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Correction to: Inhibition of glycolysis enhances the efficacy of immunotherapy via PDK‑mediated upregulation of PD‑L1. 更正为抑制糖酵解可通过 PDK 介导的 PD-L1 上调增强免疫疗法的疗效。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-17 DOI: 10.1007/s00262-024-03811-5
Ruizhi Zhang, Gan Mao, Yu Tang, Chong Li, Yisong Gao, Wenxiang Nie, Tianyu Song, Suao Liu, Peng Zhang, Kaixiong Tao, Wei Li
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引用次数: 0
Bronchoalveolar lavage fluid analysis in patients with checkpoint inhibitor pneumonitis 检查点抑制剂肺炎患者支气管肺泡灌洗液分析
IF 5.8 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-13 DOI: 10.1007/s00262-024-03834-y
Ruxuan Chen, Yujie Shi, Nan Fang, Chi Shao, Hui Huang, Ruili Pan, Yan Xu, Mengqi Wang, Xiangning Liu, Kai Xu, Rui Zhu, Mengzhao Wang

Background

Checkpoint inhibitor pneumonitis (CIP) is a relatively uncommon but potentially life-threatening immune-related adverse event (irAE). Lung biopsies have not been commonly performed for CIP patients. Bronchoalveolar lavage fluid (BALF) analysis is a useful diagnostic approach for interstitial lung disease. However, BALF features were inconsistent across different studies.

Methods

We retrospectively reviewed the medical records of 154 patients with pathologically confirmed malignancies and suffering from CIPs between July 2018 and December 2022. Patients who had bronchoalveolar lavage (BAL) data available were enrolled in our study. Patient clinical, laboratory, radiological and follow-up data were reviewed and analyzed.

Results

The BALF differential cell count and lymphocyte subset analysis were performed for 42 CIP patients. There were 32 males (76.2%). The mean age at diagnosis of CIP was 62.0 ± 10.4 (range: 31–78) years. The median time to onset of CIP was 98.5 days after the start of immunotherapy. There were 18 patients (42.9%) with low-grade CIPs and 24 patients (57.1%) with high-grade CIPs. The mean lymphocyte percentage was 36.7 ± 22.5%. There were 34 (81%) CIP patients with a lymphocytic cellular pattern. The median ratio of CD3+CD4+/CD3+CD8+ lymphocytes was 0.5 (0.3, 1.0). The ratio was less than 1.0 for 31 CIP patients (73.8%). However, there was no significant difference in the BALF features between patients with low-grade CIPs and those with high-grade CIPs.

Conclusions

The CD3+CD8+ lymphocytosis pattern was the main inflammatory profile in the BALF of CIP patients in this cohort. Targeting CD3+CD8+ lymphocytes might be a treatment option for CIPs.

背景检查点抑制剂肺炎(CIP)是一种相对少见但可能危及生命的免疫相关不良事件(irAE)。对 CIP 患者进行肺活检并不常见。支气管肺泡灌洗液(BALF)分析是诊断间质性肺病的有效方法。然而,不同研究中的 BALF 特征并不一致。方法我们回顾性地查看了 2018 年 7 月至 2022 年 12 月间 154 例经病理证实为恶性肿瘤的 CIP 患者的病历。有支气管肺泡灌洗(BAL)数据的患者被纳入我们的研究。对患者的临床、实验室、放射学和随访数据进行了回顾和分析。结果对42名CIP患者进行了BALF差异细胞计数和淋巴细胞亚群分析。其中男性 32 人(76.2%)。确诊 CIP 的平均年龄为 62.0 ± 10.4(31-78)岁。CIP 发病的中位时间为免疫疗法开始后的 98.5 天。低级别 CIP 患者有 18 人(42.9%),高级别 CIP 患者有 24 人(57.1%)。平均淋巴细胞百分比为 36.7 ± 22.5%。34例(81%)CIP患者的细胞形态为淋巴细胞。CD3+CD4+/CD3+CD8+ 淋巴细胞的中位比率为 0.5 (0.3, 1.0)。31 名 CIP 患者(73.8%)的比率小于 1.0。结论 CD3+CD8+ 淋巴细胞增多模式是该队列中 CIP 患者 BALF 的主要炎症特征。靶向 CD3+CD8+ 淋巴细胞可能是治疗 CIP 的一种选择。
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引用次数: 0
Single-cell RNA sequencing to map tumor heterogeneity in gastric carcinogenesis paving roads to individualized therapy 用单细胞 RNA 测序绘制胃癌发生过程中的肿瘤异质性图谱,为个体化治疗铺平道路
IF 5.8 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-13 DOI: 10.1007/s00262-024-03820-4
Jiao Xu, Bixin Yu, Fan Wang, Jin Yang

