首页 > 最新文献

Cancer Immunology, Immunotherapy最新文献

英文 中文
Efficacy, safety, and biomarker analysis of TACE combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma: a real-world study. TACE联合来伐替尼加辛替利单抗治疗不可切除肝细胞癌的疗效、安全性和生物标志物分析:一项真实世界研究。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-05 DOI: 10.1007/s00262-024-03857-5
Lingzhan Meng, Hu Li, Yingjie Ji, Peng Yu, Zizheng Wang, Li Cao, Bin Shi, Yanling Shao, Jin Yan, Yinjie Gao, Zhenyu Zhu

Background: The integration of transarterial chemoembolization (TACE) with systemic therapy has demonstrated improved survival outcomes in patients with unresectable hepatocellular carcinoma (HCC). However, there is limited evidence evaluating the combination of TACE with the systemic regimen of anti-PD-1/L1 inhibitor plus lenvatinib. This study aims to assess the efficacy and safety of TACE combined with lenvatinib and sintilimab in unresectable HCC patients.

Methods: Unresectable HCC patients who received TACE in combination with sintilimab plus Lenvatinib as first-line treatment from 1 January 2020 to 31 March 2023 were included for the analysis. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were evaluated by modified Response Evaluation Criteria in Solid Tumors criteria. Exploratory biomarker analysis was conducted.

Results: The study included 70 patients with unresectable HCC, predominantly male and infected with Hepatitis B. The median follow-up duration for the whole cohort was 13.8 months (95% CI 11.08-16.7). The ORR was 61.4% (95% CI, 49.0%-72.8%) and the DCR was 68.6% (95%CI, 56.4%-79.2%). The median PFS was 13.2 months (95% CI 11.0-NA), with a corresponding 1-year PFS rate of 50.3% (95% CI 39.7%-65.5%). The median OS was not reached, and the 1-year OS rate was 89.3% (95% CI 81.4%-97.9%). The most common treatment-related adverse events (TRAEs) were fatigue 38.6% (27/70), hypertension 32.9% (23/70), and hand-foot syndrome 31.4% (22/70). Most TRAEs were mild-to-moderate and manageable. In addition, significant predictive value was found in alpha-fetoprotein levels (AFP), with patients showing a level of decrease post-treatment having better PFS.

Conclusion: The combination regimen demonstrated promising efficacy in treating unresectable HCC, accompanied by manageable safety profiles. Furthermore, the results of this investigation suggest that AFP holds promise as predictive biomarkers for this treatment strategy.

背景:经动脉化疗栓塞术(TACE)与全身治疗的结合改善了不可切除肝细胞癌(HCC)患者的生存预后。然而,目前评估TACE与抗PD-1/L1抑制剂加来伐替尼的全身治疗方案联合应用的证据有限。本研究旨在评估TACE联合来伐替尼和辛替利单抗治疗不可切除的HCC患者的有效性和安全性:纳入2020年1月1日至2023年3月31日期间接受TACE联合来伐替尼和辛替利单抗一线治疗的不可切除HCC患者进行分析。总生存期(OS)、无进展生存期(PFS)、客观反应率(ORR)和疾病控制率(DCR)按照修改后的实体瘤反应评估标准进行评估。研究还进行了探索性生物标志物分析:研究纳入了70例无法切除的HCC患者,其中男性居多,且感染了乙肝。ORR为61.4%(95%CI,49.0%-72.8%),DCR为68.6%(95%CI,56.4%-79.2%)。中位 PFS 为 13.2 个月(95% CI 11.0-NA),相应的 1 年 PFS 率为 50.3%(95% CI 39.7%-65.5%)。未达到中位OS,1年OS率为89.3%(95% CI 81.4%-97.9%)。最常见的治疗相关不良事件(TRAEs)为疲劳 38.6%(27/70)、高血压 32.9%(23/70)和手足综合征 31.4%(22/70)。大多数 TRAE 为轻度至中度,可控。此外,甲胎蛋白水平(AFP)具有重要的预测价值,治疗后水平下降的患者PFS更佳:结论:联合疗法在治疗不可切除的 HCC 方面具有良好的疗效,同时安全性可控。此外,这项研究结果表明,甲胎蛋白有望成为这种治疗策略的预测性生物标志物。
{"title":"Efficacy, safety, and biomarker analysis of TACE combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma: a real-world study.","authors":"Lingzhan Meng, Hu Li, Yingjie Ji, Peng Yu, Zizheng Wang, Li Cao, Bin Shi, Yanling Shao, Jin Yan, Yinjie Gao, Zhenyu Zhu","doi":"10.1007/s00262-024-03857-5","DOIUrl":"10.1007/s00262-024-03857-5","url":null,"abstract":"<p><strong>Background: </strong>The integration of transarterial chemoembolization (TACE) with systemic therapy has demonstrated improved survival outcomes in patients with unresectable hepatocellular carcinoma (HCC). However, there is limited evidence evaluating the combination of TACE with the systemic regimen of anti-PD-1/L1 inhibitor plus lenvatinib. This study aims to assess the efficacy and safety of TACE combined with lenvatinib and sintilimab in unresectable HCC patients.</p><p><strong>Methods: </strong>Unresectable HCC patients who received TACE in combination with sintilimab plus Lenvatinib as first-line treatment from 1 January 2020 to 31 March 2023 were included for the analysis. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were evaluated by modified Response Evaluation Criteria in Solid Tumors criteria. Exploratory biomarker analysis was conducted.</p><p><strong>Results: </strong>The study included 70 patients with unresectable HCC, predominantly male and infected with Hepatitis B. The median follow-up duration for the whole cohort was 13.8 months (95% CI 11.08-16.7). The ORR was 61.4% (95% CI, 49.0%-72.8%) and the DCR was 68.6% (95%CI, 56.4%-79.2%). The median PFS was 13.2 months (95% CI 11.0-NA), with a corresponding 1-year PFS rate of 50.3% (95% CI 39.7%-65.5%). The median OS was not reached, and the 1-year OS rate was 89.3% (95% CI 81.4%-97.9%). The most common treatment-related adverse events (TRAEs) were fatigue 38.6% (27/70), hypertension 32.9% (23/70), and hand-foot syndrome 31.4% (22/70). Most TRAEs were mild-to-moderate and manageable. In addition, significant predictive value was found in alpha-fetoprotein levels (AFP), with patients showing a level of decrease post-treatment having better PFS.</p><p><strong>Conclusion: </strong>The combination regimen demonstrated promising efficacy in treating unresectable HCC, accompanied by manageable safety profiles. Furthermore, the results of this investigation suggest that AFP holds promise as predictive biomarkers for this treatment strategy.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582038","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
Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunity. 树突状细胞成熟是由带有 p53 的溶瘤腺病毒通过肿瘤衍生的外泌体诱导的,可增强全身抗肿瘤免疫力。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-05 DOI: 10.1007/s00262-024-03849-5
Tomoko Ohtani, Shinji Kuroda, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Kento Kumon, Masashi Hashimoto, Chiaki Yagi, Ryoma Sugimoto, Satoru Kikuchi, Shunsuke Kagawa, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara

