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Spatial cell interplay networks of regulatory T cells predict recurrence in patients with operable non-small cell lung cancer. 调节性 T 细胞的空间细胞相互作用网络可预测可手术非小细胞肺癌患者的复发。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-02 DOI: 10.1007/s00262-024-03762-x
Siqi Cai, Guanqun Yang, Mengyu Hu, Chaozhuo Li, Liying Yang, Wei Zhang, Jujie Sun, Fenghao Sun, Ligang Xing, Xiaorong Sun

Background: The interplay between regulatory T cells (Tregs) and neighboring cells, which is pivotal for anti-tumor immunity and closely linked to patient prognosis, remains to be fully elucidated.

Methods: Tissue microarrays of 261 operable NSCLC patients were stained by multiplex immunofluorescence (mIF) assay, and the interaction between Tregs and neighboring cells in the tumor microenvironment (TME) was evaluated. Employing various machine learning algorithms, we developed a spatial immune signature to predict the prognosis of NSCLC patients. Additionally, we explored the interplay between programmed death-1/programmed death ligand-1 (PD-1/PD-L1) interactions and their relationship with Tregs.

Results: Survival analysis indicated that the interplay between Tregs and neighboring cells in the invasive margin (IM) and tumor center was associated with recurrence in NSCLC patients. We integrated the intersection of the three algorithms to identify four crucial spatial immune features [P(CD8+Treg to CK) in IM, P(CD8+Treg to CD4) in IM, N(CD4+Treg to CK) in IM, N(CD4+Tcon to CK) in IM] and employed these characteristics to establish SIS, an independent prognosticator of recurrence in NSCLC patients [HR = 2.34, 95% CI (1.53, 3.58), P < 0.001]. Furthermore, analysis of cell interactions demonstrated that a higher number of Tregs contributed to higher PD-L1+ cells surrounded by PD-1+ cells (P < 0.001) with shorter distances (P = 0.004).

Conclusion: We dissected the cell interplay network within the TME, uncovering the spatial architecture and intricate interactions between Tregs and neighboring cells, along with their impact on the prognosis of NSCLC patients.

背景:调节性 T 细胞(Tregs)与邻近细胞之间的相互作用对抗肿瘤免疫至关重要,并与患者预后密切相关:调节性T细胞(Tregs)与邻近细胞之间的相互作用对抗肿瘤免疫至关重要,并与患者的预后密切相关,但这一相互作用仍有待全面阐明:方法:采用多重免疫荧光(mIF)检测法对261例可手术的NSCLC患者的组织芯片进行染色,并评估Tregs与肿瘤微环境(TME)中邻近细胞之间的相互作用。利用各种机器学习算法,我们建立了一个空间免疫特征来预测 NSCLC 患者的预后。此外,我们还探讨了程序性死亡-1/程序性死亡配体-1(PD-1/PD-L1)之间的相互作用及其与Tregs的关系:生存分析表明,Tregs与浸润边缘(IM)和肿瘤中心邻近细胞之间的相互作用与NSCLC患者的复发有关。我们整合了三种算法的交叉点,确定了四个关键的空间免疫特征[IM中的P(CD8+Treg to CK)、IM中的P(CD8+Treg to CD4)、IM中的N(CD4+Treg to CK)、IM中的N(CD4+Tcon to CK)],并利用这些特征建立了SIS,它是NSCLC患者复发的独立预后指标[HR = 2.34, 95% CI (1.53, 3.58),P+细胞被PD-1+细胞包围(P 结论:SIS是NSCLC患者复发的独立预后指标:我们剖析了TME内的细胞相互作用网络,揭示了Tregs与邻近细胞之间的空间结构和错综复杂的相互作用,以及它们对NSCLC患者预后的影响。
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引用次数: 0
In vitro T cell responses to PD-1 blockade are reduced by IFN-α but do not predict therapy response in melanoma patients. 体外 T 细胞对 PD-1 阻断剂的反应会因 IFN-α 而降低,但并不能预测黑色素瘤患者的治疗反应。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-05 DOI: 10.1007/s00262-024-03760-z
Laura M Timmerman, Lobke C M Hensen, Mick J M van Eijs, Rik J Verheijden, Karijn P M Suijkerbuijk, Linde Meyaard, Michiel van der Vlist