Gastric cancer (GC) is a highly heterogeneous disease with a complex tumor microenvironment (TME) that encompasses multiple cell types including cancer cells, immune cells, stromal cells, and so on. Cancer-associated cells could remodel the TME and influence the progression of GC and therapeutic response. Single-cell RNA sequencing (scRNA-seq), as an emerging technology, has provided unprecedented insights into the complicated biological composition and characteristics of TME at the molecular, cellular, and immunological resolutions, offering a new idea for GC studies. In this review, we discuss the novel findings from scRNA-seq datasets revealing the origin and evolution of GC, and scRNA-seq is a powerful tool for investigating transcriptional dynamics and intratumor heterogeneity (ITH) in GC. Meanwhile, we demonstrate that the vital immune cells within TME, including T cells, B cells, macrophages, and stromal cells, play an important role in the disease progression. Additionally, we also overview that how scRNA-seq facilitates our understanding about the effects on individualized therapy of GC patients. Spatial transcriptomes (ST) have been designed to determine spatial distribution and capture local intercellular communication networks, enabling a further understanding of the relationship between the spatial background of a particular cell and its functions. In summary, scRNA-seq and other single-cell technologies provide a valuable perspective for molecular and pathological disease characteristics and hold promise for advancing basic research and clinical practice in GC.

胃癌(GC)是一种高度异质性疾病,其肿瘤微环境(TME)十分复杂,包括癌细胞、免疫细胞、基质细胞等多种细胞类型。癌症相关细胞可重塑肿瘤微环境,并影响癌症的进展和治疗反应。单细胞 RNA 测序(scRNA-seq)作为一种新兴技术,从分子、细胞和免疫学的角度为 TME 复杂的生物组成和特征提供了前所未有的见解,为 GC 研究提供了一种新思路。在这篇综述中,我们讨论了 scRNA-seq 数据集揭示 GC 起源和进化的新发现,scRNA-seq 是研究 GC 转录动态和肿瘤内异质性(ITH)的有力工具。同时,我们证明了TME内的重要免疫细胞,包括T细胞、B细胞、巨噬细胞和基质细胞,在疾病进展中发挥着重要作用。此外,我们还概述了 scRNA-seq 如何促进我们对 GC 患者个体化治疗效果的理解。空间转录组(ST)旨在确定空间分布并捕捉局部细胞间通讯网络,从而进一步了解特定细胞的空间背景与其功能之间的关系。总之,scRNA-seq 和其他单细胞技术为了解疾病的分子和病理特征提供了宝贵的视角,有望推动 GC 的基础研究和临床实践。
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引用次数: 0
Genomic and molecular alterations associated with primary resistance to immune checkpoint inhibitors 与免疫检查点抑制剂原发性耐药性相关的基因组和分子改变
IF 5.8 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-13 DOI: 10.1007/s00262-024-03825-z
Jyoti Malhotra, Subhajyoti De, Kim Nguyen, Percy Lee, Victoria Villaflor

The clinical response to immune checkpoint inhibitors may vary by tumor type and many tumors present with either primary or acquired resistance to immunotherapy. Improved understanding of the molecular and immunologic mechanisms underlying immunotherapy resistance is essential for developing biomarkers and for guiding the optimum approach to selecting treatment regimens and sequencing. This is increasingly important for tumors with primary resistance as effective biomarkers in this setting can guide clinicians about appropriate treatment regimen selection in the first-line setting. Multiple potential biological mechanisms of primary resistance have been proposed but most are yet to be validated in prospective clinical cohorts. Individual biomarkers have poor specificity and sensitivity, and the development of validated and integrated predictive models may guide which patient will benefit from monotherapy versus combination therapy. In this review, we discuss the emerging data identifying the molecular mechanisms of primary resistance to immunotherapy and explore potential therapeutic strategies to target these.

