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.     

代谢组学和肾癌中代谢重编程的研究进展

肾细胞癌是泌尿系统常见的疾病,其癌组织中包括VHL、mTOR等代谢基因突变,这促使人们利用高通量技术来测量小分子代谢物(即代谢组学)。对肾透明细胞癌（clear cell renal cell carcinoma,ccRCC）的研究中,已经发现了由控制肿瘤能量学和生物合成的相同基因所介导的代谢途径的变化,这种经典的生化途径对肿瘤的生存优势被称为代谢重编程,从而出现了ccRCC是一种代谢性疾病的概念。本文将提供代谢组学技术的一般概述并对肾透明细胞癌相关代谢重编程研究进展作一综述。     

Predictors of immunotherapy benefit in Merkel cell carcinoma

Merkel cell carcinoma is a rare cancer for which immune checkpoint blockade is standard-of-care for recurrent/metastatic disease. However, not all patients benefit from immunotherapy. A greater understanding of molecular mechanisms and predictive biomarkers are unmet needs. We retrospectively analyzed electronic health records and next-generation sequencing data of 45 patients treated at our institution from 2013 to 2020 to understand clinical and genomic correlates of benefit from immunotherapy. Our cohort predominantly included individuals with stage III disease at primary disease diagnosis and individuals with stage IV disease at recurrent/metastatic disease diagnosis. Most received immunotherapy as first-line treatment. 43% experienced objective response (median duration of response 24.2 months, 95% confidence interval 8.8-not reached). Median overall survival was 15.5 months (95% confidence interval 9.0–28.7) (median follow-up 25.2 months). Less advanced stage at primary disease diagnosis and shorter disease-free interval between completion of initial treatment and recurrence were each associated with greater odds of response (odds ratio of 0.06, p = 0.04 for stage; odds ratio 0.75, p = 0.05 for disease-free interval). Single-nucleotide variants in ARID2 and NTRK1 were associated with response (p = 0.05, without Bonferroni correction), while none of Merkel cell polyomavirus status, total mutational burden, ultraviolet mutational signatures, and copy-number alterations predicted outcomes. Patients with shorter disease-free interval may be particularly suitable immunotherapy candidates. Our molecular findings point to ARID2 and NTRK1 as potential predictive markers and/or therapeutic targets (e.g., with Trk inhibitors), although this association needs to be confirmed in a larger sample.     

The role of tivozanib in advanced renal cell carcinoma therapy

Introduction: The efficacy of VEGF-targeting therapies in clinical trials led to their recommendation in clinical guidelines for use across the advanced or metastatic renal cell carcinoma (RCC) treatment landscape, however, tolerability (including off-target effects) has remained a challenge. Tivozanib is a selective inhibitor of all three VEGFRs, with limited off-target interaction, which demonstrates efficacy with improved tolerability relative to multikinase VEGFR-TKIs.

Areas covered: Covered here is the clinical development of tivozanib in advanced RCC, including the pivotal Phase III, multicenter, open-label, randomized clinical study comparing tivozanib with sorafenib for the treatment of VEGF- and mTOR therapy-naïve advanced RCC patients. Also covered are ongoing trials, exploring the efficacy and safety of tivozanib in the setting of refractory disease and the utility of tivozanib in combination with checkpoint inhibitors for advanced RCC. Combination of a VEGFR-TKI and immunotherapy is promising in advanced RCC, if the treatment regimens have acceptable tolerability. Here the selectivity of tivozanib may contribute to an acceptable tolerability profile when used in combination therapy.

Expert commentary: The approval of tivozanib provides an additional option for the first-line treatment of advanced or metastatic RCC patients in Europe and allows use of a VEGFR-TKI with selectivity for VEGFRs in this setting.     

以肿瘤干细胞为靶的免疫治疗

肿瘤干细胞(cancer stem cell,CSC)是肿瘤发生和转移的种子细胞,CSC具有自我更新、增殖和不完全分化的能力。CSC对化疗/放疗的抵抗以及免疫逃逸成为肿瘤复发的根源,要提高肿瘤治愈率必须彻底清除CSC。认识CSC的标记特征和"干性"调节关键分子才能有效和特异地攻击CSC。免疫治疗具有抗原识别的靶向性和时空效应性,是以CSC为靶的治疗的基础;以单克隆抗体和致敏的免疫细胞为主要治疗技术的免疫治疗清除CSC具有可实践性和挑战性。     

