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HLA-G high-expressor 3'UTR markers are linked to gastric cancer development and survival. HLA-G 高表达 3'UTR 标记与胃癌的发展和生存有关。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-16 DOI: 10.1007/s00262-024-03771-w
Christian Vaquero-Yuste, Ignacio Juarez, Marta Molina-Alejandre, Elisa María Molanes-López, Alberto Gutiérrez-Calvo, Adela López-García, Inmaculada Lasa, Remedios Gómez, Antonio Arnaiz-Villena, Jose Manuel Martín-Villa

Gastric cancer ranks fifth in both world prevalence and lethality, with a 5-year survival of less than 30%. HLA-G, a non-classical class I HLA gene, has emerged as a potential marker for cancer susceptibility and prognosis due to its immunomodulatory properties. Its level of expression is regulated by polymorphisms in the 3' untranslated region (3'UTR) polymorphisms, which form various combined haplotypes (UTR-1 to -9). In this study, we examined HLA-G 3'UTR polymorphisms in paired tissue samples from 111 patients with gastric adenocarcinoma and 119 healthy controls. Polymorphism analysis was performed using PCR and Sanger sequencing, followed by statistical analysis using SNPStats software. Survival analysis was conducted using Kaplan-Meier curves and multivariate Cox regression models. High-expressor HLA-G 3'UTR haplotypes (UTR-1 and UTR-6) were significantly associated with gastric cancer susceptibility, indicating a potential role in tumor immune evasion. Additionally, the 14 base pair insertion/deletion polymorphism (14 bp I/D) emerged as a prognostic marker, with D/D genotype carriers showing lower survival rates compared to I/D and I/I genotype carriers. Our study highlights the clinical relevance of HLA-G polymorphisms in gastric cancer, suggesting their potential as prognostic markers and therapeutic targets. Further elucidation of HLA-G-related pathways could lead to personalized treatment strategies and improved patient outcomes in gastric cancer.

胃癌的发病率和致死率均居世界第五位,5 年生存率不到 30%。HLA-G 是一种非经典的 I 类 HLA 基因,由于其免疫调节特性,已成为癌症易感性和预后的潜在标志物。其表达水平受 3' 非翻译区(3'UTR)多态性的调控,这些多态性形成了各种组合单倍型(UTR-1 至 -9)。在这项研究中,我们检测了 111 名胃癌患者和 119 名健康对照者配对组织样本中的 HLA-G 3'UTR 多态性。多态性分析采用 PCR 和 Sanger 测序法进行,然后使用 SNPStats 软件进行统计分析。采用 Kaplan-Meier 曲线和多变量 Cox 回归模型进行生存分析。高表达HLA-G 3'UTR单倍型(UTR-1和UTR-6)与胃癌易感性显著相关,表明其在肿瘤免疫逃避中的潜在作用。此外,14 个碱基对插入/缺失多态性(14 bp I/D)成为预后标记,与 I/D 和 I/I 基因型携带者相比,D/D 基因型携带者的生存率较低。我们的研究强调了胃癌中HLA-G多态性的临床意义,表明它们具有作为预后标志物和治疗靶点的潜力。进一步阐明与HLA-G相关的通路可能有助于制定个性化的治疗策略,改善胃癌患者的预后。
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引用次数: 0
Hepatitis associated with immune checkpoint inhibitors-based combinations of other therapies: A real-world pharmacovigilance analysis based on the FDA adverse event reporting system (FAERS) database. 与基于免疫检查点抑制剂的其他疗法组合相关的肝炎:基于FDA不良事件报告系统(FAERS)数据库的真实世界药物警戒分析。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-15 DOI: 10.1007/s00262-024-03858-4
Zhaohui Li, Zixiang Zhou, Nan Zhang, Binhe Tian, Xiangqi Chen, Haitao Zhao, Hanping Wang

Background: The combination regimen with immune checkpoint inhibitors (ICIs) and other therapies has been widely applied for patients with non-small-cell lung cancer (NSCLC). To date, no literature has systematically addressed the risk of hepatitis associated with the combination therapy. We conducted this pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS).

Patients and methods: A total of 587,016 NSCLC reports were extracted from FAERS database spanning from the first quarter of 2013 to the second quarter of 2023. After filtering duplicate reports, logistic regression model was used to detect safety signals, and multivariable logistic regression model was used to confirm the interaction between ICI and other drugs.