不同类型的肿瘤对免疫检查点抑制剂的临床反应可能不同,许多肿瘤对免疫疗法存在原发性或获得性耐药性。进一步了解免疫疗法耐药性的分子和免疫学机制对于开发生物标记物、指导选择治疗方案和排序的最佳方法至关重要。这对于原发性耐药的肿瘤越来越重要,因为在这种情况下,有效的生物标志物可以指导临床医生在一线治疗中选择适当的治疗方案。目前已提出了多种原发性耐药的潜在生物机制,但大多数都有待在前瞻性临床队列中验证。单个生物标志物的特异性和敏感性较差,开发经过验证的综合预测模型可指导哪些患者将从单药治疗或联合治疗中获益。在本综述中,我们将讨论确定免疫疗法原发性耐药分子机制的新数据,并探讨针对这些机制的潜在治疗策略。
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引用次数: 0
Recent clinical researches and technological development in TIL therapy TIL 疗法的最新临床研究和技术发展
IF 5.8 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-12 DOI: 10.1007/s00262-024-03793-4
Satoko Matsueda, Lei Chen, Hongmei Li, Hui Yao, Fuli Yu

Tumor-infiltrating lymphocyte (TIL) therapy represents a groundbreaking advancement in the solid cancer treatment, offering new hope to patients and their families with high response rates and long overall survival. TIL therapy involves extracting immune cells from a patient's tumor tissue, expanding them ex vivo, and infusing them back into the patient to target and eliminate cancer cells. This revolutionary approach harnesses the power of the immune system to combat cancers, ushering in a new era of T cell-based therapies along with CAR-T and TCR-therapies. In this comprehensive review, we aim to elucidate the remarkable potential of TIL therapy by delving into recent advancements in basic and clinical researches. We highlight on the evolving landscape of TIL therapy as a prominent immunotherapeutic strategy, its multifaceted applications, and the promising outcomes. Additionally, we explore the future horizons of TIL therapy, next-generation TILs, and combination therapy, to overcome the limitations and improve clinical efficacy of TIL therapy.

肿瘤浸润淋巴细胞(TIL)疗法是实体瘤治疗领域的突破性进展,它为患者及其家属带来了新的希望,因为这种疗法的反应率高、总生存期长。TIL 疗法包括从患者的肿瘤组织中提取免疫细胞,将其体外扩增,然后将其回输到患者体内,以靶向消除癌细胞。这种革命性的方法利用免疫系统的力量来对抗癌症,与 CAR-T 和 TCR 疗法一起开创了基于 T 细胞疗法的新时代。在这篇综述中,我们将深入探讨基础和临床研究的最新进展,旨在阐明 TIL 疗法的巨大潜力。我们重点介绍了 TIL 疗法作为一种重要的免疫治疗策略不断发展的情况、其多方面的应用以及充满希望的成果。此外,我们还探讨了 TIL 疗法、下一代 TILs 和联合疗法的未来前景,以克服 TIL 疗法的局限性并提高其临床疗效。
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引用次数: 0
A monoclonal antibody recognizing CD98 on human embryonic stem cells shows anti-tumor activity in hepatocellular carcinoma xenografts 识别人类胚胎干细胞 CD98 的单克隆抗体在肝细胞癌异种移植中显示出抗肿瘤活性
IF 5.8 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-11 DOI: 10.1007/s00262-024-03827-x
Keunpyo Lim, San Ha Han, Sein Han, Ji Yoon Lee, Hong Seo Choi, Dongho Choi, Chun Jeih Ryu