Prognostic histological and immune markers of renal cell carcinoma

Recent development on the fields of molecular genetics and immunology of human renal cell carcinoma (RCC) have resulted in more successful treatment of advanced and metastatic RCCs. Re-evaluation of the prognostic/predictive data aim the initial tumor staging of RCC patients to achieve better patient selection for immune and gene therapy. 125 RCC patients diagnosed according to the Heidelberg histological classification, graded, Robson staged, immune treated (Interferon-a a+ Vinblastine or Broncho-Waxom/Decaris) were followed-up clinically for 36 months. Tumor immunity markers by immunohistochemistry of tumor infiltrating lymphocytes (TIL) were detected by immunoperoxidase methods using monoclonal antibodies. Tumoral immune complexes (TIC) were visualized by fluorescent polyclonal antibodies. Histologically oncocytomas defined a better (p<0.02) and sarcomatous RCCs a worse (p<0.01) follow-up prognosis. Basically, the metastatic status (related with the stage and grade) determined the clinical outcome (p<0.00002) of the RCC patients. Tumoral immune complexes (TIC) were weak positive, while tumor infiltrating lymphocytes (TIL) weak negative predictors of the succes of Broncho-Waxom/Decaris immune therapy. Molecular genetic based histological classification, grade, stage and metastatic status parameters together with some tumor immunity parameters (TIL, TIC) can predict the success of immunotherapy of RCC patients.     

晚期肺鳞癌靶向及免疫治疗进展

肺癌是目前世界上发病率和死亡率最高的恶性肿瘤。其中,肺鳞癌（squamous-cell lung cancer,SQCLC）为一种常见的病理类型。近年来,许多学者针对肺鳞癌的靶向药物与免疫制剂进行大量的科学研究及临床试验,EGFR单克隆抗体、VEGFR的单克隆抗体、免疫检查点抑制剂等多种药物已在临床试验中取得了一定成果。本文对晚期肺鳞癌的分子靶向治疗及免疫治疗进行系统性的阐述,通过分析其在提高患者生存率、改善生存质量等方面取得的实质性研究成果,探讨目前临床上晚期肺鳞癌的靶向及免疫治疗进展及未来发展方向。     

转移性肾癌免疫治疗临床研究新进展

肾癌是泌尿系统常见的恶性实体肿瘤,其发病率逐年递增。对于早期肾癌,手术仍是最主要的治疗手段。而对于转移性肾癌（metastatic renal cell carcinoma,mRCC）,需要以内科为主的多学科综合治疗,从而最大限度改善患者的生存期。过去十年间,多种血管内皮生长因子（vascular endothelial growth factor,VEGF）和mTOR 抑制剂已获得批准用于mRCC 的治疗,极大改善了患者的预后,但近年来应用上述药物带来的治疗获益已到达一个平台期,几乎所有患者最终出现耐药。随着新的免疫治疗的发展,免疫检查点抑制剂,特别是程序性死亡受体（programmed death- 1,PD- 1）/ 程序性死亡受体配体- 1（programmed death ligand1,PD-L1）抑制剂在转移性肾癌中取得显著疗效,进一步延长患者的生存期。与单药治疗相比,PD- 1/PD-L 1 抑制剂联合其他免疫治疗或抗VEGF等靶向治疗可减少肿瘤诱导的免疫耐受,有望进一步改善预后。     

The role of metastasectomy in advanced renal cell carcinoma

Introduction: So far, clinical experiences have proved metastasectomy as the only approach in the setting of metastatic renal cell carcinoma that may achieve the ‘no evidence of disease’ status, with an associated improvement in survival.

Areas covered: This review aims to summarize the body of knowledge on therapeutic approaches to mRCC, with a specific insight on the role of metastasectomy and on which underlying factors could be good predictors to select patients who may benefit from surgery. In detail, we managed to identify as potential selection criteria: the number of lesions and their site, the DFI, patients’ performance status and, most of all, the completeness of resection.

Expert opinion: The definition of the optimal treatment strategy of mRCC patients is still an unmet clinical need. The decision-making process about treatment strategy should consider specific tumor’s and patient’s characteristics, as well as the integration of the available therapeutic approaches with the aim to reach the best clinical outcome. We consider multidisciplinary management mandatory in order to tailor the treatment approach according to the patient and disease features. The experience of clinicians may be considered crucial in order to select the best candidates for a multimodal approach.     

