免疫系统的识别和消除中发挥重要作用.小鼠肿瘤模型给予抗PD-L1单抗呈现明显的宿主抗肿瘤反应.目前,PD-1/PD-L1信号通路的免疫治疗药物在多种传统方法治疗失败的肿瘤中收到了良好的效果,且不良反应较小,为晚期肿瘤的免疫治疗提供了宝贵的临床经验.     

The renal clear cell carcinoma immune landscape

A comprehensive evaluation of the clear cell renal cell carcinoma (ccRCC) immune landscape was found using 584 RNA-sequencing datasets from The Cancer Genome Atlas (TCGA), we identified 17 key dysregulated immune-associated genes in ccRCC based on association with clinical variables and important immune pathways. Of the numerous findings from our analyses, we found that several of the 17 key dysregulated genes are heavily involved in interleukin and NF-kB signaling and that somatic copy number alteration (SCNA) hotspots may be causally associated with gene dysregulation. More importantly, we also found that key immune-associated genes and pathways are strongly upregulated in ccRCC. Our study may lend novel insights into the clinical implications of immune dysregulation in ccRCC and suggests potential immunotherapeutic targets for further evaluation.     

Programmed cell death-ligand 1 expression is associated with a favourable immune microenvironment and better overall survival in stage I pulmonary squamous cell carcinoma

BackgroundProgrammed cell death-ligand 1 (PD-L1) is expressed in a subgroup of lung cancer that may benefit from immunotherapy. The interaction between PD-L1 expression and tumour infiltrating lymphocytes (TIL) remains poorly understood. This study investigated the expression of PD-L1 in surgically resected stage I pulmonary squamous cell carcinoma (SqCC) and correlated it with TILs in tumour microenvironments, common driver mutations, and clinical outcomes.Materials and methodsOne hundred and five patients with surgically resected stage I squamous cell carcinoma were examined. Paraffin-embedded tumour sections were stained with PD-L1 antibody. Tumours with moderate-to-strong membrane staining in ≥5% of tumour cells were scored as positive for PD-L1 expression. The driver mutation epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and v-raf murine sarcoma viral oncogene homolog B (BRAF) were examined by direct sequencing, while anaplastic lymphoma kinase (ALK), phosphoinositide 3-kinase catalytic alpha (PI3KCA), and fibroblast growth factor receptor 1 (FGFR1) were analysed by immunohistochemistry. The correlations of PD-L1 expression with each subtype of TIL, driver mutations, clinicopathologic parameters, and clinical outcomes were analysed.ResultsThere was positive PD-L1 expression in 56.2% (59/105) of patients. PD-L1 expression was not associated with the common clinicopathologic features and mutations of EGFR, KRAS, BRAF, ALK, PI3KCA, and FGFR1. As regards TILs composition, tumour PD-L1 expression was significantly associated with increased tumour epithelial CD8+ T cells and stromal CD4+ T cells. Otherwise, PD-L1 (+) tumour cells were negatively correlated with PD-L1 (+) immune cells within tumour stroma. By multivariate analysis, tumour PD-L1 expression and increased CD4+ T cell infiltrations in the tumour stroma were independent predictors of better overall survival and had a trend of better disease-free survival.ConclusionsPD-L1 expression is associated with a favourable immune microenvironment in stage I pulmonary SqCC and correlates with better clinical outcome.     

肿瘤免疫抑制微环境对肿瘤免疫治疗作用的研究进展

肿瘤免疫抑制微环境是肿瘤微环境中起抑制免疫功能的部分。其组成包括抑制性细胞和抑制性细胞因子。近年来,因其在肿瘤免疫中的重要作用,CAR－T和PD－1／PD－L1信号通路已成为免疫治疗的研究热点,它们可通过不同的机制产生免疫抑制作用,从而促进肿瘤进展。因此,针对以上机制采取更有效的抗肿瘤疗法有可能减缓肿瘤进展。本文现就免疫抑制微环境对CAR－T疗法和PD－1／PD－L1信号通路在抗肿瘤过程中的作用进行综述。     

Targeting angiogenesis in metastatic renal cell carcinoma

Introduction: Renal cell carcinoma (RCC), and particularly its clear cell histological subtype, is commonly characterized by genetic alterations in the Von Hippel Lindau (VHL) tumor suppressor gene, leading to a typically exasperated angiogenesis. However, other biological and genetic peculiarities contribute to differentiate this malignancy from other solid tumors, including its immunogenicity.