CD98, also known as SLC3A2, is a multifunctional cell surface molecule consisting of amino acid transporters. CD98 is ubiquitously expressed in many types of tissues, but expressed at higher levels in cancerous tissues than in normal tissues. CD98 is also upregulated in most hepatocellular carcinoma (HCC) patients; however, the function of CD98 in HCC cells has been little studied. In this study, we generated a panel of monoclonal antibodies (MAbs) against surface proteins on human embryonic stem cells (hESCs). NPB15, one of the MAbs, bound to hESCs and various cancer cells, including HCC cells and non-small cell lung carcinoma (NSCLC) cells, but not to peripheral blood mononuclear cells (PBMCs) and primary hepatocytes. Immunoprecipitation and mass spectrometry identified the target antigen of NPB15 as CD98. CD98 depletion decreased cell proliferation, clonogenic survival, and migration and induced apoptosis in HCC cells. In addition, CD98 depletion decreased the expression of cancer stem cell (CSC) markers in HCC cells. In tumorsphere cultures, the expression of CD98 interacting with NPB15 was significantly increased, as were known CSC markers. After cell sorting by NPB15, cells with high expression of CD98 (CD98-high) showed higher clonogenic survival than cells with low expression of CD98 (CD98-low) in HCC cells, suggesting CD98 as a potential CSC marker on HCC cells. The chimeric version of NPB15 was able to induce antibody-dependent cellular cytotoxicity (ADCC) against HCC cells in vitro. NPB15 injection showed antitumor activity in an HCC xenograft mouse model. The results suggest that NPB15 may be developed as a therapeutic antibody for HCC patients.

CD98 又称 SLC3A2,是一种由氨基酸转运体组成的多功能细胞表面分子。CD98 在多种组织中普遍表达,但在癌症组织中的表达水平高于正常组织。在大多数肝细胞癌(HCC)患者中,CD98 也会上调;然而,CD98 在 HCC 细胞中的功能却鲜有研究。在这项研究中,我们生成了一组针对人类胚胎干细胞(hESCs)表面蛋白的单克隆抗体(MAbs)。其中一种单克隆抗体NPB15能与hESCs和各种癌细胞(包括HCC细胞和非小细胞肺癌(NSCLC)细胞)结合,但不能与外周血单核细胞(PBMCs)和原代肝细胞结合。免疫沉淀和质谱分析确定了 NPB15 的靶抗原为 CD98。删除 CD98 可减少 HCC 细胞的增殖、克隆存活和迁移,并诱导细胞凋亡。此外,去掉 CD98 还能降低 HCC 细胞中癌症干细胞(CSC)标志物的表达。在肿瘤球培养物中,与 NPB15 相互作用的 CD98 表达明显增加,已知的 CSC 标志物也是如此。用 NPB15 进行细胞分选后,在 HCC 细胞中,CD98 高表达的细胞(CD98-高)比 CD98 低表达的细胞(CD98-低)有更高的克隆存活率,这表明 CD98 是 HCC 细胞潜在的 CSC 标记。嵌合型 NPB15 能够在体外诱导 HCC 细胞产生抗体依赖性细胞毒性(ADCC)。NPB15 注射液在 HCC 异种移植小鼠模型中显示出抗肿瘤活性。这些结果表明,NPB15 有可能被开发成治疗 HCC 患者的抗体。
{"title":"A monoclonal antibody recognizing CD98 on human embryonic stem cells shows anti-tumor activity in hepatocellular carcinoma xenografts","authors":"Keunpyo Lim, San Ha Han, Sein Han, Ji Yoon Lee, Hong Seo Choi, Dongho Choi, Chun Jeih Ryu","doi":"10.1007/s00262-024-03827-x","DOIUrl":"https://doi.org/10.1007/s00262-024-03827-x","url":null,"abstract":"<p>CD98, also known as SLC3A2, is a multifunctional cell surface molecule consisting of amino acid transporters. CD98 is ubiquitously expressed in many types of tissues, but expressed at higher levels in cancerous tissues than in normal tissues. CD98 is also upregulated in most hepatocellular carcinoma (HCC) patients; however, the function of CD98 in HCC cells has been little studied. In this study, we generated a panel of monoclonal antibodies (MAbs) against surface proteins on human embryonic stem cells (hESCs). NPB15, one of the MAbs, bound to hESCs and various cancer cells, including HCC cells and non-small cell lung carcinoma (NSCLC) cells, but not to peripheral blood mononuclear cells (PBMCs) and primary hepatocytes. Immunoprecipitation and mass spectrometry identified the target antigen of NPB15 as CD98. CD98 depletion decreased cell proliferation, clonogenic survival, and migration and induced apoptosis in HCC cells. In addition, CD98 depletion decreased the expression of cancer stem cell (CSC) markers in HCC cells. In tumorsphere cultures, the expression of CD98 interacting with NPB15 was significantly increased, as were known CSC markers. After cell sorting by NPB15, cells with high expression of CD98 (CD98-high) showed higher clonogenic survival than cells with low expression of CD98 (CD98-low) in HCC cells, suggesting CD98 as a potential CSC marker on HCC cells. The chimeric version of NPB15 was able to induce antibody-dependent cellular cytotoxicity (ADCC) against HCC cells in vitro. NPB15 injection showed antitumor activity in an HCC xenograft mouse model. The results suggest that NPB15 may be developed as a therapeutic antibody for HCC patients.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Adding-on nivolumab to chemotherapy-stabilized patients is associated with improved survival in advanced pancreatic ductal adenocarcinoma. 在化疗稳定的晚期胰腺导管腺癌患者中增加尼妥珠单抗可提高生存率。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-09 DOI: 10.1007/s00262-024-03821-3
Shih-Hung Yang, Sung-Hsin Kuo, Jen-Chieh Lee, Bang-Bin Chen, Yan-Shen Shan, Yu-Wen Tien, Sz-Chi Chiu, Ann-Lii Cheng, Kun-Huei Yeh