Dendritic cells (DCs) are crucial in cancer immunity, because they activate cytotoxic T cells by presenting tumor antigens. Recently, oncolytic virus therapy has been recognized as a systemic immune stimulator. We previously developed a telomerase-specific oncolytic adenovirus (OBP-301) and a p53-armed OBP-301 (OBP-702), demonstrating that these viruses strongly activate systemic antitumor immunity. However, their effects on DCs remained unclear. In the present study, the aim was to elucidate the mechanisms of DC activation by OBP-702, focusing particularly on tumor-derived exosomes. Exosomes (Exo53, Exo301, or Exo702) were isolated from conditioned media of human or murine pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and PAN02) after treatment with Ad-p53, OBP-301, or OBP-702. Exo702 derived from Panc-1 and MiaPaCa-2 cells significantly upregulated CD86, CD80, CD83 (markers of DC maturation), and IFN-γ in DCs in vitro. Similarly, Exo702 derived from PAN02 cells upregulated CD86 and IFN-γ in bone marrow-derived DCs in a bilateral PAN02 subcutaneous tumor model. This DC maturation was inhibited by GW4869, an inhibitor of exosome release, and anti-CD63, an antibody targeting the exosome marker. Intratumoral injection of OBP-702 into PAN02 subcutaneous tumors significantly increased the presence of mature DCs and CD8-positive T cells in draining lymph nodes, leading to long-lasting antitumor effects through the durable activation of systemic antitumor immunity. In conclusion, tumor-derived exosomes play a significant role in DC maturation following OBP-702 treatment and are critical for the systemic activation of antitumor immunity, leading to the abscopal effect.

树突状细胞(DC)在癌症免疫中至关重要,因为它们通过呈现肿瘤抗原激活细胞毒性 T 细胞。最近,溶瘤病毒疗法被认为是一种全身性免疫刺激剂。我们之前开发了一种端粒酶特异性溶瘤腺病毒(OBP-301)和一种带有 p53 的 OBP-301 (OBP-702),证明这些病毒能强烈激活全身抗肿瘤免疫。然而,它们对直流细胞的影响仍不清楚。本研究旨在阐明 OBP-702 激活直流细胞的机制,尤其关注肿瘤衍生的外泌体。用 Ad-p53、OBP-301 或 OBP-702 处理人或鼠胰腺癌细胞系(Panc-1、MiaPaCa-2 和 PAN02)后,从其条件培养基中分离出外泌体(Exo53、Exo301 或 Exo702)。来自 Panc-1 和 MiaPaCa-2 细胞的 Exo702 能显著上调体外直流细胞中的 CD86、CD80、CD83(直流细胞成熟的标志物)和 IFN-γ。同样,在双侧 PAN02 皮下肿瘤模型中,源自 PAN02 细胞的 Exo702 上调了骨髓源性直流细胞中的 CD86 和 IFN-γ。外泌体释放抑制剂 GW4869 和靶向外泌体标记物的抗体抗 CD63 可抑制这种 DC 成熟。向 PAN02 皮下肿瘤瘤体内注射 OBP-702 能显著增加引流淋巴结中成熟 DC 和 CD8 阳性 T 细胞的存在,从而通过持久激活全身抗肿瘤免疫产生持久的抗肿瘤效果。总之,肿瘤衍生的外泌体在OBP-702治疗后的DC成熟过程中发挥了重要作用,并且对全身抗肿瘤免疫的激活至关重要,从而导致了脱灶效应。
{"title":"Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunity.","authors":"Tomoko Ohtani, Shinji Kuroda, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Kento Kumon, Masashi Hashimoto, Chiaki Yagi, Ryoma Sugimoto, Satoru Kikuchi, Shunsuke Kagawa, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara","doi":"10.1007/s00262-024-03849-5","DOIUrl":"10.1007/s00262-024-03849-5","url":null,"abstract":"<p><p>Dendritic cells (DCs) are crucial in cancer immunity, because they activate cytotoxic T cells by presenting tumor antigens. Recently, oncolytic virus therapy has been recognized as a systemic immune stimulator. We previously developed a telomerase-specific oncolytic adenovirus (OBP-301) and a p53-armed OBP-301 (OBP-702), demonstrating that these viruses strongly activate systemic antitumor immunity. However, their effects on DCs remained unclear. In the present study, the aim was to elucidate the mechanisms of DC activation by OBP-702, focusing particularly on tumor-derived exosomes. Exosomes (Exo53, Exo301, or Exo702) were isolated from conditioned media of human or murine pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and PAN02) after treatment with Ad-p53, OBP-301, or OBP-702. Exo702 derived from Panc-1 and MiaPaCa-2 cells significantly upregulated CD86, CD80, CD83 (markers of DC maturation), and IFN-γ in DCs in vitro. Similarly, Exo702 derived from PAN02 cells upregulated CD86 and IFN-γ in bone marrow-derived DCs in a bilateral PAN02 subcutaneous tumor model. This DC maturation was inhibited by GW4869, an inhibitor of exosome release, and anti-CD63, an antibody targeting the exosome marker. Intratumoral injection of OBP-702 into PAN02 subcutaneous tumors significantly increased the presence of mature DCs and CD8-positive T cells in draining lymph nodes, leading to long-lasting antitumor effects through the durable activation of systemic antitumor immunity. In conclusion, tumor-derived exosomes play a significant role in DC maturation following OBP-702 treatment and are critical for the systemic activation of antitumor immunity, leading to the abscopal effect.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582082","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
Differential T cell accumulation within intracranial and subcutaneous melanomas is associated with differences in intratumoral myeloid cells. 颅内和皮下黑色素瘤内不同的 T 细胞聚集与瘤内髓样细胞的差异有关。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03832-0
Katarzyna Stasiak, Aaron D Stevens, Ashley C Bolte, Colleen T Curley, Mirna Perusina Lanfranca, Robin S Lindsay, Ukpong B Eyo, John R Lukens, Richard J Price, Timothy N J Bullock, Victor H Engelhard

Patients with metastatic brain melanomas (MBM) experience shorter-lasting survival than patients with extracranial metastases, and this is associated with a higher fraction of dysfunctional CD8 T cells. The goal of this study was to understand the underlying cause of T cell dysfunction in MBM. To accomplish this, we compared murine B16 melanomas implanted intracranially (IC) or subcutaneously (SC). CD8 T cell activation was not altered, but representation in IC tumors was lower. Transferred activated or naïve CD8 T cells accumulated in similar numbers in both tumors, suggesting that the vasculature does not differentially impair T cell presence. Surprisingly, we found no evidence for T cell activation in draining lymph nodes of SC or IC tumor-bearing mice, consistent with the fact that dendritic cells (DC) that had acquired tumor antigen showed an immature phenotype. Instead, T cell activation occurred within both tumors, where the majority of tumor antigen+ myeloid cells were found. While, the numbers of intratumoral DC were comparable, those in IC tumors acquired less tumor antigen, and were alternatively matured based on upregulation of MHCII without upregulation of CD86. Additionally, in IC tumors, the largest population of tumor antigen+ myeloid cells were microglia. However, their presence did not influence either antigen acquisition or the phenotype of other myeloid cell populations. Overall, our data suggest that diminished representation of CD8 T cells in IC tumors is a consequence of alternatively matured DC and/or microglia that induce distinctly activated T cells, which ultimately fail to continue to accumulate inside the tumor.