Results: Of the 81,512 patients with NSCLC, 2785 cases developed hepatitis. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with targeted therapy (TT) was the highest 1.64 (95% CI, 1.32-2.02; P < 0.0001) among all therapies, while that of TT and ICI treatment were 1.07 (95% CI, 0.98-1.17; P = 0.1097) and 1.12 (95% CI, 1.03-1.22; P = 0.0111), respectively. The adjusted ROR for the interaction effect was 1.64 (95% CI, 1.32-2.02; P < 0.0001). Furthermore, the adjusted ROR of ICI combined with KRAS-targeted drugs was the highest 3.03 (95% CI, 1.49-5.93; P = 0.0016) among all targeted drugs, with an adjusted ROR of 3.03 (95% CI, 1.49-5.93; P = 0.0016), indicating a meaningful interaction of these two kinds of drugs.

Conclusion: We confirmed that combination treatment of ICI and TT is associated with the amplified risk of hepatitis, which is partly due to the interaction between ICI and TT, and the KRAS-targeted drugs may harbor the highest potential for hepatitis induction among TT drugs when combined with ICI. Besides, the combination treatment of ICI- and KRAS-targeted drugs also increases the incidence of colitis, pulmonary embolism and dehydration.

背景:免疫检查点抑制剂(ICIs)与其他疗法的联合疗法已被广泛应用于非小细胞肺癌(NSCLC)患者的治疗。迄今为止,还没有文献系统地论述了联合疗法相关的肝炎风险。我们利用食品药品管理局不良事件报告系统(FAERS)进行了这项药物警戒分析:我们从 FAERS 数据库中提取了 587,016 份 NSCLC 报告,时间跨度为 2013 年第一季度至 2023 年第二季度。过滤重复报告后,使用逻辑回归模型检测安全性信号,并使用多变量逻辑回归模型确认ICI与其他药物之间的相互作用:结果:在81512例NSCLC患者中,有2785例出现肝炎。多变量逻辑回归分析显示,ICI联合靶向治疗(TT)的调整ROR最高,为1.64(95% CI,1.32-2.02;P 结论:我们证实了ICI联合靶向治疗(TT)与其他药物的相互作用:我们证实了 ICI 和 TT 的联合治疗与肝炎风险的增加有关,部分原因是 ICI 和 TT 之间的相互作用,而 KRAS 靶向药物与 ICI 联合治疗时,可能是 TT 药物中诱发肝炎可能性最大的药物。此外,ICI 和 KRAS 靶向药物联合治疗还会增加结肠炎、肺栓塞和脱水的发生率。
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引用次数: 0
Hepatic arterial infusion chemotherapy combined with systemic therapy sequentially or simultaneously for advanced hepatocellular carcinoma. 肝动脉灌注化疗与全身治疗相继或同时治疗晚期肝细胞癌。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-14 DOI: 10.1007/s00262-024-03872-6
Yu-Zhe Cao, Jia-Yu Pan, Guang-Lei Zheng, Chao An, Meng-Xuan Zuo

Background and aims: The goal of this study was to compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with targeted therapy and PD-(L)1 blockade (triple therapy), either sequentially (SE) or simultaneously (SI), in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC).

Approach and results: From January 1, 2018, to June 1, 2022, 575 patients with BCLC stage C HCC who underwent SE or SI triple therapy were retrospectively enrolled. Propensity score matching (PSM; 1:1) was performed to eliminate possible confounder imbalances across cohorts. We used the Kaplan-Meier method and a log-rank test to compare the overall survival (OS) and progression-free survival (PFS) rates between the SI and SE groups. The tumor response and the incidence of adverse events (AEs) were reported. After PSM, 182 patients in each of the two groups were matched. The median OS in the SI group was significantly longer than that in the SE group (28.8 vs. 16.1 months; P = 0.002), and the median PFS was significantly improved in the SI versus SE group (9.6 vs. 7.0 months; P = 0.01). The objective response rate based on the mRECIST was higher in the SI group (58% vs. 37%; P < 0.001). The total incidences of grade 3-4 AEs were 111/182 (60.9%) and 128/182 (70.3%) in the SE and SI groups, respectively. No grade 5 AEs were reported in either group.

Conclusions: Simultaneous HAIC plus targeted therapy and PD-(L)1 blockade significantly improved outcomes compared to the sequential regimen in patients with BCLC stage C HCC, with no unexpected AEs.

Clinical relevance statement: The patients who received hepatic arterial infusion chemotherapy combined with targeted therapy and PD-(L)1 blockade simultaneously have a better prognosis than those who received it sequentially.