Background: Immune checkpoint inhibitors (ICIs) are rarely used to treat advanced pancreatic ductal adenocarcinoma (PDAC) due to marginal efficacy.

Patients and methods: This study included 92 consecutive patients diagnosed with advanced or recurrent PDAC who received nivolumab-based treatment. Univariate and multivariate analyses were used to identify prognostic factors. A control group of 301 patients with PDAC who achieved disease control with palliative chemotherapy but without ICIs was selected for comparison using propensity score matching (PSM).

Results: The median overall survival (OS) since nivolumab treatment was 15.8 (95% confidence interval [CI], 12.5-19.0), 2.4 (95% CI 1.2-3.6), and 1.1 (95% CI 1.0-1.2) months in patients who received add-on nivolumab after achieving disease control with chemotherapy, in those who received concomitant nivolumab and chemotherapy without prerequisite confirmation of disease control, and in those who received nivolumab without concomitant chemotherapy, respectively (P < 0.001). After PSM, the median overall survival (OS) since initiation of the concomitant chemotherapy that achieved disease control was significantly longer (P = 0.026) in patients who received add-on nivolumab (19.8 months; 95% CI 14.5-25.1) than in those who received chemotherapy alone (13.8 months; 95% CI 10.8-16.9). The immune profiling of the tumors in resected patients revealed higher scores of CD8+ T cells to Tregs in patients with add-on nivolumab comparing to those who received chemotherapy alone.

Conclusion: Adding-on nivolumab was associated with improved OS in patients with advanced PDAC who achieved disease control following chemotherapy.

背景:由于疗效甚微,免疫检查点抑制剂(ICIs)很少用于治疗晚期胰腺导管腺癌(PDAC):本研究纳入了92例连续确诊为晚期或复发性PDAC的患者,这些患者接受了基于nivolumab的治疗。采用单变量和多变量分析确定预后因素。使用倾向评分匹配法(PSM)选择了301名接受姑息化疗但未使用ICIs的PDAC患者作为对照组进行比较:nivolumab治疗后的中位总生存期(OS)分别为15.8个月(95%置信区间[CI],12.5-19.0)、2.4个月(95% CI,1.2-3.6)和1.1个月(95% CI,1.0-1.2)。在化疗达到疾病控制后接受附加尼妥珠单抗治疗的患者中,在未确认疾病控制的前提下同时接受尼妥珠单抗和化疗的患者中,以及在未同时接受化疗的情况下接受尼妥珠单抗治疗的患者中,尼妥珠单抗对Tregs的影响分别为1.1(95% CI 1.0-1.2)个月、2.4(95% CI 1.2-3.6)个月和1.1(95% CI 1.0-1.2)个月:在化疗后病情得到控制的晚期PDAC患者中,加用nivolumab与OS的改善有关。
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引用次数: 0
Secretome and immune cell attraction analysis of head and neck cancers. 头颈部癌症的分泌组和免疫细胞吸引力分析。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-09 DOI: 10.1007/s00262-024-03809-z
Tara Muijlwijk, Niels E Wondergem, Fatima Ekhlas, Naomi Remkes, Dennis N L M Nijenhuis, Lennart Fritz, Sonja H Ganzevles, Iris H C Miedema, C René Leemans, Jos B Poell, Ruud H Brakenhoff, Rieneke van de Ven