Areas covered: This review focuses on the present and future role of antiangiogenic drugs, administered either alone (as it has been in the past few years), or in combination with other agents (e.g. immune checkpoint inhibitors), in the treatment of metastatic RCC.

Expert commentary: Due to its peculiar pathogenesis, it is unrealistic to expect to be able to get rid of antiangiogenic agents for the treatment of this disease; however, we do expect that combinations of VEGF/VEGFRs-targeting agents with immune checkpoint inhibitors will gradually replace antiangiogenic monotherapies as the standard of care, at least in the first line setting of metastatic RCC patients. Biomarkers discovery remains the highest priority in order to further improve the percentage of patients benefitting of our treatment.     

Statins and survival outcomes in patients with metastatic renal cell carcinoma

BackgroundA growing body of evidence has demonstrated the anti-neoplastic activity of statins. The objective of this study was to investigate the effect of statin use on survival in patients with metastatic renal cell carcinoma (mRCC) treated in the modern therapy era.Patients and methodsWe conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression and the Kaplan–Meier method.ResultsWe identified 4736 patients treated with sunitinib (n = 1059), sorafenib (n = 772), axitinib (n = 896), temsirolimus (n = 457), temsirolimus + interferon (IFN)-α (n = 208), bevacizumab + temsirolimus (n = 393), bevacizumab + IFN-α (n = 391) or IFN-α (n = 560), of whom 511 were statin users. Overall, statin users demonstrated an improved overall survival (OS) compared to non-users (25.6 versus 18.9 months, adjusted hazard ratio [aHR] 0.801, 95% confidence interval [CI] 0.659–0.972, p = 0.025). When stratified by therapy type, a benefit in OS was demonstrated in statin users compared to non-users in individuals receiving therapy targeting vascular endothelial growth factor (28.4 versus 22.2 months, aHR 0.749, 95% CI 0.584–0.961, p = 0.023) or mammalian target of rapamycin (18.6 versus 14.0 months, aHR 0.657, 95% CI 0.445–0.972, p = 0.035) but not in those receiving IFN-α (15.6 versus 14.8 months, aHR 1.292, 95% CI 0.703–2.275, p = 0.410). Adverse events were similar between users and non-users.ConclusionsWe demonstrate that statin use may be associated with improved survival in patients with mRCC treated in the targeted therapy era. Statins could represent an adjunct therapy for patients with mRCC; however, this is hypothesis generating and requires prospective evaluation.     

Microarray analysis of microRNA expression in renal clear cell carcinoma

Aim

To explore the microRNA (miRNA) expression in renal clear cell carcinoma (RCCC).

Methods

We compared the miRNA expression profiles in 11 pairs of RCCC and adjacent nontumorous tissue (NT) from 11 RCCC patients, using a mammalian miRNA microarray containing whole human mature and precursor miRNA sequences. To verify microarray results, Northern blotting was carried out on 5 randomly selected miRNAs.

Results

Totally 81 miRNAs were identified valid expression in RCCC samples, 48 of which specifically detected in RCCC samples, 17 of which detected downregulated in RCCC compared to NT sample, 2 upregulated and 14 without significant difference. MiRNAs in RCCC tissues exhibit an overall higher expression level than NT tissue. The chip results were confirmed by northern blot analysis.

Conclusion

Our study may help to clarify the molecular mechanisms involved in the pathogenesis of RCCC, and miRNAs potentially serve as a novel diagnostic biomarker of RCCC.     