背景和目的:本研究旨在比较肝动脉灌注化疗(HAIC)联合靶向治疗和PD-(L)1阻断(三联疗法)序贯(SE)或同步(SI)治疗巴塞罗那肝癌诊所(BCLC)C期肝细胞癌(HCC)的疗效和安全性:从2018年1月1日至2022年6月1日,回顾性纳入了575例接受SE或SI三联疗法的BCLC C期HCC患者。我们进行了倾向得分匹配(PSM;1:1),以消除各队列中可能存在的混杂因素不平衡。我们采用卡普兰-梅耶法和对数秩检验比较了SI组和SE组的总生存期(OS)和无进展生存期(PFS)。我们还报告了肿瘤反应和不良事件(AEs)的发生率。PSM 后,两组各有 182 名患者进行了配对。SI组的中位OS明显长于SE组(28.8个月对16.1个月;P = 0.002),SI组的中位PFS明显优于SE组(9.6个月对7.0个月;P = 0.01)。基于mRECIST的客观反应率在SI组更高(58% vs. 37%; P 结论:SI组的客观反应率高于SE组:对于 BCLC C 期 HCC 患者,HAIC 加靶向治疗和 PD-(L)1 阻断同时进行可显著改善预后,且无意外 AEs:同时接受肝动脉灌注化疗联合靶向治疗和PD-(L)1阻断治疗的患者比顺序接受治疗的患者预后更好。
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引用次数: 0
"Tumor immunology meets oncology" (TIMO), 18 April-20 April 2024, in Brandenburg an der Havel, Germany. "肿瘤免疫学与肿瘤学"(TIMO),2024 年 4 月 18 日至 2024 年 4 月 20 日,德国勃兰登堡 an der Havel。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-13 DOI: 10.1007/s00262-024-03877-1
Barbara Seliger

The TIMO meeting XVIII 2024 covered both basic and translational tumor immunological topics, which were presented by national and international scientists and clinicians.

TIMO XVIII 2024 会议涵盖了基础和转化肿瘤免疫学主题,由国内外科学家和临床医生发表演讲。
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引用次数: 0
Loop33 × 123 CAR-T targeting CD33 and CD123 against immune escape in acute myeloid leukemia. 以 CD33 和 CD123 为靶点的 Loop33 × 123 CAR-T 对抗急性髓性白血病的免疫逃逸。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-13 DOI: 10.1007/s00262-024-03847-7
Haotian Ma, Zhifeng Yan, Runxia Gu, Yingxi Xu, Shaowei Qiu, Haiyan Xing, Kejing Tang, Zheng Tian, Qing Rao, Min Wang, Jianxiang Wang

Background: Immunotherapy, such as chimeric antigen receptor T (CAR-T) cells targeting CD33 or CD123, has been well developed over the past decade for the treatment of acute myeloid leukemia (AML). However, the inability to sustain tumor-free survival and the possibility of relapse due to antigen loss have raised concerns. A dual targeting of CD33 and CD123 is needed for better outcomes.

Methods: Based on our previously constructed CD33 and CD123 monovalent CAR-T, Loop33 × 123 and Loop123 × 33 CAR-T were constructed with molecular cloning techniques. All CAR-T cells were generated by lentivirus transduction of T cells from healthy donors. Phenotype detection was evaluated on day 7 concerning activation, exhaustion, and subtype proportions. Coculture killing assays were conducted using various AML cell lines and primary AML cells. Degranulation and cytokine secretion levels were detected by flow cytometry. Cell-derived xenograft models were established using wild-type Molm 13 cell lines, or a mixture of Molm 13-KO33 and Molm 13-KO123 cells as an ideal model of immune escape. By monitoring body weight and survival of tumor-bearing mice, Loop33 × 123 and Loop123 × 33 CAR-T cells were further assessed for their efficacy in vivo.

Results: In vitro study, our results demonstrated that Loop33 × 123 CAR-T cells could efficiently eliminate AML cell lines and primary AML cells with elevated degranulation and cytokine secretion levels. Compared with our previously constructed monovalent CD33 or CD123 CAR-T cells, Loop33 × 123 CAR-T cells showed superior advantages in an immune escape model. In vivo studies further confirmed that Loop33 × 123 CAR-T cells could effectively prolong the survival of mice without significant toxicity. However, Loop123 × 33 CAR-T cells failed to show the same effects. Furthermore, Loop33 × 123 CAR-T cells efficiently circumvented potential immune escape, a challenge where monovalent CAR-T cells failed.

Conclusions: Loop33 × 123 CAR-T targeting CD33 and CD123 could efficiently eliminate AML cells and prolong survival of tumor-bearing mice, while addressing the issue of immune escape.