PD-1 blockade therapy has revolutionized melanoma treatment, but still not all patients benefit and pre-treatment identification of those patients is difficult. Increased expression of inflammatory markers such as interleukin (IL)-6 in blood of patients correlates with poor treatment response. We set out to study the effect of inflammatory cytokines on PD-1 blockade in vitro. For this, we studied the effect of IL-6 and type I interferon (IFN) in vitro on human T cells in a mixed leukocyte reaction (MLR) in the absence or presence of PD-1 blockade. While IL-6 reduced IFN-γ secretion by T cells in both the presence and absence of PD-1 blockade, IFN-α specifically reduced the IFN-γ secretion only in the presence of PD-1 blockade. IFN-α reduced T cell proliferation independent of PD-1 blockade and reduced the percentage of cells producing IFN-γ only in the presence of PD-1 blockade. Next we determined the type I IFN score in a cohort of 22 melanoma patients treated with nivolumab. In this cohort, we did not find a correlation between clinical response and type I IFN score, nor between clinical response and IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade. We conclude that IFN-α reduces the effectiveness of PD-1 blockade in vitro, but that in this cohort, type I IFN score in vivo, nor IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade correlated to decreased therapy responses in patients.

PD-1阻断疗法给黑色素瘤治疗带来了革命性的变化,但并非所有患者都能从中获益,而且很难在治疗前识别出这些患者。患者血液中白细胞介素(IL)-6 等炎症标志物的表达增加与治疗反应不佳有关。我们着手在体外研究炎性细胞因子对 PD-1 阻断的影响。为此,我们在体外研究了IL-6和I型干扰素(IFN)在没有或存在PD-1阻断的情况下对混合白细胞反应(MLR)中人类T细胞的影响。在存在和不存在 PD-1 阻断的情况下,IL-6 都会减少 T 细胞分泌的 IFN-γ,而 IFN-α 只有在存在 PD-1 阻断的情况下才会特异性地减少 IFN-γ 的分泌。IFN-α 可减少 T 细胞的增殖,而与 PD-1 阻断无关,并且只有在 PD-1 阻断的情况下才能减少产生 IFN-γ 的细胞百分比。接下来,我们测定了接受 nivolumab 治疗的 22 例黑色素瘤患者的 IFN 评分。在这个队列中,我们没有发现临床反应与 I 型 IFN 评分之间存在相关性,也没有发现临床反应与 PD-1 阻断作用下 MLR 体外 IFN-γ 分泌之间存在相关性。我们的结论是,IFN-α会降低体外PD-1阻断剂的效果,但在该队列中,体内I型IFN评分和体外PD-1阻断剂存在时MLR中IFN-γ的分泌与患者治疗反应的下降无关。
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引用次数: 0
Blockade of the TIGIT-CD155/CD112 axis enhances functionality of NK-92 but not cytokine-induced memory-like NK cells toward CD155-expressing acute myeloid leukemia. 阻断 TIGIT-CD155/CD112 轴可增强 NK-92 的功能,但不能增强细胞因子诱导的记忆样 NK 细胞对表达 CD155 的急性髓性白血病的功能。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-05 DOI: 10.1007/s00262-024-03766-7
Katharina Seel, Ronja Larissa Schirrmann, Daniel Stowitschek, Tamar Ioseliani, Lea Roiter, Alina Knierim, Maya C André

TIGIT is an alternative checkpoint receptor (CR) whose inhibition promotes Graft-versus-Leukemia effects of NK cells. Given the significant immune-permissiveness of NK cells circulating in acute myeloid leukemia (AML) patients, we asked whether adoptive transfer of activated NK cells would benefit from additional TIGIT-blockade. Hence, we characterized cytokine-induced memory-like (CIML)-NK cells and NK cell lines for the expression of inhibitory CRs. In addition, we analyzed the transcription of CR ligands in AML patients (CCLE and Beat AML 2.0 cohort) in silico and evaluated the efficacy of CR blockade using in vitro cytotoxicity assays, CD69, CD107a and IFN-γ expression. Alternative but not classical CRs were abundantly expressed on healthy donor NK cells and even further upregulated on CIML-NK cells. In line with our finding that CD155, one important TIGIT-ligand, is reliably expressed on AMLs, we show improved killing of CD155+-AML blasts by NK-92 but interestingly not CIML-NK cells in the presence of TIGIT-blockade. Additionally, our in silico data (n = 671) show that poor prognosis AML patients rather displayed a CD86low CD112/CD155high phenotype, whereas patients with a better outcome rather exhibited a CD86high CD112/CD155low phenotype. Collectively, our data evidence that the complex CR ligand expression profile on AML blasts may be one explanation for the intrinsic NK cell exhaustion observed in AML patients which might be overcome with adoptive NK-92 transfer in combination with TIGIT-blockade.