与颅外转移患者相比,转移性脑黑色素瘤(MBM)患者的存活期更短,而这与功能失调的 CD8 T 细胞比例较高有关。本研究的目的是了解T细胞功能障碍在MBM中的根本原因。为此,我们比较了植入颅内(IC)或皮下(SC)的小鼠 B16 黑色素瘤。CD8 T 细胞活化没有改变,但在 IC 肿瘤中的代表性较低。转移的活化或天真 CD8 T 细胞在两种肿瘤中积累的数量相似,这表明血管不会对 T 细胞的存在造成不同程度的影响。令人惊讶的是,我们没有在SC或IC肿瘤小鼠的引流淋巴结中发现T细胞活化的证据,这与获得肿瘤抗原的树突状细胞(DC)表现出不成熟表型的事实一致。相反,T细胞活化发生在两种肿瘤内,在肿瘤内发现了大多数肿瘤抗原+髓系细胞。虽然瘤内DC的数量相当,但IC肿瘤中的DC获得的肿瘤抗原较少,而且是根据MHCII的上调而非CD86的上调成熟的。此外,在 IC 肿瘤中,肿瘤抗原+髓系细胞的最大群体是小胶质细胞。但是,它们的存在既不影响抗原的获得,也不影响其他髓系细胞群的表型。总之,我们的数据表明,CD8 T 细胞在 IC 肿瘤中的代表性降低是另类成熟的 DC 和/或小胶质细胞诱导出明显活化的 T 细胞的结果,这些 T 细胞最终无法继续在肿瘤内聚集。
{"title":"Differential T cell accumulation within intracranial and subcutaneous melanomas is associated with differences in intratumoral myeloid cells.","authors":"Katarzyna Stasiak, Aaron D Stevens, Ashley C Bolte, Colleen T Curley, Mirna Perusina Lanfranca, Robin S Lindsay, Ukpong B Eyo, John R Lukens, Richard J Price, Timothy N J Bullock, Victor H Engelhard","doi":"10.1007/s00262-024-03832-0","DOIUrl":"10.1007/s00262-024-03832-0","url":null,"abstract":"<p><p>Patients with metastatic brain melanomas (MBM) experience shorter-lasting survival than patients with extracranial metastases, and this is associated with a higher fraction of dysfunctional CD8 T cells. The goal of this study was to understand the underlying cause of T cell dysfunction in MBM. To accomplish this, we compared murine B16 melanomas implanted intracranially (IC) or subcutaneously (SC). CD8 T cell activation was not altered, but representation in IC tumors was lower. Transferred activated or naïve CD8 T cells accumulated in similar numbers in both tumors, suggesting that the vasculature does not differentially impair T cell presence. Surprisingly, we found no evidence for T cell activation in draining lymph nodes of SC or IC tumor-bearing mice, consistent with the fact that dendritic cells (DC) that had acquired tumor antigen showed an immature phenotype. Instead, T cell activation occurred within both tumors, where the majority of tumor antigen<sup>+</sup> myeloid cells were found. While, the numbers of intratumoral DC were comparable, those in IC tumors acquired less tumor antigen, and were alternatively matured based on upregulation of MHCII without upregulation of CD86. Additionally, in IC tumors, the largest population of tumor antigen<sup>+</sup> myeloid cells were microglia. However, their presence did not influence either antigen acquisition or the phenotype of other myeloid cell populations. Overall, our data suggest that diminished representation of CD8 T cells in IC tumors is a consequence of alternatively matured DC and/or microglia that induce distinctly activated T cells, which ultimately fail to continue to accumulate inside the tumor.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564104","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
Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer. 将共济失调毛细血管扩张症和 Rad3 相关抑制与消融放疗相结合,可重塑肿瘤微环境并增强肺癌的免疫治疗反应。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03864-6
Jenny Ling-Yu Chen, Chun-Kai Pan, Li-Cheng Lin, Yu-Sen Huang, Tsung-Hsuan Huang, Shu-Jyuan Yang, Sung-Hsin Kuo, Yu-Li Lin

We investigated the combined effects of ataxia telangiectasia and Rad3-related (ATR) inhibition, ablative radiotherapy, and immune checkpoint inhibitor (ICI) therapy against lung cancer. ATR inhibitor was administered combined with ablative radiotherapy to assess its radiosensitizing effect on lung cancer cells. Treatment response and survival were evaluated in vivo using A549 xenograft flank tumor and synchronous LLC lung and flank tumor mouse models. Mice received ablative radiotherapy (12 Gy/d for 2 d), ATR inhibitor, and ICI. The tumor microenvironment was assessed in irradiated flank and non-irradiated lung tumors. Programmed death-ligand 1 expression was upregulated after irradiation. ATR inhibition attenuated this upregulation. ATR inhibitor pretreatment decreased cell survival after irradiation by inhibiting DNA double-strand break repair, inducing mitotic cell death, and altering cell cycle progression. ATR inhibition enhanced radiation-induced damage-associated molecular patterns determined by high mobility group box 1 quantification and activated the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Combined ATR inhibition and ablative radiotherapy inhibited tumor growth and improved survival in mice. Adding ICI therapy further enhanced local antitumor effects, reducing the metastatic lung tumor burden and remodeling the tumor microenvironment through immunogenic cell death induction and enhanced immune cell infiltration. Triple therapy increased immune cell infiltration in distant non-irradiated lung tumors and stimulated the generation of protective T-cell immunity in splenocytes. Safety analysis showed minimal toxicity. ATR inhibition enhanced the efficacy of ablative radiotherapy and immunotherapy in lung cancer. These findings underscore the importance of combination therapies for enhancing systemic antitumor immune responses and outcomes.

我们研究了共济失调毛细血管扩张症和Rad3相关(ATR)抑制剂、消融放疗和免疫检查点抑制剂(ICI)疗法对肺癌的联合作用。ATR 抑制剂与烧蚀放疗联合使用,以评估其对肺癌细胞的放射增敏作用。使用A549异种侧腹肿瘤和同步LLC肺部和侧腹肿瘤小鼠模型对治疗反应和存活率进行了体内评估。小鼠接受了消融放疗(12 Gy/d,2 d)、ATR抑制剂和ICI。对照射过的侧腹肿瘤和未照射过的肺部肿瘤的肿瘤微环境进行了评估。照射后,程序性死亡配体1的表达上调。ATR抑制剂减轻了这种上调。ATR抑制剂通过抑制DNA双链断裂修复、诱导有丝分裂期细胞死亡和改变细胞周期进程,降低了辐照后细胞的存活率。ATR抑制增强了高迁移率组盒1定量测定的辐射诱导损伤相关分子模式,并激活了环GMP-AMP合成酶-干扰素基因刺激器通路。联合抑制 ATR 和消融放疗可抑制肿瘤生长并提高小鼠存活率。加入 ICI 治疗可进一步增强局部抗肿瘤效果,减少转移性肺肿瘤负荷,并通过诱导免疫原性细胞死亡和增强免疫细胞浸润重塑肿瘤微环境。三联疗法增加了远处非辐照肺肿瘤的免疫细胞浸润,并刺激脾细胞产生保护性T细胞免疫。安全性分析表明毒性极小。ATR抑制增强了肺癌消融放疗和免疫疗法的疗效。这些发现强调了联合疗法对增强全身抗肿瘤免疫反应和疗效的重要性。
{"title":"Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer.","authors":"Jenny Ling-Yu Chen, Chun-Kai Pan, Li-Cheng Lin, Yu-Sen Huang, Tsung-Hsuan Huang, Shu-Jyuan Yang, Sung-Hsin Kuo, Yu-Li Lin","doi":"10.1007/s00262-024-03864-6","DOIUrl":"10.1007/s00262-024-03864-6","url":null,"abstract":"<p><p>We investigated the combined effects of ataxia telangiectasia and Rad3-related (ATR) inhibition, ablative radiotherapy, and immune checkpoint inhibitor (ICI) therapy against lung cancer. ATR inhibitor was administered combined with ablative radiotherapy to assess its radiosensitizing effect on lung cancer cells. Treatment response and survival were evaluated in vivo using A549 xenograft flank tumor and synchronous LLC lung and flank tumor mouse models. Mice received ablative radiotherapy (12 Gy/d for 2 d), ATR inhibitor, and ICI. The tumor microenvironment was assessed in irradiated flank and non-irradiated lung tumors. Programmed death-ligand 1 expression was upregulated after irradiation. ATR inhibition attenuated this upregulation. ATR inhibitor pretreatment decreased cell survival after irradiation by inhibiting DNA double-strand break repair, inducing mitotic cell death, and altering cell cycle progression. ATR inhibition enhanced radiation-induced damage-associated molecular patterns determined by high mobility group box 1 quantification and activated the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Combined ATR inhibition and ablative radiotherapy inhibited tumor growth and improved survival in mice. Adding ICI therapy further enhanced local antitumor effects, reducing the metastatic lung tumor burden and remodeling the tumor microenvironment through immunogenic cell death induction and enhanced immune cell infiltration. Triple therapy increased immune cell infiltration in distant non-irradiated lung tumors and stimulated the generation of protective T-cell immunity in splenocytes. Safety analysis showed minimal toxicity. ATR inhibition enhanced the efficacy of ablative radiotherapy and immunotherapy in lung cancer. These findings underscore the importance of combination therapies for enhancing systemic antitumor immune responses and outcomes.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564102","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
Immune checkpoint inhibitors-related thyroid dysfunction: influencing factor analysis, prediction model development, and management strategy proposal. 免疫检查点抑制剂相关甲状腺功能障碍:影响因素分析、预测模型开发和管理策略建议。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03816-0
Xinya Li, Zaiwei Song, Yixuan Chen, Jingjing Wu, Dan Jiang, Zhen Zhang, Zeyuan Wang, Rongsheng Zhao