背景:过去十年来,针对 CD33 或 CD123 的嵌合抗原受体 T(CAR-T)细胞等免疫疗法在治疗急性髓性白血病(AML)方面得到了长足发展。然而,无法维持无瘤生存以及抗原丢失导致复发的可能性引发了人们的担忧。为了取得更好的疗效,需要CD33和CD123的双重靶向:方法:基于我们之前构建的 CD33 和 CD123 单价 CAR-T,利用分子克隆技术构建了 Loop33 × 123 和 Loop123 × 33 CAR-T。所有 CAR-T 细胞都是通过慢病毒转导健康供体的 T 细胞产生的。表型检测在第 7 天进行评估,涉及活化、衰竭和亚型比例。使用各种急性髓细胞白血病细胞系和原代急性髓细胞白血病细胞进行了共培养杀伤试验。通过流式细胞术检测脱颗粒和细胞因子分泌水平。使用野生型 Molm 13 细胞系或 Molm 13-KO33 和 Molm 13-KO123 混合细胞建立了细胞衍生异种移植模型,作为免疫逃逸的理想模型。通过监测肿瘤小鼠的体重和存活率,进一步评估了 Loop33 × 123 和 Loop123 × 33 CAR-T 细胞在体内的疗效:结果:在体外研究中,我们的结果表明 Loop33 × 123 CAR-T 细胞能有效清除脱颗粒和细胞因子分泌水平升高的急性髓性白血病细胞系和原代急性髓性白血病细胞。与我们之前构建的单价 CD33 或 CD123 CAR-T 细胞相比,Loop33 × 123 CAR-T 细胞在免疫逃逸模型中表现出更优越的优势。体内研究进一步证实,Loop33 × 123 CAR-T 细胞能有效延长小鼠的存活时间,且无明显毒性。然而,Loop123 × 33 CAR-T 细胞未能显示出同样的效果。此外,Loop33 × 123 CAR-T细胞还能有效规避潜在的免疫逃逸,而这正是单价CAR-T细胞无法应对的挑战:结论:以 CD33 和 CD123 为靶点的 Loop33 × 123 CAR-T 可以有效清除急性髓细胞白血病细胞,延长肿瘤小鼠的生存期,同时解决免疫逃逸问题。
{"title":"Loop33 × 123 CAR-T targeting CD33 and CD123 against immune escape in acute myeloid leukemia.","authors":"Haotian Ma, Zhifeng Yan, Runxia Gu, Yingxi Xu, Shaowei Qiu, Haiyan Xing, Kejing Tang, Zheng Tian, Qing Rao, Min Wang, Jianxiang Wang","doi":"10.1007/s00262-024-03847-7","DOIUrl":"10.1007/s00262-024-03847-7","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy, such as chimeric antigen receptor T (CAR-T) cells targeting CD33 or CD123, has been well developed over the past decade for the treatment of acute myeloid leukemia (AML). However, the inability to sustain tumor-free survival and the possibility of relapse due to antigen loss have raised concerns. A dual targeting of CD33 and CD123 is needed for better outcomes.</p><p><strong>Methods: </strong>Based on our previously constructed CD33 and CD123 monovalent CAR-T, Loop33 × 123 and Loop123 × 33 CAR-T were constructed with molecular cloning techniques. All CAR-T cells were generated by lentivirus transduction of T cells from healthy donors. Phenotype detection was evaluated on day 7 concerning activation, exhaustion, and subtype proportions. Coculture killing assays were conducted using various AML cell lines and primary AML cells. Degranulation and cytokine secretion levels were detected by flow cytometry. Cell-derived xenograft models were established using wild-type Molm 13 cell lines, or a mixture of Molm 13-KO33 and Molm 13-KO123 cells as an ideal model of immune escape. By monitoring body weight and survival of tumor-bearing mice, Loop33 × 123 and Loop123 × 33 CAR-T cells were further assessed for their efficacy in vivo.</p><p><strong>Results: </strong>In vitro study, our results demonstrated that Loop33 × 123 CAR-T cells could efficiently eliminate AML cell lines and primary AML cells with elevated degranulation and cytokine secretion levels. Compared with our previously constructed monovalent CD33 or CD123 CAR-T cells, Loop33 × 123 CAR-T cells showed superior advantages in an immune escape model. In vivo studies further confirmed that Loop33 × 123 CAR-T cells could effectively prolong the survival of mice without significant toxicity. However, Loop123 × 33 CAR-T cells failed to show the same effects. Furthermore, Loop33 × 123 CAR-T cells efficiently circumvented potential immune escape, a challenge where monovalent CAR-T cells failed.</p><p><strong>Conclusions: </strong>Loop33 × 123 CAR-T targeting CD33 and CD123 could efficiently eliminate AML cells and prolong survival of tumor-bearing mice, while addressing the issue of immune escape.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"20"},"PeriodicalIF":4.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Overcoming immunosuppression in cancer: how ketogenic diets boost immune checkpoint blockade. 克服癌症中的免疫抑制:生酮饮食如何促进免疫检查点阻断。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-13 DOI: 10.1007/s00262-024-03867-3
Victoria E Stefan, Daniela D Weber, Roland Lang, Barbara Kofler