TIGIT是一种替代性检查点受体(CR),抑制它可促进NK细胞的移植物抗白血病效应。鉴于急性髓性白血病(AML)患者体内循环的 NK 细胞具有明显的免疫容许性,我们提出了一个问题:活化的 NK 细胞的收养性转移是否会从额外的 TIGIT 抑制中获益。因此,我们对细胞因子诱导记忆样(CIML)-NK 细胞和 NK 细胞系的抑制性 CRs 表达进行了鉴定。此外,我们还对 AML 患者(CCLE 和 Beat AML 2.0 队列)中 CR 配体的转录进行了硅学分析,并使用体外细胞毒性试验、CD69、CD107a 和 IFN-γ 表达评估了 CR 阻断的疗效。健康供体 NK 细胞中大量表达替代 CR,而非传统 CR,在 CIML-NK 细胞中甚至进一步上调。我们发现,CD155(一种重要的 TIGIT 配体)在急性髓细胞上可靠表达,与此相一致的是,我们发现 NK-92 对 CD155+-AML 病灶的杀伤力有所提高,但有趣的是,在 TIGIT 受体阻断的情况下,CIML-NK 细胞对 CD155+-AML 病灶的杀伤力并没有提高。此外,我们的硅学数据(n = 671)显示,预后不良的急性髓细胞性白血病患者表现出 CD86 低 CD112/CD155 高的表型,而预后较好的患者则表现出 CD86 高 CD112/CD155 低的表型。总之,我们的数据证明,急性髓细胞白细胞上复杂的CR配体表达谱可能是急性髓细胞白血病患者出现内在NK细胞衰竭的原因之一,而采用NK-92转移结合TIGIT阻断疗法可能会克服这一问题。
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引用次数: 0
Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers. 免疫检查点抑制剂作为dMMR/MSI-H结直肠癌和胃癌的新辅助治疗和辅助治疗的长期存活率。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-05 DOI: 10.1007/s00262-024-03764-9
Zhenghang Wang, Siyuan Cheng, Yanhong Yao, Shengde Liu, Zimin Liu, Ning Liu, Yongdong Jin, Yinjie Zhang, Fei Yin, Guangjie Han, Jingdong Zhang, Qiwei Wang, Dong Yan, Li Wang, Hongxia Lu, Ting Deng, Zhi Ji, Hui Gao, Weijia Fang, Hangyu Zhang, Zhiyu Chen, Jianling Zou, Yong Tang, Chunlei Xu, Jiayi Li, Huajun Qu, Liying Bao, Baoshan Cao, Xicheng Wang, Ting Xu, Yu Sun, Lin Shen, Zhi Peng, Jian Li

Background: The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H).

Methods: This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable.

Results: In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease.