Background: With the extensive utilization of immune checkpoint inhibitors (ICIs) across various cancers, ICIs-related thyroid dysfunction (ICI-TD) has become a growing concern in clinical practice. This study aimed to devise an individualized management strategy for ICI-TD to enhance the early identification and proactive management in cancer patients.

Methods: We designed and conducted a three-phase study. Initially, we analyzed the influencing factors through a systematic review and meta-analysis, which adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Moreover, the study protocol was registered with PROSPERO (CRD42019131133). Subsequently, prediction models for ICI-TD were developed utilizing 11 algorithms based on the real-world cohort data from July 20, 2018 (the approval date of the first ICIs, Pembrolizumab in China), to October 31, 2022. Considering discrimination, calibration, and clinical utility, we selected the model with the best performance for web calculator development. Finally, individualized management strategies for ICI-TD were proposed by combining evidence-based analysis with practical considerations.

Results: The systematic review encompassed 21 observational studies involving 4,145 patients, revealing associations between ICI-TD and factors such as female gender, age, receipt of Pembrolizumab (versus other ICIs), and baseline levels of thyroid-stimulating hormone, free thyroxine, and antithyroid antibodies. In the prediction model development phase, 621 participants were enrolled, with 36 patients developing ICI-TD. The model based on the LightGBM algorithm demonstrated superior performance, leading to the development of a web calculator. Based on these findings and existing guidelines, individualized monitoring and treatment pathways for pharmacists were devised.

Conclusion: This study offers comprehensive insights into managing ICI-TD, potentially enhancing tailored cancer immunotherapy management.

背景:随着免疫检查点抑制剂(ICIs)在各种癌症中的广泛应用,ICIs相关甲状腺功能障碍(ICI-TD)已成为临床实践中日益关注的问题。本研究旨在为ICI-TD制定个体化管理策略,以加强对癌症患者的早期识别和积极管理:我们设计并开展了一项三阶段研究。首先,我们根据系统综述和荟萃分析(PRISMA)指南,通过系统综述和荟萃分析分析了影响因素。此外,研究方案已在 PROSPERO 注册(CRD42019131133)。随后,根据从2018年7月20日(中国首个ICIs--彭博利珠单抗的批准日期)到2022年10月31日的真实世界队列数据,利用11种算法开发了ICI-TD的预测模型。考虑到辨别力、校准和临床实用性,我们选择了性能最佳的模型用于网络计算器的开发。最后,结合循证分析和实际情况,提出了ICI-TD的个体化管理策略:系统综述包括21项观察性研究,涉及4145名患者,揭示了ICI-TD与女性性别、年龄、接受Pembrolizumab治疗(与其他ICI相比)以及促甲状腺激素、游离甲状腺素和抗甲状腺抗体基线水平等因素之间的关联。在预测模型开发阶段,共招募了 621 名参与者,其中 36 名患者出现了 ICI-TD。基于 LightGBM 算法的模型表现出卓越的性能,因此开发了网络计算器。根据这些研究结果和现有指南,为药剂师设计了个性化的监测和治疗路径:本研究为 ICI-TD 的管理提供了全面的见解,有可能加强量身定制的癌症免疫疗法管理。
{"title":"Immune checkpoint inhibitors-related thyroid dysfunction: influencing factor analysis, prediction model development, and management strategy proposal.","authors":"Xinya Li, Zaiwei Song, Yixuan Chen, Jingjing Wu, Dan Jiang, Zhen Zhang, Zeyuan Wang, Rongsheng Zhao","doi":"10.1007/s00262-024-03816-0","DOIUrl":"10.1007/s00262-024-03816-0","url":null,"abstract":"<p><strong>Background: </strong>With the extensive utilization of immune checkpoint inhibitors (ICIs) across various cancers, ICIs-related thyroid dysfunction (ICI-TD) has become a growing concern in clinical practice. This study aimed to devise an individualized management strategy for ICI-TD to enhance the early identification and proactive management in cancer patients.</p><p><strong>Methods: </strong>We designed and conducted a three-phase study. Initially, we analyzed the influencing factors through a systematic review and meta-analysis, which adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Moreover, the study protocol was registered with PROSPERO (CRD42019131133). Subsequently, prediction models for ICI-TD were developed utilizing 11 algorithms based on the real-world cohort data from July 20, 2018 (the approval date of the first ICIs, Pembrolizumab in China), to October 31, 2022. Considering discrimination, calibration, and clinical utility, we selected the model with the best performance for web calculator development. Finally, individualized management strategies for ICI-TD were proposed by combining evidence-based analysis with practical considerations.</p><p><strong>Results: </strong>The systematic review encompassed 21 observational studies involving 4,145 patients, revealing associations between ICI-TD and factors such as female gender, age, receipt of Pembrolizumab (versus other ICIs), and baseline levels of thyroid-stimulating hormone, free thyroxine, and antithyroid antibodies. In the prediction model development phase, 621 participants were enrolled, with 36 patients developing ICI-TD. The model based on the LightGBM algorithm demonstrated superior performance, leading to the development of a web calculator. Based on these findings and existing guidelines, individualized monitoring and treatment pathways for pharmacists were devised.</p><p><strong>Conclusion: </strong>This study offers comprehensive insights into managing ICI-TD, potentially enhancing tailored cancer immunotherapy management.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564107","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
Uncovering the role of tumor cGAS expression in predicting response to PD-1/L1 inhibitors in non-small cell lung cancer. 揭示肿瘤 cGAS 表达在预测非小细胞肺癌患者对 PD-1/L1 抑制剂反应中的作用。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03861-9
Yuichi Ozawa, Yasuhiro Koh, Ryota Shibaki, Yuhei Harutani, Hiroaki Akamatsu, Atsushi Hayata, Takeya Sugimoto, Yuka Kitamura, Junya Fukuoka, Masanori Nakanishi, Nobuyuki Yamamoto

Objectives: The impact of cGAS/STING tumor expression on PD-1/L1 inhibitor efficacy and the tumor microenvironment remain to be elucidated.