Immune checkpoint blockade (ICB) is now part of the standard of care in the treatment of many forms of cancer, yet it lacks efficacy in some patients, necessitating adjunct therapies to support the anti-tumor immune response. Ketogenic diets (KDs), i.e., high-fat low-carbohydrate diets, have been shown to have antiproliferative and immunomodulatory effects in various preclinical cancer studies. Here, we review current knowledge of the complex interplay of KDs and the anti-tumor immune response in the context of ICB therapy, to update our understanding of diet-induced immunometabolic reprogramming in cancer. Preclinical cancer studies have revealed increased activation of and infiltration by tumor-fighting immune cells, especially CD8+ T cells, but also M1 macrophages and natural killer cells, in response to a KD regimen. In contrast, immune-suppressive cells such as regulatory CD4+ T lymphocytes, M2 macrophages, and myeloid-derived suppressor cells were reported to be decreased or largely unaffected in tumors of KD-fed mice. KDs also showed synergism with ICB therapy in several preclinical tumor studies. The observed effects are ascribed to the ability of KDs to improve immune cell infiltration and induce downregulation of immune-inhibitory processes, thus creating a more immunogenic tumor microenvironment. The studies reviewed herein show that altering the metabolic composition of the tumor microenvironment by a KD can boost the anti-tumor immune response and diminish even immunotherapy-resistant as well as immunologically "cold" tumors. However, the exact underlying mechanisms remain to be elucidated, requiring further studies before KDs can be successfully implemented as an adjunct tumor therapy to improve survival rates for cancer patients.

免疫检查点阻断疗法(ICB)现已成为治疗多种癌症的标准疗法之一,但它对一些患者缺乏疗效,因此需要辅助疗法来支持抗肿瘤免疫反应。生酮饮食(KDs),即高脂肪低碳水化合物饮食,在各种临床前癌症研究中已被证明具有抗增殖和免疫调节作用。在此,我们回顾了目前在 ICB 疗法中 KDs 与抗肿瘤免疫反应之间复杂相互作用的知识,以更新我们对饮食诱导的癌症免疫代谢重编程的理解。临床前癌症研究显示,抗肿瘤免疫细胞,尤其是 CD8+ T 细胞,以及 M1 巨噬细胞和自然杀伤细胞的活化和浸润增加,是对 KD 方案的反应。与此相反,据报道,免疫抑制细胞(如调节性 CD4+ T 淋巴细胞、M2 巨噬细胞和髓源性抑制细胞)在喂食 KD 的小鼠肿瘤中减少或基本不受影响。在几项临床前肿瘤研究中,KD 还显示出与 ICB 疗法的协同作用。所观察到的效果归因于 KDs 能够改善免疫细胞浸润并诱导免疫抑制过程的下调,从而创造一个更具免疫原性的肿瘤微环境。本文回顾的研究表明,通过 KD 改变肿瘤微环境的代谢组成,可以增强抗肿瘤免疫反应,甚至可以减少免疫治疗耐药和免疫 "冷 "肿瘤。然而,其确切的内在机制仍有待阐明,需要进一步研究,才能成功地将 KD 作为肿瘤辅助疗法,提高癌症患者的生存率。
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引用次数: 0
Cryo-thermal therapy reshaped the tumor immune microenvironment to enhance the efficacy of adoptive T cell therapy. 低温疗法重塑了肿瘤免疫微环境,提高了采用T细胞疗法的疗效。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-13 DOI: 10.1007/s00262-024-03884-2
Shicheng Wang, Peng Peng, Junjun Wang, Zelu Zhang, Ping Liu, Lisa X Xu

Background: Adoptive cell therapies (ACT) exhibit excellent efficacy in hematological malignancy. However, its application in solid tumors still has many challenges partly due to the tumor immune microenvironment. Cryo-thermal therapy (CTT) can induce an acute inflammatory response and remold the immune environment, providing an appropriate environment for the activation of adaptive immunity. However, it remains unclear whether CTT can enhance the efficacy of ACT.