Progressive immune dysfunction with advancing disease stage in renal cell carcinoma

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肾癌术后免疫治疗T细胞亚群检测及疗效观察

目的:检测肾癌术后患者IL-2免疫治疗前后对外周血T淋巴细胞亚群的水平影响,进一步观察其对肾癌术后患者的疗效。方法:肾癌术后患者98例随机分为两组:实验组58例采用IL-2治疗,皮下注射小剂量（60-100万IU/次）,隔日1次,共3月,以后每年方案同前1年。对照组40例只给予肾癌根治术,不予免疫治疗。应用流式细胞技术检测两组患者不同时间段（治疗前,治疗后2月、6月）外周血CD3+、CD4+、CD8+、CD4+/CD8+,并进行对比研究。观察两组治疗后1年、3年生存率、生活质量(KPS)评分以及不良反应。结果:实验组与对照组CD3+、CD4+、CD4+/CD8+在治疗前无明显差异(P＞0.05),治疗后2月、6月较对照组明显升高(P＜0.05)。术后1年实验组生存率100％(58/58),对照组97.5%（39/40）,两者无明显差异(P＞0.05);术后3年实验组生存率84.5％（49/58）,明显高于对照组（67.5%,27/40)(P＜0.05)。实验组术后1年生活质量评分平均升高19.6分,3年生活质量评分平均升高11.5分,均明显高于对照组3.7分、1.4分(P＜0.05)。实验组不良反应共12例,均为一过性,未影响免疫治疗。对照组无相关不良反应。结论:肾癌根治术后应用IL-2进行免疫治疗,可以提高患者免疫水平,发挥抗肿瘤作用,提高生存率,改善生活质量,不良反应较轻。     

免疫药物及传统药物在晚期肾癌治疗中的价值

目的:对比免疫药物及传统药物在晚期肾癌治疗中的价值。方法:晚期肾癌患者120例根据随机抽签法分为治疗组与对照组各60例,所有患者都手术根除切除,对照组术后给予舒尼替尼靶向药物治疗,治疗组术后给予干扰素-α免疫药物治疗,跟踪时间有一个月。结果:两组的有效率为88.3%、66.7%,与之前做对比,治疗组效果明显好(P＜0.05),治疗后血清CD3和CD4值比治疗前明显高(P＜0.05),而且治疗组治疗后的血清CD3和CD4值高于对照组(P＜0.05)。治疗过程治疗组的恶心、呕吐、疲乏等症状的总体发生情况明显低于对照组(P＜0.05),所有不良反应经对症治疗后症状消退。治疗后随访调查1年,治疗组的半年与1年生存率分别为100.0%和96.7%,对照组为91.7%和85.0%,治疗组的生存率比较高(P＜0.05)。结论:相对于传统药物治疗,免疫药物在晚期肾癌治疗中的应用能使得机体免疫功能得到部分恢复,从而提高治疗疗效,降低不良反应的发生,促进生存率的提高。     

免疫治疗联合放疗治疗晚期非小细胞肺癌的进展

晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）患者手术、放疗、化疗治疗效果欠佳,预后较差。近年来针对NSCLC免疫治疗联合放疗的研究越来越多,可取得较好的肿瘤控制效果。本文就NSCLC免疫治疗联合放射治疗的相关进展进行综述。     

Adjuvant therapy for advanced renal cell carcinoma

Introduction: Locally advanced, non-metastatic renal cell carcinoma (RCC) is conventionally managed with surgery. However, patients are at a high risk of RCC recurrence and have poor survival outcomes. An effective adjuvant systemic treatment is needed to improve on these outcomes. Targeted molecular and immune-based therapies have been investigated, or are under investigation, but their role in this setting remains unclear.

Areas covered: A comprehensive search of PubMed and ClinicalTrials.gov was performed for relevant literature. The following topics pertinent to adjuvant therapy in RCC were evaluated: strategies for patient selection, cytokine-based immunotherapy, vaccine therapy, VEGF and non-VEGF targeted molecular agents, and immune checkpoint inhibitors.

Expert commentary: Strong evidence for the incorporation of adjuvant therapy in high-risk RCC is lacking. Multiple targeted molecular therapies have been examined with only one approved for use. Genetic and molecular-based prognostic models are needed to determine who may benefit from adjuvant therapy. Developing adjuvant therapy strategies in the future depends on the results of important ongoing trials with immunotherapy and targeted agents.     

Sarcomatoid differentiation as a prognostic factor for immunotherapy in metastatic renal cell carcinoma