Methods: In a post-hoc analysis of a prospective biomarker study with 106 advanced NSCLC patients treated with PD-1/L1 inhibitors from December 2015 to September 2018, tumor tissue before treatment from 68 patients was analyzed. cGAS and STING expression were measured using immunohistochemical staining and H-scores. Additionally, 40 serum proteins were quantified before and 4-6 weeks after treatment initiation.

Results: Median cGAS and STING H-scores were 220 (range, 5-300) and 190 (range, 0-300), respectively. There were no differences in cGAS or STING H-scores between the high (tumor proportion score [TPS] ≥ 50) and low (TPS < 50) PD-L1groups (p = 0.990 and 0.283, respectively). Unexpectedly, patients with high cGAS (H-score ≥ 220) demonstrated significantly shorter progression-free survival (PFS) of PD-1/L1 inhibitors when the PD-L1 TPS was high (median PFS: 143 days vs. not reached; p = 0.028); PFS at 18 months was 7% and 53% in the high and low cGAS groups, respectively while STING expression did not impact PFS. In serum protein analyses, high cGAS H-score was associated with significantly higher TGF-β1 and TGF-β2 before PD-1/L1 inhibition (47.5 vs. 22.3 ng/l, p = 0.023; 2118 vs. 882 pg/ml, p = 0.037); additionally, the cGAS H-score significantly correlated with TGF-β1 (r = 0.451, p = 0.009) and TGF-β2 (r = 0.375, p = 0.031) basal levels.

Conclusion: cGAS expression, but not STING, predicts poor PD-1/L1 inhibitor efficacy in NSCLC with high PD-L1, potentially due to a TGF-β-mediated immunosuppressive environment (UMIN000024414).

目的:cGAS/STING肿瘤表达对PD-1/L1抑制剂疗效和肿瘤微环境的影响仍有待阐明:cGAS/STING肿瘤表达对PD-1/L1抑制剂疗效和肿瘤微环境的影响仍有待阐明:在2015年12月至2018年9月对106例接受PD-1/L1抑制剂治疗的晚期NSCLC患者进行的一项前瞻性生物标志物研究的事后分析中,分析了68例患者治疗前的肿瘤组织,使用免疫组化染色和H-评分测量了cGAS和STING的表达。此外,还对治疗开始前和治疗开始后4-6周的40种血清蛋白进行了量化:结果:cGAS和STING H评分的中位数分别为220(范围为5-300)和190(范围为0-300)。结论:在PD-L1较高的NSCLC中,cGAS表达(而非STING)可预测PD-1/L1抑制剂疗效不佳,这可能是由于TGF-β介导的免疫抑制环境所致 (UMIN000024414)。
{"title":"Uncovering the role of tumor cGAS expression in predicting response to PD-1/L1 inhibitors in non-small cell lung cancer.","authors":"Yuichi Ozawa, Yasuhiro Koh, Ryota Shibaki, Yuhei Harutani, Hiroaki Akamatsu, Atsushi Hayata, Takeya Sugimoto, Yuka Kitamura, Junya Fukuoka, Masanori Nakanishi, Nobuyuki Yamamoto","doi":"10.1007/s00262-024-03861-9","DOIUrl":"10.1007/s00262-024-03861-9","url":null,"abstract":"<p><strong>Objectives: </strong>The impact of cGAS/STING tumor expression on PD-1/L1 inhibitor efficacy and the tumor microenvironment remain to be elucidated.</p><p><strong>Methods: </strong>In a post-hoc analysis of a prospective biomarker study with 106 advanced NSCLC patients treated with PD-1/L1 inhibitors from December 2015 to September 2018, tumor tissue before treatment from 68 patients was analyzed. cGAS and STING expression were measured using immunohistochemical staining and H-scores. Additionally, 40 serum proteins were quantified before and 4-6 weeks after treatment initiation.</p><p><strong>Results: </strong>Median cGAS and STING H-scores were 220 (range, 5-300) and 190 (range, 0-300), respectively. There were no differences in cGAS or STING H-scores between the high (tumor proportion score [TPS] ≥ 50) and low (TPS < 50) PD-L1groups (p = 0.990 and 0.283, respectively). Unexpectedly, patients with high cGAS (H-score ≥ 220) demonstrated significantly shorter progression-free survival (PFS) of PD-1/L1 inhibitors when the PD-L1 TPS was high (median PFS: 143 days vs. not reached; p = 0.028); PFS at 18 months was 7% and 53% in the high and low cGAS groups, respectively while STING expression did not impact PFS. In serum protein analyses, high cGAS H-score was associated with significantly higher TGF-β1 and TGF-β2 before PD-1/L1 inhibition (47.5 vs. 22.3 ng/l, p = 0.023; 2118 vs. 882 pg/ml, p = 0.037); additionally, the cGAS H-score significantly correlated with TGF-β1 (r = 0.451, p = 0.009) and TGF-β2 (r = 0.375, p = 0.031) basal levels.</p><p><strong>Conclusion: </strong>cGAS expression, but not STING, predicts poor PD-1/L1 inhibitor efficacy in NSCLC with high PD-L1, potentially due to a TGF-β-mediated immunosuppressive environment (UMIN000024414).</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564096","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
Breaking the shield of solid tumors: a combined approach for enhanced efficacy of CAR-T cells. 打破实体肿瘤的防护罩:增强 CAR-T 细胞疗效的综合方法。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03817-z
Marat Khaliulin, Aygul Valiullina, Alexey Petukhov, Youyong Yuan, Sheila Spada, Emil Bulatov

The use of chimeric antigen receptor (CAR)-T cells has enhanced the range of available therapeutic modalities in the context of cancer treatment. CAR-T cells have demonstrated considerable efficacy in the targeted eradication of blood cancer cells, thereby stimulating substantial interest in the advancement of such therapeutic approaches. However, the efficacy of CAR-T cells against solid tumor cells has been limited due to the presence of various obstacles. Solid tumors exhibit antigenic diversity and an immunosuppressive microenvironment, which presents a challenge for immune cells attempting to penetrate the tumor. CAR-T cells also demonstrate decreased proliferative activity and cytotoxicity. Furthermore, concerns exist regarding tumor antigen loss and therapy-associated toxicity. Currently, scientists are working to enhance the structure of the CAR and improve the survival and efficiency of CAR-T cells in recognizing tumor antigens in solid tumors. Chemotherapy drugs are frequently employed in the treatment of malignant neoplasms and can also be used prior to cell therapy to enhance CAR-T cell engraftment. Recent studies have demonstrated that chemotherapy drugs can mitigate the suppressive impact of TME, eliminate the physical barrier by destroying the tumor stroma, and facilitate greater penetration of immune cells and CAR-T cells into the tumor. This, in turn, increases their survival, persistence, and cytotoxicity, as well as affects the metabolism of immune cells inside the tumor. However, the effectiveness of the combined approach against solid tumors depends on several factors, including the type of tumor, dosage, population of CAR-T cells, and individual characteristics of the body. This review examines the principal obstacles to the utilization of CAR-T cells against solid tumors, proposes solutions to these issues, and assesses the potential advantages of a combined approach to radiation exposure, which has the potential to enhance the sensitivity of the tumor to other agents.