Methods: A bilateral B16F10 tumor-bearing mouse model was used to assess whether CTT could enhance the efficacy of ACT. The right large tumor was subjected to CTT, and the left small tumor was collected for flow cytometry, RNA-seq, immunohistochemistry and TCR Vβ sequencing. Finally, bilateral B16F10 tumor-bearing mice and 4T1 tumor-bearing mice were used to assess the efficacy after CTT combined with ACT.

Results: CTT dramatically reshaped the immune microenvironment in distal tumors to an acute inflammatory state by promoting innate cell infiltration, increasing cytokine production by macrophages and DCs. The remodeling of the tumor immune microenvironment further enhanced the antitumor efficiency of ACT by increasing the proliferation of T cells, promoting activation of the effector functions of T cells and boosting the expansion of TCR clones.

Conclusions: Our results suggest that CTT can significantly reshape the tumor immunosuppressive microenvironment and convert "cold tumors" into "hot tumors," thereby enhancing ACT-induced immune responses and maximizing the therapeutic effect of ACT.

背景:适应性细胞疗法(ACT)在血液恶性肿瘤中表现出卓越的疗效。然而,在实体瘤中的应用仍面临许多挑战,部分原因在于肿瘤免疫微环境。低温热疗(CTT)可诱导急性炎症反应,重塑免疫环境,为激活适应性免疫提供合适的环境。然而,CTT 是否能增强 ACT 的疗效仍不清楚:方法:采用双侧 B16F10 肿瘤小鼠模型来评估 CTT 是否能增强 ACT 的疗效。方法:采用双侧 B16F10 肿瘤小鼠模型,评估 CTT 是否能增强 ACT 的疗效,对右侧大肿瘤进行 CTT,收集左侧小肿瘤进行流式细胞术、RNA-seq、免疫组化和 TCR Vβ 测序。最后,用双侧B16F10肿瘤小鼠和4T1肿瘤小鼠评估CTT联合ACT后的疗效:结果:CTT通过促进先天性细胞浸润、增加巨噬细胞和DC产生的细胞因子,将远端肿瘤的免疫微环境显著重塑为急性炎症状态。肿瘤免疫微环境的重塑通过增加T细胞的增殖、促进T细胞效应功能的激活和促进TCR克隆的扩增,进一步提高了ACT的抗肿瘤效率:我们的研究结果表明,CTT能显著重塑肿瘤免疫抑制微环境,将 "冷肿瘤 "转化为 "热肿瘤",从而增强ACT诱导的免疫反应,最大限度地提高ACT的治疗效果。
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引用次数: 0
Periodontitis promotes tumor growth and immune evasion via PD-1/PD-L1. 牙周炎通过 PD-1/PD-L1 促进肿瘤生长和免疫逃避。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-13 DOI: 10.1007/s00262-024-03865-5
Suli Wang, Fujiao Nie, Qiuyue Yin, Haoyang Tian, Pizhang Gong, Jinhong Ju, Jiayi Liu, Pishan Yang, Chengzhe Yang

Background: Our study investigated the role of experimental periodontitis on tumor growth, local and systemic immunosuppressive status, and programmed death receptor 1 (PD-1) / programmed death ligand 1 (PD-L1) expression in oral squamous cell carcinoma (OSCC) and prostate cancer.

Methods: Mouse oral or prostate cancer xenograft models were divided into control, periodontitis and periodontitis + anti-PD-1 groups. Tumor volume and weight were recorded and the levels of relevant immune-suppressive cells and T cells were detected by flow cytometry or immunofluorescence. THP-1 cells were stimulated using conditioned media of LPS-stimulated Cal-27 cells and PD-L1 expression was measured by quantitative real-time PCR, western blotting and immunofluorescence. Tumor specimens from OSCC patients with or without periodontitis were also collected for immunofluorescence.

Results: Periodontitis significantly promoted tumor volume and weight. Compared to the control, the proportions of tumor-associated macrophages (TAMs), regulatory T cells (Tregs), PD-L1+TAMs and PD-1+CD8+T cells increased, while CD8+T cells decreased in the periodontitis group. Immunofluorescence demonstrated that there was an increase in PD-L1+TAMs and PD-1+CD8+T cells, but a decrease in IFN-γ+CD8+T cells in both xenografts and clinical OSCC samples with periodontitis. In vitro, LPS-stimulated Cal-27 cells had a stronger potential to induce PD-L1 expression in macrophages compared with unstimulated Cal-27 cells. And the promoting effect of periodontitis on tumor growth and immune evasion was significantly attenuated after anti-PD-1 therapy.