舒尼替尼治疗肾细胞癌的新进展

肾细胞癌（ｒｅｎａｌｃｅｌｌｃａｒｃｉｎｏｍａ,ＲＣＣ）是最常见的肾脏肿瘤,其发病率呈逐年上升趋势,近年来随着ＲＣＣ增殖分子机制研究的深入和新的分子靶向药物不断问世,ＲＣＣ患者的生存率及生活质量均得到显著提高,ＲＣＣ的治疗进入了分子靶向时代。更重要是的,多靶点药物舒尼替尼已经取代传统的ＩＦＮ被列为转移性ＲＣＣ的一线标准治疗药物,联合分子靶向治疗与免疫治疗将是未来的发展方向。本文就舒尼替尼治疗ＲＣＣ的研究现状及进展作一综述。     

A rapid and systemic complete response to stereotactic body radiation therapy and pembrolizumab in a patient with metastatic renal cell carcinoma

Stereotactic body radiation therapy (SBRT) of local tumor would induce an abscopal effect that has been observed in several kinds of human cancers; one important mechanism may involve the improved activation of the host immune system. The immune checkpoint inhibitor can overcome immune tolerance and enhance the activation of antitumor T cells. The combined treatment of SBRT and checkpoint inhibitor may represent a new promising therapeutic approach. Herein, we reported a patient with metastatic renal cell carcinoma (RCC) treated with concurrent SBRT and anti-PD-1 antibody, pembrolizumab, by which the patient achieved an amazingly systemic complete response in only 2.2 months after starting treatment. This case report indicates that the advanced RCC may benefit from the combining treatment of local SBRT and PD-1 inhibitor and provide a useful paradigm worthy of establishing a clinical trial for patients with advanced renal cell carcinoma.     

Thymidylate synthetase allelic imbalance in clear cell renal carcinoma

Purpose  To investigate the allelic status of the thymidylate synthetase (TYMS) gene, located at chromosome band 18p11.32, in renal cell carcinoma (RCC). TYMS is a key target of the 5-fluorouracil (5-FU)-based class of drugs, frequently considered in combination therapies in advanced RCC. TYMS variants, such as the TYMS polymorphic 5′-untranslated region variable number tandem repeat sequence (VNTR), are under investigation to guide 5-FU treatment. Yet, no information is available with regard to changes in TYMS allele frequencies in RCC malignances. Methods  Blood and matched tumor samples were collected from 41 histological proven clear cell RCC affected patients (30 males, 11 females.). TYMS VNTR genotype was first determined in blood to identify heterozygotes employing PCR techniques. To evaluate for allelic imbalance, fragment analysis was performed both in blood and matched tumor DNA of the heterozygote patients. Microsatellite analysis, employing the markers D18S59 and D18S476 mapping, respectively, at the TYMS locus (18p11.32) and 1.5 Mb downstream of the TYMS gene sequence (18p11.31), was performed to confirm TYMS allelic imbalance in tumors. Results  Germ-line TYMS VNTR distribution was: 2R/2R (19.5%), TYMS 2R/3R (36.6%) and TYMS 3R/3R (43.9%). Allelic imbalance for the TYMS tandem repeat region was detected in 26.6% of the heterozygote patients. Microsatellite analysis confirmed the allelic imbalance detected by TYMS VNTR analysis and revealed that the overall frequence of allelic imbalance of chromosome band 18p11.32 was 35%, while the overall allelic imbalance of chromosome band 18p11.31 was 28%. Conclusions  By focusing on the TYMS polymorphic variants in renal cancer, we here provide evidence, to our knowledge, for the first time showing loss of 18p11.32 and 18p11.31 in renal cell carcinomas. As allelic imbalances involving TYMS locus may be an important variable affecting 5-FU responsiveness, this study may contribute to explain different responses of advanced RCC in combined chemotherapeutic regimens incorporating fluoropyridines.     