BACKGROUND: The objective of the current study was to determine the significance of sarcomatoid differentiation as a prognostic factor for immunotherapy in metastatic renal cell carcinoma (RCC). METHODS: Patients with metastatic RCC were included in this study and were categorized according to sarcomatoid differentiation. RESULTS: Patients with sarcomatoid differentiation had more aggressive tumor characteristics than those without sarcomatoid differentiation. After immunotherapy, the median progression-free survival was 9.0 months (95% confidence interval [CI] 1.4-52.7) for patient without sarcomatoid differentiation and 3.2 months (95% CI 0.4-42.9) for patients with sarcomatoid differentiation, respectively (P=0.0001). The median overall survival was 22.2 months (95% CI 3.2-75.4) and 10.0 months (95% CI 0.7-60.1) in both groups. When comparing patients with sarcomatoid differentiation, there was no significant difference of overall survival in the immunotherapy group and the no immunotherapy group. Multivariate Cox proportional hazards model analysis showed that T stage (Hazard ratio [HR] 1.71; 95% CI 1.07-2.74; P=0.024), sarcomatoid differentiation (HR 2.18; 95% CI 1.30-3.66; P = 0.003), and the number of metastasis sites (HR 1.81; 95% CI 1.14-2.88; P=0.012) were independent predictors of progression-free survival. Sarcomatoid differentiation and the number of metastasis sites were independent prognostic predictors of overall survival. The estimated relative risks of sarcomatoid differentiation and the number of metastasis sites were 2.83 (95% CI 1.49-5.40; P=0.002) and 2.31 (95% CI 1.29-4.16; P=0.005), respectively. CONCLUSIONS: Our findings suggest that sarcomatoid differentiation is an important prognostic factor for immunotherapy in metastatic RCC.     

以树突状细胞疫苗为基础的肿瘤免疫治疗

树突状细胞（DC）是目前发现的人体内功能最强的专职抗原呈递细（APC），近年来，以DC为基础的肿瘤免疫治疗越来越引起人们的重视，本文就Dc生物学特征、Dc瘤疫苗分类、抗瘤机制、抗原负载或转染方法、优缺点及其临床研究作一综述。     

Cancer stem cell-immune cell collusion in immunotherapy

Immunotherapy has pioneered a new era of tumor treatment, in which the immune checkpoint blockade (ICB) exerts significant superiority in overcoming tumor immune escape. However, the formation of an immune-suppressive tumor microenvironment (TME) and the lack of effective activation of the immune response have become major obstacles limiting its development. Emerging reports indicate that cancer stem cells (CSCs) potentially play important roles in treatment resistance and progressive relapse, while current research is usually focused on CSCs themselves. In this review, we mainly emphasize the collusions between CSCs and tumor-infiltrating immune cells. We focus on the summary of CSC-immune cell crosstalk signaling pathways in ICB resistance and highlight the application of targeted drugs to improve the ICB response.     

The genomic landscape of metastatic clear cell renal cell carcinoma after systemic therapy

Primary clear cell renal cell carcinoma (ccRCC) has been previously characterized, but the genomic landscape of metastatic ccRCC is largely unexplored. Here, we performed whole exome sequencing (WES) in 68 samples from 44 patients with ccRCC, including 52 samples from a metastatic site. SETD2, PBRM1, APC and VHL were the most frequently mutated genes in the metastatic ccRCC cohort. RBM10 and FBXW7 were also among the 10 most frequently mutated genes in metastatic tissues. Recurrent somatic copy number variations (CNV) were observed at the previously identified regions 3p25, 9p21 and 14q25, but also at 6p21 (CDKN1A) and 13q14 (RB1). No statistically significant differences were found between samples from therapy‐naïve and pretreated patients. Clonal evolution analyses with multiple samples from 13 patients suggested that early appearance of CNVs at 3p25, 9p21 and 14q25 may be associated with rapid clinical progression. Overall, the genomic landscapes of primary and metastatic ccRCC seem to share frequent CNVs at 3p25, 9p21 and 14q25. Future work will clarify the implication of RBM10 and FBXW7 mutations and 6p21 and 13q14 CNVs in metastatic ccRCC.     

转移性肾癌靶向治疗和免疫治疗的现状与进展

近年来,转移性肾癌的治疗方式从细胞因子药物的治疗,到现在的针对血管生成、哺乳动物的雷帕霉素途径、免疫应答的药物的应用发生了巨大的变化。尽管耐药仍然是一个巨大的挑战,但通过对这些药物的应用及药物联合应用,转移性肾癌的治疗疗效得到大大的提高。目前新的治疗方法正在迅速发展,治疗前景一片大好。     

Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological type of esophageal cancer, predominantly constituting 90% of cases worldwide. Despite the development of multidisciplinary therapeutic approaches, its prognosis remains unfavorable. Recently, the development of monoclonal antibodies inhibiting programmed death 1 (PD‐1) or programmed death‐ligand 1 (PD‐L1) has led to marked therapeutic responses among multiple malignancies including ESCC. However, only a few patients achieved clinical benefits due to resistance. Therefore, precise and accurate predictive biomarkers should be identified for personalized immunotherapy in clinical settings. Because the tumor immune microenvironment can potentially influence the patient's response to immune checkpoint inhibitors, tumor immunity, such as PD‐L1 expression on tumors, tumor‐infiltrating lymphocytes, tumor‐associated macrophages, and myeloid‐derived suppressor cells, in ESCC should be further investigated. In this review, accumulated evidence regarding the tumor immune microenvironment and immune checkpoint inhibitors in ESCC are summarized.