Conclusion: Periodontitis may facilitate tumor growth and immune escape evidenced by the increased immune-suppressive cells and the decreased functional T cells, via enhancing PD-1/PD-L1 expression in the tumor microenvironment.

研究背景我们的研究探讨了实验性牙周炎对口腔鳞状细胞癌(OSCC)和前列腺癌的肿瘤生长、局部和全身免疫抑制状态以及程序性死亡受体1(PD-1)/程序性死亡配体1(PD-L1)表达的影响:小鼠口腔癌或前列腺癌异种移植模型分为对照组、牙周炎组和牙周炎+抗PD-1组。记录肿瘤体积和重量,用流式细胞术或免疫荧光法检测相关免疫抑制细胞和 T 细胞的水平。使用 LPS 刺激 Cal-27 细胞的条件培养基刺激 THP-1 细胞,并通过实时定量 PCR、Western 印迹和免疫荧光检测 PD-L1 的表达。研究人员还收集了有牙周炎或无牙周炎的 OSCC 患者的肿瘤标本进行免疫荧光:结果:牙周炎明显增加了肿瘤的体积和重量。与对照组相比,牙周炎组肿瘤相关巨噬细胞(TAMs)、调节性T细胞(Tregs)、PD-L1+TAMs和PD-1+CD8+T细胞的比例增加,而CD8+T细胞的比例减少。免疫荧光显示,在牙周炎的异种移植物和临床 OSCC 样本中,PD-L1+TAMs 和 PD-1+CD8+T 细胞增加,但 IFN-γ+CD8+T 细胞减少。在体外,与未受刺激的 Cal-27 细胞相比,LPS 刺激的 Cal-27 细胞具有更强的诱导巨噬细胞表达 PD-L1 的潜力。结论:牙周炎可能会促进肿瘤的生长和免疫逃避:结论:牙周炎可通过增强肿瘤微环境中 PD-1/PD-L1 的表达,促进肿瘤的生长和免疫逃逸,表现为免疫抑制细胞的增加和功能性 T 细胞的减少。
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引用次数: 0
NLRP12/C1qA positive feedback in tumor-associated macrophages regulates immunosuppression through LILRB4/NF-κB pathway in lung adenocarcinoma. 肿瘤相关巨噬细胞中的 NLRP12/C1qA 正反馈通过 LILRB4/NF-κB 通路调节肺腺癌的免疫抑制。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-11 DOI: 10.1007/s00262-024-03880-6
Jiaxin Yin, Yuxiao Song, Yang Fu, Jun Wang, Zhimin Zhang, Shasha Ruan, Gaoli Liu, Bicheng Zhang

The anti-tumor immune response is greatly hindered by the protumor polarization of tumor-associated macrophages (TAMs). Cancer-related inflammation plays a central role in TAMs protumor polarization. Our study explored the unique positive feedback loop between inflammasome and complement in TAMs. The present study identified NOD-like receptors family pyrin domain containing 12 (NLRP12) formed positive feedback with C1qA and drove TAMs protumor polarization via the LILRB4/NF-κB pathway. In addition, NLRP12 was predominantly expressed in TAMs and was associated with poorer prognosis in lung adenocarcinoma (LUAD) patients. Knocking down LILRB4 inhibited TAMs protumor polarization. NLRP12-overexpressing TAMs promoted tumor cells' malignant progression and inhibited T cells' proliferation and cytotoxic function. Lastly, NLRP12 knockout (NLRP12-/-) reversed macrophage polarization, enhanced T-cell anti-tumor immunity, and suppressed tumor growth. Our findings highlighted the essential role of NLRP12/C1qA positive feedback loop and the LILRB4/NF-κB pathway in promoting TAMs protumor polarization. Inhibition of NLRP12 suppressed tumor development and promoted immune response. NLRP12 may be a promising target for LUAD immunotherapy.