线粒体钙离子摄入蛋白1在肾透明细胞癌组织中的表达及其临床意义

目的 探讨线粒体钙离子摄入蛋白1（mitochondrial calcium uptake 1,MICU1）在肾透明细胞癌（renal clear cell carcinoma,RCCC）组织中的表达及其临床意义。方法 以2016年1月—2018年12月于延安大学附属医院行根治性肾切除术的30例RCCC患者为研究对象。采用免疫组织化学法检测RCCC组织及癌旁正常组织中MICU1蛋白的表达。采用瞬时转染法分别将MICU1干涉片段和MICU1过表达质粒转染到CAKI-1细胞中（siMICU1组和MICU1组）,分别设置相应的阴性对照（siCtrl组和EV组）。采用Western blot检测蛋白表达,MTS实验和EdU实验检测细胞的增殖能力。收集TCGA数据库中517例RCCC组织转录组数据,分析MICU1 mRNA表达与RCCC患者临床病理特征及预后的关系。结果 MICU1蛋白在RCCC组织中表达水平低于癌旁正常组织（P<0.001）。成功构建过表达MICU1细胞和干涉MICU1细胞,MTS实验和EdU实验显示,MICU1组的细胞增殖能力低于EV组（P<0.05）,siMICU1组的细胞增殖能力高于siCtrl组（P<0.05）。TCGA数据库分析结果显示,MICU1表达与性别、TNM分期有关（P<0.05）;MICU1低表达患者生存率低于高表达患者（χ²=19.290,P＜0.001）;多因素Cox回归显示,MICU1低表达是影响RCCC患者总生存期的独立危险因素（HR=1.641, 95%CI：1.191~2.261,P=0.002）。结论　MICU1在RCCC组织中呈低表达,且可促进RCCC细胞增殖。     

Extremely acute exacerbation of interstitial pneumonia after interferon-alpha treatment for metastatic renal cell carcinoma

We report the case of a 62-year-old Japanese man who presented with right renal cell carcinoma and multiple metastases. The patient had a past medical history of idiopathic interstitial pneumonia 6 years previously. He had received pulse corticosteroid therapy and oral prednisolone, which resulted in marked clinical improvement. He had been followed up for the interstitial pneumonia, without medication, for 5 years and the idiopathic interstitial pneumonia was inactive when the metastatic renal cell carcinoma was diagnosed. However, the patient presented with extremely acute exacerbation of the interstitial pneumonia that occurred after only three intramuscular injections of standard-dose interferon-alpha. Urologists should be aware of this complication in the treatment of renal cell carcinoma patients who have a prior history of interstitial pneumonia.     

Landscape of immune cell infiltration in clear cell renal cell carcinoma to aid immunotherapy

The tumor microenvironment, comprised of tumor cells and tumor-infiltrating immune cells, is closely associated with the clinical outcome of clear cell renal cell carcinoma (ccRCC) patients. However, the landscape of immune infiltration in ccRCC has not been fully elucidated. Herein, we applied multiple computational methods and various datasets to reveal the immune infiltrative landscape of ccRCC patients. The tumor immune infiltration (TII) levels of 525 ccRCC patients using a single-sample gene were examined and further categorized into immune infiltration subgroups. The TII score was characterized by distinct clinical traits and showed a significant divergence based on gender, grade, and stage. A high TII score was associated with the ERBB signaling pathway, the TGF-β signaling pathway, and the MTOR signaling pathway, as well as a better prognosis. Furthermore, patients with high TII scores exhibited greater sensitivity to pazopanib. The low TII score was characterized by a high immune infiltration level of CD8⁺ T cells, T follicular helper cells, and regulatory T cells (Tregs). Moreover, the immune check point genes, including CTLA-4, LAG3, PD-1, and IDO1, presented a high expression level in the low TII score group. Patients in the high TII score group demonstrated significant therapeutic advantages and clinical benefits. The findings in this study have the potential to assist in the strategic design of immunotherapeutic treatments for ccRCC.