Immune checkpoint inhibitors are approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) but the response rate is only 13-18%. For an effective antitumor immune response, trafficking of immune cells to the tumor microenvironment (TME) is essential. We aimed to better understand immune cell migration as well as the involved chemokines in HNSCC. A transwell assay was used to study immune cell migration toward TME-conditioned medium. While T cell migration was not observed, conventional dendritic cell (cDC) migration was induced by TME-conditioned media. cDC migration correlated with various proteins in the TME secretome. CCL8, CXCL5, CCL13 and CCL7 were tested in validation experiments and addition of these chemokines induced cDC migration. Using single cell RNA-sequencing, we observed expression of CCL8, CXCL5, CCL13 and CCL7 in cancer-associated fibroblasts (CAFs). Depleting fibroblasts led to reduced cDC migration. Thus CAFs, while often seen as suppressors of antitumor immunity, play a role in attracting cDCs toward the head and neck cancer TME, which might be crucial for effective antitumor immunity and response to therapies. Indeed, we found RNA expression signatures of the indicated chemokines, cDC and CAF subpopulations, to be significantly higher in baseline tumor specimen of patients with a major pathological response to pre-surgical anti-PD-1 treatment compared to non-responding patients.

免疫检查点抑制剂已被批准用于治疗复发性/转移性头颈部鳞状细胞癌(HNSCC),但反应率仅为13%-18%。要想获得有效的抗肿瘤免疫反应,免疫细胞向肿瘤微环境(TME)的迁移至关重要。我们的目的是更好地了解免疫细胞迁移以及 HNSCC 中涉及的趋化因子。我们采用跨孔试验来研究免疫细胞向 TME 条件培养基的迁移。虽然没有观察到 T 细胞迁移,但 TME 条件培养基诱导了传统树突状细胞(cDC)迁移。在验证实验中测试了 CCL8、CXCL5、CCL13 和 CCL7,添加这些趋化因子可诱导 cDC 迁移。利用单细胞 RNA 测序,我们在癌症相关成纤维细胞(CAFs)中观察到了 CCL8、CXCL5、CCL13 和 CCL7 的表达。消耗成纤维细胞可减少 cDC 的迁移。因此,CAFs 虽然通常被视为抗肿瘤免疫的抑制因子,但却在吸引 cDCs 向头颈癌 TME 转移方面发挥作用,这可能是有效抗肿瘤免疫和对疗法产生反应的关键。事实上,我们发现,与无应答患者相比,对手术前抗 PD-1 治疗有重大病理反应的患者的基线肿瘤标本中,所述趋化因子、cDC 和 CAF 亚群的 RNA 表达特征明显更高。
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引用次数: 0
Adjuvant chemoradiotherapy plus pembrolizumab for locally advanced esophageal squamous cell carcinoma with high risk of recurrence following neoadjuvant chemoradiotherapy: a single-arm phase II study. 辅助化放疗加pembrolizumab治疗新辅助化放疗后复发风险高的局部晚期食管鳞癌:一项单臂II期研究。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-09 DOI: 10.1007/s00262-024-03826-y
Jhe-Cyuan Guo, Ta-Chen Huang, Hung-Yang Kuo, Chia-Chi Lin, Feng-Ming Hsu, Jason Chia-Hsien Cheng, Yen-Lin Huang, Min-Shu Hsieh, Pei-Ming Huang, Jang-Ming Lee, Shu-Ling Wu, Chih-Hung Hsu

Background: Adjuvant nivolumab reduces recurrence in patients with locoregional esophageal cancer who had pathological residual disease after neoadjuvant chemoradiotherapy and R0 resection. However, the efficacy of adjuvant anti-PD-1 therapy in patients at higher risk of recurrence remains unclear.