肿瘤相关巨噬细胞(TAMs)的原肿瘤极化极大地阻碍了抗肿瘤免疫反应。与癌症相关的炎症在 TAMs 原瘤极化中起着核心作用。我们的研究探索了 TAMs 中炎性体和补体之间独特的正反馈回路。本研究发现,NOD样受体家族含吡林结构域12(NLRP12)与C1qA形成正反馈,并通过LILRB4/NF-κB途径驱动TAMs原瘤极化。此外,NLRP12主要在TAMs中表达,与肺腺癌(LUAD)患者较差的预后有关。敲除 LILRB4 可抑制 TAMs 原癌极化。NLRP12高表达的TAMs促进了肿瘤细胞的恶性发展,并抑制了T细胞的增殖和细胞毒功能。最后,NLRP12基因敲除(NLRP12-/-)可逆转巨噬细胞极化,增强T细胞抗肿瘤免疫力,抑制肿瘤生长。我们的研究结果突显了NLRP12/C1qA正反馈环和LILRB4/NF-κB通路在促进TAMs原发性肿瘤极化中的重要作用。抑制 NLRP12 可抑制肿瘤发展并促进免疫反应。NLRP12可能是LUAD免疫疗法的一个有前途的靶点。
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引用次数: 0
Pretransplant immunotherapy increases acute rejection yet improves survival outcome of HCC patients with MVI post-liver transplantation. 移植前免疫疗法会增加急性排斥反应,但却能改善肝移植后患有MVI的HCC患者的存活率。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-11 DOI: 10.1007/s00262-024-03853-9
Xinjun Lu, Qi Zhu, Junfeng Cai, Zuozhong Yang, Guangxiang Gu, Li Pang, Mingye Su, Fapeng Zhang, Haoming Lin, Wenrui Wu, Leibo Xu, Chao Liu

Immune checkpoint inhibitor (ICI)-based immunotherapy has emerged as the most promising strategy for hepatocellular carcinoma (HCC) downstaging prior to liver transplantation (LT). However, further evidence is required to assess the feasibility and safety of pretransplant ICI exposure. We retrospective analyzed 159 HCC patients who underwent LT at our institution from June 2019 to December 2023, and 39 recipients (39/159, 24.5%) received pretransplant ICI therapy. The perioperative acute rejection rate and rejection-related mortality rate in the ICI group were 23.1% (9/39) and 12.8% (5/39), respectively, which were significantly higher than those in the non-ICI group, at 5% (6/120, P = 0.002) and 0% (0/120, P = 0.001). There was no significant difference in the 90-day post-transplant overall survival (OS) (P = 0.447) and recurrence-free survival (RFS) (P = 0.723) between these two groups. We found 37.1% (59/159) recipients were found to have microvascular invasion (MVI), no matter whether the HCC tumor is within Milan criteria or not. Notably, though MVI was identified as a risk factor for the LT recipients, pretransplant ICI exposure appeared to be a protective factor for HCC patients with MVI which benefits its overall survival. Besides, the RFS and OS in the ICI exposure recipients with MVI were comparable to the non-ICI exposure recipients without MVI. However, no synergistic anti-tumor effects were observed with pretransplant ICI immunotherapy when combined with locoregional of TACE, HAIC, RFA and systematic of lenvatinib or sorafenib downstaging treatments, nor with post-transplant adjuvant of systematic or FOLFOX chemotherapy. Further comprehensive studies are needed to balance the dual natural effects of immunotherapy by optimizing downstaging protocols and patient selection to reduce acute rejection and improve long-term survival.

基于免疫检查点抑制剂(ICI)的免疫疗法已成为肝移植(LT)前肝细胞癌(HCC)降期治疗最有前途的策略。然而,还需要进一步的证据来评估移植前接触 ICI 的可行性和安全性。我们回顾性分析了2019年6月至2023年12月在我院接受LT的159例HCC患者,其中39例受者(39/159,24.5%)接受了移植前ICI治疗。ICI组围手术期急性排斥反应率和排斥反应相关死亡率分别为23.1%(9/39)和12.8%(5/39),显著高于非ICI组的5%(6/120,P=0.002)和0%(0/120,P=0.001)。两组患者移植后 90 天的总生存期(OS)(P = 0.447)和无复发生存期(RFS)(P = 0.723)无明显差异。我们发现,无论 HCC 肿瘤是否符合米兰标准,37.1%(59/159)的受者被发现有微血管侵犯(MVI)。值得注意的是,虽然微血管侵犯被认为是LT受者的一个危险因素,但移植前接触ICI似乎是微血管侵犯HCC患者的一个保护因素,有利于其总体生存。此外,有MVI的ICI受者的RFS和OS与无MVI的非ICI受者相当。不过,移植前 ICI 免疫疗法与 TACE、HAIC、RFA 和来伐替尼或索拉非尼降期系统性治疗的局部联合,以及移植后系统性化疗或 FOLFOX 化疗的辅助治疗,均未观察到协同抗肿瘤效果。需要进一步开展综合研究,通过优化降期方案和患者选择来平衡免疫疗法的双重自然效应,从而减少急性排斥反应,提高长期生存率。
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引用次数: 0
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Cancer Immunology, Immunotherapy
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