嵌合抗原受体(CAR)-T 细胞的使用扩大了癌症治疗的可用治疗方法范围。CAR-T 细胞在有针对性地根除血癌细胞方面已显示出相当大的疗效,从而激发了人们对推进此类治疗方法的浓厚兴趣。然而,由于存在各种障碍,CAR-T 细胞对实体瘤细胞的疗效受到了限制。实体瘤表现出抗原多样性和免疫抑制微环境,这给试图穿透肿瘤的免疫细胞带来了挑战。CAR-T 细胞的增殖活性和细胞毒性也有所下降。此外,肿瘤抗原丢失和治疗相关毒性也令人担忧。目前,科学家们正在努力增强 CAR 的结构,提高 CAR-T 细胞的存活率和识别实体瘤中肿瘤抗原的效率。化疗药物是治疗恶性肿瘤的常用药物,也可在细胞治疗前使用,以提高 CAR-T 细胞的接种率。最近的研究表明,化疗药物可减轻TME的抑制作用,通过破坏肿瘤基质消除物理屏障,促进免疫细胞和CAR-T细胞更好地穿透肿瘤。这反过来又会提高它们的存活率、持久性和细胞毒性,并影响肿瘤内免疫细胞的新陈代谢。然而,联合疗法对实体瘤的疗效取决于多种因素,包括肿瘤类型、剂量、CAR-T 细胞的数量以及机体的个体特征。这篇综述探讨了利用 CAR-T 细胞治疗实体瘤的主要障碍,提出了解决这些问题的方法,并评估了辐射照射联合方法的潜在优势,因为这种方法有可能提高肿瘤对其他药物的敏感性。
{"title":"Breaking the shield of solid tumors: a combined approach for enhanced efficacy of CAR-T cells.","authors":"Marat Khaliulin, Aygul Valiullina, Alexey Petukhov, Youyong Yuan, Sheila Spada, Emil Bulatov","doi":"10.1007/s00262-024-03817-z","DOIUrl":"10.1007/s00262-024-03817-z","url":null,"abstract":"<p><p>The use of chimeric antigen receptor (CAR)-T cells has enhanced the range of available therapeutic modalities in the context of cancer treatment. CAR-T cells have demonstrated considerable efficacy in the targeted eradication of blood cancer cells, thereby stimulating substantial interest in the advancement of such therapeutic approaches. However, the efficacy of CAR-T cells against solid tumor cells has been limited due to the presence of various obstacles. Solid tumors exhibit antigenic diversity and an immunosuppressive microenvironment, which presents a challenge for immune cells attempting to penetrate the tumor. CAR-T cells also demonstrate decreased proliferative activity and cytotoxicity. Furthermore, concerns exist regarding tumor antigen loss and therapy-associated toxicity. Currently, scientists are working to enhance the structure of the CAR and improve the survival and efficiency of CAR-T cells in recognizing tumor antigens in solid tumors. Chemotherapy drugs are frequently employed in the treatment of malignant neoplasms and can also be used prior to cell therapy to enhance CAR-T cell engraftment. Recent studies have demonstrated that chemotherapy drugs can mitigate the suppressive impact of TME, eliminate the physical barrier by destroying the tumor stroma, and facilitate greater penetration of immune cells and CAR-T cells into the tumor. This, in turn, increases their survival, persistence, and cytotoxicity, as well as affects the metabolism of immune cells inside the tumor. However, the effectiveness of the combined approach against solid tumors depends on several factors, including the type of tumor, dosage, population of CAR-T cells, and individual characteristics of the body. This review examines the principal obstacles to the utilization of CAR-T cells against solid tumors, proposes solutions to these issues, and assesses the potential advantages of a combined approach to radiation exposure, which has the potential to enhance the sensitivity of the tumor to other agents.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564089","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
Nicotine promotes M2 macrophage polarization through α5-nAChR/SOX2/CSF-1 axis in lung adenocarcinoma. 尼古丁通过α5-nAChR/SOX2/CSF-1轴促进肺腺癌M2巨噬细胞极化
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03866-4
Guiyu Kang, Hui Song, Lei Bo, Qi Liu, Qiang Li, Jingtan Li, Pan Pan, Jingting Wang, Yanfei Jia, Haiji Sun, Xiaoli Ma

α5-nicotinic acetylcholine receptor (α5-nAChR) plays a vital part in lung adenocarcinoma (LUAD). However, it is not comprehensively understood that how the α5-nAChR affects LUAD. Through diverse bioinformatics analyses and immunohistochemistry, the expressions of α5-nAChR and SOX2 as well as their relations were dissected. α5-nAChR regulated the differentiation of monocytes into M2 macrophages by targeting the STAT3/SOX2/CSF-1 signaling in the coculture system by western blotting and ChIP. α5-nAChR-mediated macrophage-mediated LUAD cell migration via SOX2/CSF-1 signaling in the cocultured medium. Correlations of α5-nAChR, SOX2 and M2 phenotype tumor-associated macrophages (TAMs) were validated in mouse LUAD models and clinical samples. α5-nAChR expression was connected to SOX2 expression, smoking and bad prognosis of LUAD among clinical samples. Nicotine-induced SOX2 expression was mediated by α5-nAChR via STAT3. Additionally, SOX2-mediated macrophage colony-stimulating factor (CSF-1) expression contributed to LUAD progression in vitro. Furthermore, α5-nAChR expression was strongly linked to pSTAT3, SOX2 and M2 macrophage marker CD206 expression and negatively correlated with M1 macrophage marker CD86 expression in vivo. It is indicated that M2 macrophages are mediated by the new α5-nAChR /SOX2/CSF-1 axis in nicotine-related LUAD, which is a potential therapeutic strategy for cancer.