Methods: This phase II trial (ClinicalTrials.gov identifier: NCT03322267) enrolled patients with locally advanced esophageal squamous cell carcinoma (ESCC) received neoadjuvant chemoradiotherapy plus esophagectomy but still had various risk factors for recurrence, such as involved or close margins (≤ 1 mm), extranodal extension of the involved lymph nodes, and the ypN2-3 stage. Patients received adjuvant therapy composed of a course of cisplatin-based chemoradiotherapy and pembrolizumab (200 mg, IV every 3 weeks) for 18 cycles. The primary endpoint was 1-year relapse-free survival (RFS) rate.

Results: Twenty-five patients were enrolled. The risk factors were tumor margins of ≤ 1 mm (18 patients), extranodal extension of the involved lymph nodes (9 patients), and the ypN2-3 stage (9 patients). The median follow-up duration was 21.6 months (95% CI: 18.7-33.2). The rate of 1-year RFS was 60.0%. The median duration of RFS and overall survival was 14.3 (95% CI: 9.0-19.5) and 21.6 (95% CI: 0.0-45.5) months, respectively. Treatment-emergent adverse events of any grade and those of ≥ 3 grade occurred in 56% and 8% of all patients receiving cisplatin-based chemoradiotherapy and in 79.2% and 12.5% of those receiving pembrolizumab.

Conclusions: Adjuvant chemoradiotherapy followed by pembrolizumab is feasible and may be associated with improved 1-year RFS rate in patients at high risk of recurrence after trimodality therapy for locally advanced ESCC. Trial registration number ClinicalTrials.gov (No. NCT03322267).

背景新辅助化放疗和R0切除术后有病理残留的局部食管癌患者接受nivolumab辅助治疗可减少复发。然而,对于复发风险较高的患者,抗PD-1辅助治疗的疗效仍不明确:这项II期试验(ClinicalTrials.gov标识符:NCT03322267)招募了局部晚期食管鳞状细胞癌(ESCC)患者,这些患者接受了新辅助化放疗加食管切除术,但仍存在各种复发风险因素,如受累或边缘较近(≤1毫米)、受累淋巴结的结外扩展以及ypN2-3分期。患者接受的辅助治疗包括一个疗程的顺铂为基础的化放疗和pembrolizumab(200毫克,每3周静脉注射一次),共18个周期。主要终点是1年无复发生存率(RFS):25名患者入组。风险因素包括肿瘤边缘≤1毫米(18例患者)、受累淋巴结向结外扩展(9例患者)和ypN2-3分期(9例患者)。中位随访时间为21.6个月(95% CI:18.7-33.2)。1年RFS率为60.0%。RFS和总生存期的中位数分别为14.3个月(95% CI:9.0-19.5)和21.6个月(95% CI:0.0-45.5)。在接受顺铂为基础的化放疗的所有患者中,56%和8%发生了任何级别的治疗突发不良事件,在接受pembrolizumab治疗的患者中,79.2%和12.5%发生了≥3级的治疗突发不良事件:在局部晚期ESCC三模式治疗后复发风险较高的患者中,辅助化放疗后使用pembrolizumab是可行的,并可提高1年RFS率。试验注册号:ClinicalTrials.gov(编号:NCT03322267)。
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引用次数: 0
Disruptions in antigen processing and presentation machinery on sarcoma. 肉瘤抗原处理和递呈机制的紊乱。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-09 DOI: 10.1007/s00262-024-03822-2
Salvatore Lorenzo Renne, Laura Sama', Sonia Kumar, Omer Mintemur, Laura Ruspi, Ilaria Santori, Federico Sicoli, Alexia Bertuzzi, Alice Laffi, Arturo Bonometti, Piergiuseppe Colombo, Vittoria D'amato, Alessandra Bressan, Marta Scorsetti, Luigi Terracciano, Pierina Navarria, Maurizio D'incalci, Vittorio Quagliuolo, Fabio Pasqualini, Fabio Grizzi, Ferdinando Carlo Maria Cananzi