Conclusion: With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

背景:对于存在错配修复缺陷(dMMR)或微卫星不稳定性高(MSI-H)的结直肠癌(CRC)和胃癌(GC),免疫检查点抑制剂(ICIs)在新辅助和辅助治疗中的长期生存获益尚不明确:这项回顾性研究招募了在中国17个中心至少接受过一次新辅助ICIs(新辅助队列,NAC)或辅助ICIs(辅助队列,AC)治疗的dMMR/MSI-H CRC和GC患者。如果所有肿瘤病灶均可根治性切除,IV期患者也符合条件:在 NAC(n = 124)中,CRC 和 GC 的客观反应率分别为 75.7% 和 55.4%,病理完全反应率分别为 73.4% 和 47.7%。CRC的3年无病生存率(DFS)和总生存率(OS)分别为96%(95%CI 90-100%)和100%(中位随访[mFU] 29.4个月),GC的3年无病生存率(mFU 33.0个月)和总生存率(OS)分别为84%(72-96%)和93%(85-100%)。在AC(n = 48)中,CRC(mFU 35.5个月)的3年DFS和OS率分别为94%(84-100%)和100%,GC(mFU 40.4个月)的3年DFS和OS率分别为92%(82-100%)和96%(88-100%)。在7例远处复发的患者中,4例接受了PD1和CTLA4双重阻断联合或不联合化疗和靶向药物治疗,其中3例部分应答,1例疾病进展:本研究通过较长时间的随访表明,新辅助和辅助 ICIs 可为 dMMR/MSI-H CRC 和 GC 带来良好的 DFS 和 OS,这一点应在进一步的随机临床试验中得到证实。
{"title":"Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers.","authors":"Zhenghang Wang, Siyuan Cheng, Yanhong Yao, Shengde Liu, Zimin Liu, Ning Liu, Yongdong Jin, Yinjie Zhang, Fei Yin, Guangjie Han, Jingdong Zhang, Qiwei Wang, Dong Yan, Li Wang, Hongxia Lu, Ting Deng, Zhi Ji, Hui Gao, Weijia Fang, Hangyu Zhang, Zhiyu Chen, Jianling Zou, Yong Tang, Chunlei Xu, Jiayi Li, Huajun Qu, Liying Bao, Baoshan Cao, Xicheng Wang, Ting Xu, Yu Sun, Lin Shen, Zhi Peng, Jian Li","doi":"10.1007/s00262-024-03764-9","DOIUrl":"10.1007/s00262-024-03764-9","url":null,"abstract":"<p><strong>Background: </strong>The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H).</p><p><strong>Methods: </strong>This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable.</p><p><strong>Results: </strong>In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease.</p><p><strong>Conclusion: </strong>With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11226604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533758","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
Correction to: New CEACAM-targeting 2A3 single-domain antibody-based chimeric antigen receptor T-cells produce anticancer effects in vitro and in vivo. 更正为基于 CEACAM 靶向 2A3 单域抗体的新型嵌合抗原受体 T 细胞在体外和体内产生抗癌效果。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-05 DOI: 10.1007/s00262-024-03727-0
Iga Jancewicz, Magdalena Śmiech, Magdalena Winiarska, Radoslaw Zagozdzon, Pawel Wisniewski
{"title":"Correction to: New CEACAM-targeting 2A3 single-domain antibody-based chimeric antigen receptor T-cells produce anticancer effects in vitro and in vivo.","authors":"Iga Jancewicz, Magdalena Śmiech, Magdalena Winiarska, Radoslaw Zagozdzon, Pawel Wisniewski","doi":"10.1007/s00262-024-03727-0","DOIUrl":"10.1007/s00262-024-03727-0","url":null,"abstract":"","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11226685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537664","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
Efficacy of adjuvant immune checkpoint inhibitors pembrolizumab or nivolumab in melanoma patients ≥ 75 years: results of a real-world cohort including 456 patients. pembrolizumab或nivolumab辅助免疫检查点抑制剂对≥75岁黑色素瘤患者的疗效:包括456名患者的真实世界队列结果。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-05 DOI: 10.1007/s00262-024-03750-1
A Gawaz, I Wolff, L Nanz, L Flatz, A Forschner

Background: Immune checkpoint inhibitors (ICI) applied in patients with melanoma in an adjuvant setting have proven safety and efficacy in several studies, but data on elderly patients aged 75 years or more is scarce. Aim of this study was to investigate efficacy and safety of adjuvant ICI in patients aged ≥ 75 years compared to patients < 75 years in a real-world setting.

Methods: We retrospectively analyzed clinical data, including occurrence of immune-related adverse events (irAE) and outcome of 456 patients that had been treated with adjuvant ICI between January 1st, 2018 and December 20th, 2022. We then compared patients aged ≥ 75 years (n = 117) to patients < 75 years (n = 339) in terms of safety and disease-free survival (DFS).

Results and conclusion: ICI were well tolerated in both groups, with no significant difference observed in the overall occurrence of irAE. However, within the elderly subgroup, there was a significantly higher proportion of skin or nephrological toxicity and colitis/diarrhea compared to the other group. In terms of efficacy, a significantly shorter DFS in patients aged ≥ 75 years was observed. Adjuvant ICI in patients ≥ 75 years was less effective and furthermore associated with an increased risk for skin, renal or bowel toxicity. Therefore, in elderly patients, adjuvant ICI should be used with precaution.