α5-烟碱乙酰胆碱受体(α5-nAChR)在肺腺癌(LUAD)中起着至关重要的作用。然而,人们对α5-nAChR如何影响肺腺癌的认识并不全面。α5-nAChR通过靶向STAT3/SOX2/CSF-1信号,在共培养系统中调控单核细胞向M2巨噬细胞的分化。在共培养培养基中,α5-nAChR 通过 SOX2/CSF-1 信号介导巨噬细胞介导的 LUAD 细胞迁移。在小鼠 LUAD 模型和临床样本中验证了 α5-nAChR、SOX2 和 M2 表型肿瘤相关巨噬细胞(TAMs)的相关性。尼古丁诱导的SOX2表达是由α5-nAChR通过STAT3介导的。此外,SOX2介导的巨噬细胞集落刺激因子(CSF-1)的表达也有助于LUAD在体外的进展。此外,α5-nAChR 的表达与 pSTAT3、SOX2 和 M2 巨噬细胞标记 CD206 的表达密切相关,而与体内 M1 巨噬细胞标记 CD86 的表达呈负相关。研究表明,在尼古丁相关 LUAD 中,M2 巨噬细胞是由新的α5-nAChR /SOX2/CSF-1 轴介导的,这是一种潜在的癌症治疗策略。
{"title":"Nicotine promotes M2 macrophage polarization through α5-nAChR/SOX2/CSF-1 axis in lung adenocarcinoma.","authors":"Guiyu Kang, Hui Song, Lei Bo, Qi Liu, Qiang Li, Jingtan Li, Pan Pan, Jingting Wang, Yanfei Jia, Haiji Sun, Xiaoli Ma","doi":"10.1007/s00262-024-03866-4","DOIUrl":"10.1007/s00262-024-03866-4","url":null,"abstract":"<p><p>α5-nicotinic acetylcholine receptor (α5-nAChR) plays a vital part in lung adenocarcinoma (LUAD). However, it is not comprehensively understood that how the α5-nAChR affects LUAD. Through diverse bioinformatics analyses and immunohistochemistry, the expressions of α5-nAChR and SOX2 as well as their relations were dissected. α5-nAChR regulated the differentiation of monocytes into M2 macrophages by targeting the STAT3/SOX2/CSF-1 signaling in the coculture system by western blotting and ChIP. α5-nAChR-mediated macrophage-mediated LUAD cell migration via SOX2/CSF-1 signaling in the cocultured medium. Correlations of α5-nAChR, SOX2 and M2 phenotype tumor-associated macrophages (TAMs) were validated in mouse LUAD models and clinical samples. α5-nAChR expression was connected to SOX2 expression, smoking and bad prognosis of LUAD among clinical samples. Nicotine-induced SOX2 expression was mediated by α5-nAChR via STAT3. Additionally, SOX2-mediated macrophage colony-stimulating factor (CSF-1) expression contributed to LUAD progression in vitro. Furthermore, α5-nAChR expression was strongly linked to pSTAT3, SOX2 and M2 macrophage marker CD206 expression and negatively correlated with M1 macrophage marker CD86 expression in vivo. It is indicated that M2 macrophages are mediated by the new α5-nAChR /SOX2/CSF-1 axis in nicotine-related LUAD, which is a potential therapeutic strategy for cancer.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564138","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
New insights into the immunomodulatory potential of sialic acid on monocyte-derived dendritic cells. 关于单核细胞衍生树突状细胞上的唾液酸免疫调节潜力的新见解。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03863-7
Zélia Silva, João Amorim Rabaça, Vanessa Luz, Rita Adubeiro Lourenço, Mariolina Salio, Alexandra Couto Oliveira, Pedro Bule, Sebastian Springer, Paula Alexandra Videira

Sialic acids at the cell surface of dendritic cells (DCs) play an important immunomodulatory role, and their manipulation enhances DC maturation, leading to heightened T cell activation. Particularly, at the molecular level, the increased stability of surface MHC-I molecules in monocyte-derived DCs (MoDCs) underpins an improved DC: T cell interaction. In this study, we focused on the impact of sialic acid remodelling by treatment with Clostridium perfringens sialidase on MoDCs' phenotypic and functional characteristics. Our investigation juxtaposes this novel approach with the conventional cytokine-based maturation regimen commonly employed in clinical settings.Notably, C. perfringens sialidase remarkably increased MHC-I levels compared to other sialidases having different specificities, supporting the idea that higher MHC-I is due to the cleavage of specific sialoglycans on cell surface proteins. Sialidase treatment induced rapid elevated surface expression of MHC-I, MHC-II and CD40 within an hour, a response not fully replicated by 48 h cytokine cocktail treatment. These increases were also observable 48 h post sialidase treatment. While CD86 and PD-L1 showed significant increases after 48 h of cytokine maturation, 48 h post sialidase treatment showed a higher increase in CD86 and shorter increase in PD-L1. CCR-7 expression was significantly increased 48 h after sialidase treatment but not significantly affected by cytokine maturation. Both treatments promoted higher secretion of the IL-12 cytokine. However, the cytokine cocktail induced a more pronounced IL-12 production. SNA lectin staining analysis demonstrated that the sialic acid profile is significantly altered by sialidase treatment, but not by the cytokine cocktail, which causes only slight sialic acid upregulation. Notably, the lipid-presenting molecules CD1a, CD1b and CD1c remained unaffected by sialidase treatment in MoDCs, a finding also further supported by experiments performed on C1R cells. Inhibition of endogenous sialidases Neu1 and Neu3 during MoDC differentiation did not affect surface MHC-I expression and cytokine secretion. Yet, sialidase activity in MoDCs was minimal, suggesting that sialidase inhibition does not significantly alter MHC-I-related functions. Our study highlights the unique maturation profile induced by sialic acid manipulation in MoDCs. These findings provide insights into the potential of sialic acid manipulation as a rapid immunomodulatory strategy, offering promising avenues for targeted interventions in inflammatory contexts.

树突状细胞(DC)细胞表面的唾液酸起着重要的免疫调节作用,操纵唾液酸可提高 DC 的成熟度,从而增强 T 细胞的活化。特别是在分子水平上,单核细胞衍生 DC(MoDCs)表面 MHC-I 分子稳定性的增加是改善 DC 与 T 细胞相互作用的基础。在本研究中,我们重点研究了用产气荚膜梭状芽孢杆菌硅糖苷酶处理硅酸重塑对 MoDCs 表型和功能特征的影响。值得注意的是,与其他具有不同特异性的硅糖苷酶相比,产气荚膜梭状芽孢杆菌硅糖苷酶能显著提高 MHC-I 的水平,这支持了一种观点,即更高的 MHC-I 水平是由于细胞表面蛋白上的特定硅糖被裂解所致。硅糖苷酶处理可在一小时内诱导 MHC-I、MHC-II 和 CD40 的表面表达迅速升高,这种反应在细胞因子鸡尾酒处理 48 小时后不能完全复制。硅糖苷酶处理 48 小时后也能观察到这些增加。CD86和PD-L1在细胞因子成熟48小时后显著增加,而在硅糖苷酶处理48小时后,CD86的增加幅度更大,PD-L1的增加幅度更短。硅糖苷酶处理 48 小时后,CCR-7 的表达明显增加,但细胞因子成熟对其影响不大。两种处理方法都能促进 IL-12 细胞因子的分泌。然而,鸡尾酒细胞因子诱导的IL-12分泌更为明显。SNA 凝集素染色分析表明,硅糖苷酶处理会显著改变硅糖酸谱,而细胞因子鸡尾酒则不会,因为后者只会导致硅糖酸轻微上调。值得注意的是,MoDCs 中的脂质呈递分子 CD1a、CD1b 和 CD1c 不受硅糖苷酶处理的影响,这一发现也得到了 C1R 细胞实验的进一步支持。在 MoDC 分化过程中抑制内源性硅糖苷酶 Neu1 和 Neu3 不会影响表面 MHC-I 的表达和细胞因子的分泌。然而,MoDC 中的硅糖苷酶活性极低,这表明硅糖苷酶抑制不会显著改变 MHC-I 相关功能。我们的研究强调了通过操纵硅酸诱导 MoDCs 成熟的独特特征。这些发现让我们了解到了操纵硅唾液酸作为一种快速免疫调节策略的潜力,为在炎症环境中进行有针对性的干预提供了前景广阔的途径。
{"title":"New insights into the immunomodulatory potential of sialic acid on monocyte-derived dendritic cells.","authors":"Zélia Silva, João Amorim Rabaça, Vanessa Luz, Rita Adubeiro Lourenço, Mariolina Salio, Alexandra Couto Oliveira, Pedro Bule, Sebastian Springer, Paula Alexandra Videira","doi":"10.1007/s00262-024-03863-7","DOIUrl":"10.1007/s00262-024-03863-7","url":null,"abstract":"<p><p>Sialic acids at the cell surface of dendritic cells (DCs) play an important immunomodulatory role, and their manipulation enhances DC maturation, leading to heightened T cell activation. Particularly, at the molecular level, the increased stability of surface MHC-I molecules in monocyte-derived DCs (MoDCs) underpins an improved DC: T cell interaction. In this study, we focused on the impact of sialic acid remodelling by treatment with Clostridium perfringens sialidase on MoDCs' phenotypic and functional characteristics. Our investigation juxtaposes this novel approach with the conventional cytokine-based maturation regimen commonly employed in clinical settings.Notably, C. perfringens sialidase remarkably increased MHC-I levels compared to other sialidases having different specificities, supporting the idea that higher MHC-I is due to the cleavage of specific sialoglycans on cell surface proteins. Sialidase treatment induced rapid elevated surface expression of MHC-I, MHC-II and CD40 within an hour, a response not fully replicated by 48 h cytokine cocktail treatment. These increases were also observable 48 h post sialidase treatment. While CD86 and PD-L1 showed significant increases after 48 h of cytokine maturation, 48 h post sialidase treatment showed a higher increase in CD86 and shorter increase in PD-L1. CCR-7 expression was significantly increased 48 h after sialidase treatment but not significantly affected by cytokine maturation. Both treatments promoted higher secretion of the IL-12 cytokine. However, the cytokine cocktail induced a more pronounced IL-12 production. SNA lectin staining analysis demonstrated that the sialic acid profile is significantly altered by sialidase treatment, but not by the cytokine cocktail, which causes only slight sialic acid upregulation. Notably, the lipid-presenting molecules CD1a, CD1b and CD1c remained unaffected by sialidase treatment in MoDCs, a finding also further supported by experiments performed on C1R cells. Inhibition of endogenous sialidases Neu1 and Neu3 during MoDC differentiation did not affect surface MHC-I expression and cytokine secretion. Yet, sialidase activity in MoDCs was minimal, suggesting that sialidase inhibition does not significantly alter MHC-I-related functions. Our study highlights the unique maturation profile induced by sialic acid manipulation in MoDCs. These findings provide insights into the potential of sialic acid manipulation as a rapid immunomodulatory strategy, offering promising avenues for targeted interventions in inflammatory contexts.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564124","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
Phenotypic insights into genetic risk factors for immune-related adverse events in cancer immunotherapy. 癌症免疫疗法中免疫相关不良事件遗传风险因素的表型研究。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03854-8
Haochuan Ma, Dili Song, Haibo Zhang, Taidong Li, Xing Jin