Background: The antigen processing machinery (APM) plays a critical role in generating tumor-specific antigens that can be recognized and targeted by the immune system. Proper functioning of APM components is essential for presenting these antigens on the surface of tumor cells, enabling immune detection and destruction. In many cancers, defects in APM can lead to immune evasion, contributing to tumor progression and poor clinical outcomes. However, the status of the APM in sarcomas is not well characterized, limiting the development of effective immunotherapeutic strategies for these patients.

Methods: We investigated 126 patients with 8 types of bone and soft tissue sarcoma operated between 2001-2021. Tissue microarrays mapped 11 specific areas in each case. The presence/absence of APM protein was determined through immunohistochemistry. Bayesian networks were used.

Results: All investigated sarcomas had some defects in APM. The least damaged component was HLA Class I subunit β2-microglobulin and HLA Class II. The proteasome LMP10 subunit was defective in leiomyosarcoma (LMS), myxoid liposarcoma (MLPS), and dedifferentiated liposarcoma (DDLPS), while MHC I transporting unit TAP2 was altered in undifferentiated pleomorphic sarcoma (UPS), gastrointestinal stromal tumor (GIST), and chordoma (CH). Among different neoplastic areas, high-grade areas showed different patterns of expression compared to high lymphocytic infiltrate areas. Heterogeneity at the patient level was also observed. Loss of any APM component was prognostic of distant metastasis (DM) for LMS and DDLPS and of overall survival (OS) for LMS.

Conclusion: Sarcomas exhibit a high degree of defects in APM components, with differences among histotypes and tumoral areas. The most commonly altered APM components were HLA Class I subunit β2-microglobulin, HLA Class I subunit α (HC10), and MHC I transporting unit TAP2. The loss of APM components was prognostic of DM and OS and clinically relevant for LMS and DDLPS. This study explores sarcoma molecular mechanisms, enriching personalized therapeutic approaches.

背景:抗原处理机制(APM)在产生可被免疫系统识别和靶向的肿瘤特异性抗原方面发挥着关键作用。APM 组件的正常运行对于将这些抗原呈现在肿瘤细胞表面、使免疫检测和摧毁肿瘤细胞至关重要。在许多癌症中,APM 的缺陷会导致免疫逃避,从而导致肿瘤进展和不良的临床结果。然而,肉瘤中 APM 的状况还没有得到很好的描述,这限制了为这些患者制定有效的免疫治疗策略:我们调查了 2001-2021 年间接受手术的 126 例 8 种类型骨与软组织肉瘤患者。组织芯片绘制了每个病例的 11 个特定区域。通过免疫组化确定是否存在 APM 蛋白。研究使用了贝叶斯网络:结果:所有被研究的肉瘤都存在APM缺陷。受损最少的成分是HLA I类亚基β2-微球蛋白和HLA II类。蛋白酶体LMP10亚基在巨肌瘤(LMS)、肌样脂肪肉瘤(MLPS)和去分化脂肪肉瘤(DDLPS)中存在缺陷,而MHC I转运单位TAP2在未分化多形性肉瘤(UPS)、胃肠道间质瘤(GIST)和脊索瘤(CH)中发生了改变。在不同的肿瘤区域中,高级别区域与淋巴细胞高浸润区域的表达模式不同。在患者层面也观察到了异质性。任何 APM 成分的缺失都是 LMS 和 DDLPS 远处转移(DM)和 LMS 总生存(OS)的预后因素:结论:肉瘤显示出 APM 成分的高度缺陷,不同组织类型和肿瘤区域之间存在差异。最常见的APM成分改变是HLA I类亚单位β2-微球蛋白、HLA I类亚单位α(HC10)和MHC I运输单位TAP2。APM成分的缺失对DM和OS有预后作用,对LMS和DDLPS有临床意义。这项研究探索了肉瘤的分子机制,丰富了个性化治疗方法。
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Cancer Immunology, Immunotherapy
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