背景:在多项研究中,黑色素瘤患者辅助应用免疫检查点抑制剂(ICI)的安全性和有效性已得到证实,但关于75岁或以上老年患者的数据却很少。本研究的目的是调查 ICI 在年龄≥ 75 岁患者中辅助治疗的疗效和安全性:我们回顾性分析了2018年1月1日至2022年12月20日期间接受辅助ICI治疗的456名患者的临床数据,包括免疫相关不良事件(irAE)的发生情况和结果。然后,我们将年龄≥75岁的患者(n = 117)与结果和结论进行了比较:两组患者对 ICI 的耐受性都很好,在虹膜睫状体E的总体发生率方面没有观察到明显差异。然而,在老年亚组中,皮肤或肾毒性以及结肠炎/腹泻的比例明显高于其他组别。在疗效方面,观察到年龄≥75 岁的患者的 DFS 明显较短。≥75岁患者的辅助ICI疗效较差,而且皮肤、肾脏或肠道毒性风险增加。因此,老年患者应谨慎使用 ICI 辅助治疗。
{"title":"Efficacy of adjuvant immune checkpoint inhibitors pembrolizumab or nivolumab in melanoma patients ≥ 75 years: results of a real-world cohort including 456 patients.","authors":"A Gawaz, I Wolff, L Nanz, L Flatz, A Forschner","doi":"10.1007/s00262-024-03750-1","DOIUrl":"10.1007/s00262-024-03750-1","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICI) applied in patients with melanoma in an adjuvant setting have proven safety and efficacy in several studies, but data on elderly patients aged 75 years or more is scarce. Aim of this study was to investigate efficacy and safety of adjuvant ICI in patients aged ≥ 75 years compared to patients < 75 years in a real-world setting.</p><p><strong>Methods: </strong>We retrospectively analyzed clinical data, including occurrence of immune-related adverse events (irAE) and outcome of 456 patients that had been treated with adjuvant ICI between January 1st, 2018 and December 20th, 2022. We then compared patients aged ≥ 75 years (n = 117) to patients < 75 years (n = 339) in terms of safety and disease-free survival (DFS).</p><p><strong>Results and conclusion: </strong>ICI were well tolerated in both groups, with no significant difference observed in the overall occurrence of irAE. However, within the elderly subgroup, there was a significantly higher proportion of skin or nephrological toxicity and colitis/diarrhea compared to the other group. In terms of efficacy, a significantly shorter DFS in patients aged ≥ 75 years was observed. Adjuvant ICI in patients ≥ 75 years was less effective and furthermore associated with an increased risk for skin, renal or bowel toxicity. Therefore, in elderly patients, adjuvant ICI should be used with precaution.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11226568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537665","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
Correction to: The radiomics nomogram predicts the prognosis of pancreatic cancer patients with hepatic metastasis after chemoimmunotherapy. 更正:放射组学提名图预测化疗免疫疗法后肝转移胰腺癌患者的预后。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-05 DOI: 10.1007/s00262-024-03739-w
Wenxin Lu, Guangyu Wu, Xianyuan Miao, Jingyu Ma, Yanling Wang, Haiyan Xu, Daiyuan Shentu, Shengbai Xue, Qing Xia, Yu Wang, Liwei Wang
{"title":"Correction to: The radiomics nomogram predicts the prognosis of pancreatic cancer patients with hepatic metastasis after chemoimmunotherapy.","authors":"Wenxin Lu, Guangyu Wu, Xianyuan Miao, Jingyu Ma, Yanling Wang, Haiyan Xu, Daiyuan Shentu, Shengbai Xue, Qing Xia, Yu Wang, Liwei Wang","doi":"10.1007/s00262-024-03739-w","DOIUrl":"10.1007/s00262-024-03739-w","url":null,"abstract":"","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11229438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533756","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
A "Prime and Expand" strategy using the multifunctional fusion proteins to generate memory-like NK cells for cell therapy. 利用多功能融合蛋白的 "激活和扩展 "策略,生成记忆型 NK 细胞用于细胞疗法。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-03 DOI: 10.1007/s00262-024-03765-8
Niraj Shrestha, Michael J Dee, Pallavi Chaturvedi, Gilles M Leclerc, Mary Mathyer, Celeste Dufour, Laura Arthur, Michelle Becker-Hapak, Mark Foster, Ethan McClain, Natalia Valderrama Pena, Karen Kage, Xiaoyun Zhu, Varghese George, Bai Liu, Jack Egan, Christian Echeverri, Meng Wang, Lijing You, Lin Kong, Liying Li, Melissa M Berrien-Elliott, Matthew L Cooper, Todd A Fehniger, Peter R Rhode, Hing C Wong