Background: Immune-related adverse events (irAEs) pose substantial challenges in the realm of cancer immunotherapy, frequently affecting treatment efficacy and patient safety. To address the urgent need for identifying risk factors associated with irAEs, we conducted a comprehensive phenotype-wide Mendelian randomization analysis (MR-PheWAS).

Methods: Utilizing publicly accessible genome-wide association study (GWAS) data, this investigation evaluated the impact of over 5000 exposure variables on susceptibility to irAEs using univariate Mendelian randomization (MR). We categorized these correlations and further explored potential mechanisms by which associated traits might influence irAEs through multivariate MR.

Results: MR-PheWAS identified numerous risk factors for irAEs, encompassing both previously documented and novel associations. Specifically, we identified 105 traits with probable causal relationships to all-grade irAEs and 119 traits with suggestive associations. For high-grade irAEs, we categorized 122 traits as probably associated and 141 as suggestively associated. Notably, multivariate MR analyses uncovered intricate interactions, particularly highlighting how diabetes impacts all-grade irAEs through mediators such as body mass index and sex hormone-binding globulin.

Conclusions: This study has not only identified new risk factors for irAEs but also confirmed several well-established ones. Further investigation is crucial to validate and assess these identified risk factors within clinical trials. A mechanistic understanding of these causal factors is essential for improving the management and prevention of irAEs.

背景:免疫相关不良事件(irAEs)给癌症免疫疗法领域带来了巨大挑战,经常影响治疗效果和患者安全。为了满足确定与irAEs相关的风险因素的迫切需要,我们进行了一项全面的全表型孟德尔随机分析(MR-PheWAS):本研究利用公开的全基因组关联研究(GWAS)数据,采用单变量孟德尔随机分析法(MR)评估了 5000 多个暴露变量对虹膜AEs易感性的影响。我们对这些相关性进行了分类,并通过多变量 MR 进一步探讨了相关性状可能影响虹膜急性损伤的潜在机制:结果:MR-PheWAS 发现了许多虹膜睫状体异常的风险因素,其中既有先前记录的相关因素,也有新发现的相关因素。具体来说,我们发现了 105 个特征与所有等级的虹膜急性心肌梗死可能存在因果关系,119 个特征与虹膜急性心肌梗死有提示性关联。对于高级别虹膜急性心动过速,我们将 122 个性状归类为可能相关,141 个性状归类为提示相关。值得注意的是,多变量磁共振分析发现了错综复杂的相互作用,特别强调了糖尿病如何通过体重指数和性激素结合球蛋白等介导因素影响所有等级的虹膜睫状体异常:这项研究不仅发现了新的虹膜AEs风险因素,还证实了几个已经确立的风险因素。进一步的调查对于在临床试验中验证和评估这些已确定的风险因素至关重要。从机理上理解这些致病因素对于改善虹膜急性心动过速的管理和预防至关重要。
{"title":"Phenotypic insights into genetic risk factors for immune-related adverse events in cancer immunotherapy.","authors":"Haochuan Ma, Dili Song, Haibo Zhang, Taidong Li, Xing Jin","doi":"10.1007/s00262-024-03854-8","DOIUrl":"10.1007/s00262-024-03854-8","url":null,"abstract":"<p><strong>Background: </strong>Immune-related adverse events (irAEs) pose substantial challenges in the realm of cancer immunotherapy, frequently affecting treatment efficacy and patient safety. To address the urgent need for identifying risk factors associated with irAEs, we conducted a comprehensive phenotype-wide Mendelian randomization analysis (MR-PheWAS).</p><p><strong>Methods: </strong>Utilizing publicly accessible genome-wide association study (GWAS) data, this investigation evaluated the impact of over 5000 exposure variables on susceptibility to irAEs using univariate Mendelian randomization (MR). We categorized these correlations and further explored potential mechanisms by which associated traits might influence irAEs through multivariate MR.</p><p><strong>Results: </strong>MR-PheWAS identified numerous risk factors for irAEs, encompassing both previously documented and novel associations. Specifically, we identified 105 traits with probable causal relationships to all-grade irAEs and 119 traits with suggestive associations. For high-grade irAEs, we categorized 122 traits as probably associated and 141 as suggestively associated. Notably, multivariate MR analyses uncovered intricate interactions, particularly highlighting how diabetes impacts all-grade irAEs through mediators such as body mass index and sex hormone-binding globulin.</p><p><strong>Conclusions: </strong>This study has not only identified new risk factors for irAEs but also confirmed several well-established ones. Further investigation is crucial to validate and assess these identified risk factors within clinical trials. A mechanistic understanding of these causal factors is essential for improving the management and prevention of irAEs.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564141","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
期刊
Cancer Immunology, Immunotherapy
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1