Adoptive cellular therapy (ACT) using memory-like (ML) natural killer (NK) cells, generated through overnight ex vivo activation with IL-12, IL-15, and IL-18, has shown promise for treating hematologic malignancies. We recently reported that a multifunctional fusion molecule, HCW9201, comprising IL-12, IL-15, and IL-18 domains could replace individual cytokines for priming human ML NK cell programming ("Prime" step). However, this approach does not include ex vivo expansion, thereby limiting the ability to test different doses and schedules. Here, we report the design and generation of a multifunctional fusion molecule, HCW9206, consisting of human IL-7, IL-15, and IL-21 cytokines. We observed > 300-fold expansion for HCW9201-primed human NK cells cultured for 14 days with HCW9206 and HCW9101, an IgG1 antibody, recognizing the scaffold domain of HCW9206 ("Expand" step). This expansion was dependent on both HCW9206 cytokines and interactions of the IgG1 mAb with CD16 receptors on NK cells. The resulting "Prime and Expand" ML NK cells exhibited elevated metabolic capacity, stable epigenetic IFNG promoter demethylation, enhanced antitumor activity in vitro and in vivo, and superior persistence in NSG mice. Thus, the "Prime and Expand" strategy represents a simple feeder cell-free approach to streamline manufacturing of clinical-grade ML NK cells to support multidose and off-the-shelf ACT.

使用IL-12、IL-15和IL-18在体外过夜激活产生的记忆样(ML)自然杀伤(NK)细胞进行的适应性细胞疗法(ACT)已显示出治疗血液恶性肿瘤的前景。我们最近报道了一种由 IL-12、IL-15 和 IL-18 结构域组成的多功能融合分子 HCW9201,它可以取代单个细胞因子,用于人类 ML NK 细胞编程的启动("启动 "步骤)。然而,这种方法不包括体内外扩增,因此限制了测试不同剂量和计划的能力。在此,我们报告了由人类 IL-7、IL-15 和 IL-21 细胞因子组成的多功能融合分子 HCW9206 的设计和生成。我们观察到,用 HCW9206 和 HCW9101(一种 IgG1 抗体,可识别 HCW9206 的支架结构域)培养 14 天的 HCW9201 激发的人 NK 细胞扩增了 300 倍以上("扩增 "步骤)。这种扩增既依赖于 HCW9206 细胞因子,也依赖于 IgG1 mAb 与 NK 细胞上 CD16 受体的相互作用。由此产生的 "Prime and Expand" ML NK 细胞表现出更高的代谢能力、稳定的表观遗传 IFNG 启动子去甲基化、更强的体外和体内抗肿瘤活性,以及在 NSG 小鼠体内更强的持久性。因此,"Prime and Expand "策略代表了一种简单的无饲养细胞方法,可简化临床级 ML NK 细胞的生产,支持多剂量和现成的 ACT。
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引用次数: 0
Tumor-intrinsic IFNα and CXCL10 are critical for immunotherapeutic efficacy by recruiting and activating T lymphocytes in tumor microenvironment. 肿瘤内源性 IFNα 和 CXCL10 通过招募和激活肿瘤微环境中的 T 淋巴细胞,对免疫治疗效果至关重要。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-02 DOI: 10.1007/s00262-024-03761-y
Chun-Chia Cheng, Jungshan Chang, Ai-Sheng Ho, Zong-Lin Sie, Cheng-Liang Peng, Chih-Liang Wang, Kapil Dev, Chun-Chao Chang

Tumor immunotherapies targeting PD-(L)1 exhibit anti-tumor efficacy in only 10-30% of patients with various cancers. Literature has demonstrated that a "hot tumor" which contains high T lymphocytes in the tumor microenvironment exhibits a better response to immunotherapies than a "cold tumor." This study aimed to investigate whether tumor-intrinsic IFNα and CXCL10 determine the recruitment and activation of CD8+ T cells to become "hot tumor." In this study, we found that CXCL10 overexpressed in a variety of tumors including lung, colon, and liver tumors with a correlation with PD-L1. High PD-L1 and CXCL10 are associated with better survival rates in tumor patients receiving immunotherapies. IFNs-downstream transcriptional factor IRF-1 and STAT1 were correlated with PD-L1 and CXCL10 expression. We demonstrated that IRF-1 and STAT1 were both bound with the promoters of PD-L1 and CXCL10, sharing the same signaling pathway and determining IFNs-mediated PD-L1 and CXCL10 expression. In addition, IFNα significantly increased activation marker IFNγ in PBMCs, promoting M1 type monocyte differentiation, CD4+ T, and CD8+ T cell activation. Particularly, we found that CD8+ T lymphocytes abundantly expressed CXCR3, a receptor of CXCL10, by flow cytometry, indicating that tumor-intrinsic CXCL10 potentially recruited CD8+ T in tumor microenvironment. To demonstrate the hypothesis, immunotherapy-sensitive CT26 and immunotherapy-resistant LL/2 were used and we found that CT26 cells exhibited higher IFNα, IFNγ, CXCL10, and PD-L1 levels compared to LL/2, leading to higher IFNγ expression in mouse splenocytes. Moreover, we found that CD8+ T cells were recruited by CXCL10 in vitro, whereas SCH546738, an inhibitor of CXCR3, inhibited T cell migration and splenocytes-mediated anti-tumor effect. We then confirmed that CT26-derived tumor was sensitive to αPD-L1 immunotherapy and LL/2-tumor was resistant, whereas αPD-L1 significantly increased T lymphocyte activation marker CD107a in CT26-derived BALB/c mice. In conclusion, this study revealed that CXCL10 expression is correlated with PD-L1 in tumors, sharing the same signaling pathway and associating with better immunotherapeutic efficacy. Further evidence in the syngeneic tumor models demonstrated that immunotherapy-sensitive CT26 intrinsically exhibited higher IFNα and CXCL10 compared to immunotherapy-resistant LL/2 to recruit and activate CD8+ T cells in the tumor microenvironment, exhibiting "hot tumor" characteristic of sensitizing αPD-L1 immunotherapies.

以 PD-(L)1 为靶点的肿瘤免疫疗法仅对 10-30% 的各种癌症患者有抗肿瘤疗效。文献表明,肿瘤微环境中含有大量T淋巴细胞的 "热肿瘤 "比 "冷肿瘤 "对免疫疗法的反应更好。本研究旨在探讨肿瘤内源性IFNα和CXCL10是否决定了CD8+ T细胞的募集和活化成为 "热肿瘤"。在这项研究中,我们发现 CXCL10 在肺癌、结肠癌和肝癌等多种肿瘤中过表达,并与 PD-L1 相关。高 PD-L1 和 CXCL10 与接受免疫疗法的肿瘤患者生存率的提高有关。IFNs 下游转录因子 IRF-1 和 STAT1 与 PD-L1 和 CXCL10 的表达相关。我们证实,IRF-1和STAT1均与PD-L1和CXCL10的启动子结合,共享相同的信号通路,决定了IFNs介导的PD-L1和CXCL10的表达。此外,IFNα能显著增加PBMCs中的活化标志物IFNγ,促进M1型单核细胞分化、CD4+ T和CD8+ T细胞活化。特别是,我们通过流式细胞术发现 CD8+ T 淋巴细胞大量表达 CXCR3(CXCL10 的受体),这表明肿瘤内源性 CXCL10 有可能在肿瘤微环境中招募 CD8+ T。为了证明这一假设,我们使用了对免疫疗法敏感的 CT26 和对免疫疗法耐受的 LL/2,结果发现 CT26 细胞比 LL/2 表现出更高的 IFNα、IFNγ、CXCL10 和 PD-L1 水平,从而导致小鼠脾细胞中更高的 IFNγ 表达。此外,我们发现 CD8+ T 细胞在体外被 CXCL10 募集,而 CXCR3 抑制剂 SCH546738 则抑制 T 细胞迁移和脾细胞介导的抗肿瘤效应。我们随后证实,CT26 衍生的肿瘤对 αPD-L1 免疫疗法敏感,而 LL/2 衍生的肿瘤则耐药,而 αPD-L1 能显著增加 CT26 衍生的 BALB/c 小鼠的 T 淋巴细胞活化标志物 CD107a。总之,这项研究揭示了肿瘤中CXCL10的表达与PD-L1相关,共享相同的信号通路,并与更好的免疫治疗效果相关。在共生肿瘤模型中的进一步证据表明,与免疫治疗耐药的LL/2相比,免疫治疗敏感的CT26本质上表现出更高的IFNα和CXCL10,可招募和激活肿瘤微环境中的CD8+ T细胞,表现出对αPD-L1免疫疗法敏感的 "热肿瘤 "特征。
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引用次数: 0
Altered expression of cytokines, chemokines, growth factors, and soluble receptors in patients with colorectal cancer, and correlation with treatment outcome. 结直肠癌患者体内细胞因子、趋化因子、生长因子和可溶性受体的表达变化及其与治疗效果的关系。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-02 DOI: 10.1007/s00262-024-03746-x
M Stayoussef, X Weili, A Habel, M Barbirou, S Bedoui, A Attia, Y Omrani, K Zouari, H Maghrebi, W Y Almawi, B Bouhaouala-Zahar, A Larbi, B Yacoubi-Loueslati

Insofar as they play an important role in the pathogenesis of colorectal cancer (CRC), this study analyzes the serum profile of cytokines, chemokines, growth factors, and soluble receptors in patients with CRC and cancer-free controls as possible CRC signatures. Serum levels of 65 analytes were measured in patients with CRC and age- and sex-matched cancer-free controls using the ProcartaPlex Human Immune Monitoring 65-Plex Panel. Of the 65 tested analytes, 8 cytokines (CSF-3, IFN-γ, IL-12p70, IL-18, IL-20, MIF, TNF-α and TSLP), 8 chemokines (fractalkine, MIP-1β, BLC, Eotaxin-1, Eotaxin-2, IP-10, MIP-1a, MIP-3a), 2 growth factors (FGF-2, MMP-1), and 4 soluble receptors (APRIL, CD30, TNFRII, and TWEAK), were differentially expressed in CRC. ROC analysis confirmed the high association of TNF-α, BLC, Eotaxin-1, APRIL, and Tweak with AUC > 0.70, suggesting theranostic application. The expression of IFN-γ, IL-18, MIF, BLC, Eotaxin-1, Eotaxin-2, IP-10, and MMP1 was lower in metastatic compared to non-metastatic CRC; only AUC of MIF and MIP-1β were > 0.7. Moreover, MDC, IL-7, MIF, IL-21, and TNF-α are positively associated with tolerance to CRC chemotherapy (CT) (AUC > 0.7), whereas IL-31, Fractalkine, Eotaxin-1, and Eotaxin-2 were positively associated with resistance to CT. TNF-α, BLC, Eotaxin-1, APRIL, and Tweak may be used as first-line early detection of CRC. The variable levels of MIF and MIP-1β between metastatic and non-metastatic cases assign prognostic nature to these factors in CRC progression. Regarding tolerance to CT, MDC, IL-7, MIF, IL-21, and TNF-α are key when down-regulated or resistant to treatment is observed.

鉴于细胞因子、趋化因子、生长因子和可溶性受体在结直肠癌(CRC)的发病机制中起着重要作用,本研究分析了 CRC 患者和无癌症对照者血清中细胞因子、趋化因子、生长因子和可溶性受体的概况,以作为可能的 CRC 标志。研究人员使用 ProcartaPlex 人类免疫监测 65-Plex Panel 检测了 CRC 患者和年龄与性别匹配的无癌症对照者血清中 65 种分析物的水平。在检测的 65 种分析物中,8 种细胞因子(CSF-3、IFN-γ、IL-12p70、IL-18、IL-20、MIF、TNF-α 和 TSLP)、8 种趋化因子(fractalkine、MIP-1β、BLC、Eotaxin-1、IP-10、MIP-1a、MIP-3a)、2 种生长因子(FGF-2、MMP-1)和 4 种可溶性受体(APRIL、CD30、TNFRII 和 TWEAK)在 CRC 中的表达存在差异。ROC分析证实,TNF-α、BLC、Eotaxin-1、APRIL和Tweak的AUC>0.70,具有很高的相关性,这提示了治疗学的应用。与非转移性 CRC 相比,转移性 CRC 中 IFN-γ、IL-18、MIF、BLC、Eotaxin-1、Eotaxin-2、IP-10 和 MMP1 的表达量较低;只有 MIF 和 MIP-1β 的 AUC > 0.7。此外,MDC、IL-7、MIF、IL-21 和 TNF-α 与 CRC 化疗(CT)耐受性呈正相关(AUC > 0.7),而 IL-31、Fractalkine、Eotaxin-1 和 Eotaxin-2 与 CRC 化疗耐受性呈正相关。TNF-α、BLC、Eotaxin-1、APRIL和Tweak可作为CRC的一线早期检测指标。在转移性和非转移性病例中,MIF和MIP-1β的水平各不相同,这说明这些因素对CRC的进展具有预后作用。关于对 CT 的耐受性,MDC、IL-7、MIF、IL-21 和 TNF-α 是观察到下调或耐受治疗的关键因素。
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引用次数: 0
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Cancer Immunology, Immunotherapy
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