Pub Date : 2024-09-25eCollection Date: 2024-01-01DOI: 10.1080/2162402X.2024.2407532
Michaela Feodoroff, Firas Hamdan, Gabriella Antignani, Sara Feola, Manlio Fusciello, Salvatore Russo, Jacopo Chiaro, Katja Välimäki, Teijo Pellinen, Rui M Branca, Janne Lehtiö, Federica D Alessio, Paolo Bottega, Virpi Stigzelius, Janita Sandberg, Jonna Clancy, Jukka Partanen, Minna Malmstedt, Antti Rannikko, Vilja Pietiäinen, Mikaela Grönholm, Vincenzo Cerullo
Immunotherapy has emerged as a promising approach for cancer treatment, with oncolytic adenoviruses showing power as immunotherapeutic agents. In this study, we investigated the immunotherapeutic potential of an adenovirus construct expressing CXCL9, CXCL10, or IL-15 in clear cell renal cell carcinoma (ccRCC) tumor models. Our results demonstrated robust cytokine secretion upon viral treatment, suggesting effective transgene expression. Subsequent analysis using resistance-based transwell migration and microfluidic chip assays demonstrated increased T-cell migration in response to chemokine secretion by infected cells in both 2D and 3D cell models. Flow cytometry analysis revealed CXCR3 receptor expression across T-cell subsets, with the highest percentage found on CD8+ T-cells, underscoring their key role in immune cell migration. Alongside T-cells, we also detected NK-cells in the tumors of immunocompromised mice treated with cytokine-encoding adenoviruses. Furthermore, we identified potential immunogenic antigens that may enhance the efficacy and specificity of our armed oncolytic adenoviruses in ccRCC. Overall, our findings using ccRCC cell line, in vivo humanized mice, physiologically relevant PDCs in 2D and patient-derived organoids (PDOs) in 3D suggest that chemokine-armed adenoviruses hold promise for enhancing T-cell migration and improving immunotherapy outcomes in ccRCC. Our study contributes to the development of more effective ccRCC treatment strategies by elucidating immune cell infiltration and activation mechanisms within the tumor microenvironment (TME) and highlights the usefulness of PDOs for predicting clinical relevance and validating novel immunotherapeutic approaches. Overall, our research offers insights into the rational design and optimization of viral-based immunotherapies for ccRCC.
免疫疗法已成为一种前景广阔的癌症治疗方法,溶瘤腺病毒作为免疫治疗药物显示出强大的威力。在本研究中,我们研究了表达 CXCL9、CXCL10 或 IL-15 的腺病毒构建体在透明细胞肾细胞癌(ccRCC)肿瘤模型中的免疫治疗潜力。我们的结果表明,病毒处理后细胞因子分泌旺盛,表明转基因表达有效。随后使用基于抗性的透孔迁移和微流控芯片测定法进行的分析表明,在二维和三维细胞模型中,T细胞迁移增加是对感染细胞分泌趋化因子的反应。流式细胞术分析表明,CXCR3受体在各T细胞亚群中均有表达,其中CD8+ T细胞的表达量最高,这表明它们在免疫细胞迁移中发挥着关键作用。除了 T 细胞,我们还在接受细胞因子编码腺病毒治疗的免疫缺陷小鼠肿瘤中检测到了 NK 细胞。此外,我们还发现了潜在的免疫原性抗原,这些抗原可能会提高我们的武装溶瘤腺病毒在ccRCC中的疗效和特异性。总之,我们使用ccRCC细胞系、体内人源化小鼠、二维生理学相关PDCs和三维患者衍生器官组织(PDOs)的研究结果表明,趋化因子武装腺病毒有望增强T细胞迁移,改善ccRCC的免疫治疗效果。我们的研究通过阐明肿瘤微环境(TME)中的免疫细胞浸润和激活机制,为开发更有效的ccRCC治疗策略做出了贡献,并强调了PDOs在预测临床相关性和验证新型免疫治疗方法方面的有用性。总之,我们的研究为合理设计和优化基于病毒的 ccRCC 免疫疗法提供了启示。
{"title":"Enhancing T-cell recruitment in renal cell carcinoma with cytokine-armed adenoviruses.","authors":"Michaela Feodoroff, Firas Hamdan, Gabriella Antignani, Sara Feola, Manlio Fusciello, Salvatore Russo, Jacopo Chiaro, Katja Välimäki, Teijo Pellinen, Rui M Branca, Janne Lehtiö, Federica D Alessio, Paolo Bottega, Virpi Stigzelius, Janita Sandberg, Jonna Clancy, Jukka Partanen, Minna Malmstedt, Antti Rannikko, Vilja Pietiäinen, Mikaela Grönholm, Vincenzo Cerullo","doi":"10.1080/2162402X.2024.2407532","DOIUrl":"10.1080/2162402X.2024.2407532","url":null,"abstract":"<p><p>Immunotherapy has emerged as a promising approach for cancer treatment, with oncolytic adenoviruses showing power as immunotherapeutic agents. In this study, we investigated the immunotherapeutic potential of an adenovirus construct expressing CXCL9, CXCL10, or IL-15 in clear cell renal cell carcinoma (ccRCC) tumor models. Our results demonstrated robust cytokine secretion upon viral treatment, suggesting effective transgene expression. Subsequent analysis using resistance-based transwell migration and microfluidic chip assays demonstrated increased T-cell migration in response to chemokine secretion by infected cells in both 2D and 3D cell models. Flow cytometry analysis revealed CXCR3 receptor expression across T-cell subsets, with the highest percentage found on CD8+ T-cells, underscoring their key role in immune cell migration. Alongside T-cells, we also detected NK-cells in the tumors of immunocompromised mice treated with cytokine-encoding adenoviruses. Furthermore, we identified potential immunogenic antigens that may enhance the efficacy and specificity of our armed oncolytic adenoviruses in ccRCC. Overall, our findings using ccRCC cell line, <i>in vivo</i> humanized mice, physiologically relevant PDCs in 2D and patient-derived organoids (PDOs) in 3D suggest that chemokine-armed adenoviruses hold promise for enhancing T-cell migration and improving immunotherapy outcomes in ccRCC. Our study contributes to the development of more effective ccRCC treatment strategies by elucidating immune cell infiltration and activation mechanisms within the tumor microenvironment (TME) and highlights the usefulness of PDOs for predicting clinical relevance and validating novel immunotherapeutic approaches. Overall, our research offers insights into the rational design and optimization of viral-based immunotherapies for ccRCC.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2407532"},"PeriodicalIF":6.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11441019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142356459","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}
Pub Date : 2024-09-22eCollection Date: 2024-01-01DOI: 10.1080/2162402X.2024.2406576
Bo He, Larissa Dymond, Kira H Wood, Edward R Bastow, Jiulia Satiaputra, Ji Li, Anna Johansson-Percival, Juliana Hamzah, M Priyanthi Kumarasinghe, Mohammed Ballal, Jonathan Foo, Mikael Johansson, Hooi C Ee, Scott W White, Louise Winteringham, Ruth Ganss
Gastrointestinal stromal tumors (GISTs) harbor diverse immune cell populations but so far immunotherapy in patients has been disappointing. Here, we established cord blood humanized mouse models of localized and disseminated GIST to explore the remodeling of the tumor environment for improved immunotherapy. Specifically, we assessed the ability of a cancer vascular targeting peptide (VTP) to bind to mouse and patient GIST angiogenic blood vessels and deliver the TNF superfamily member LIGHT (TNFS14) into tumors. LIGHT-VTP treatment of GIST in humanized mice improved vascular function and tumor oxygenation, which correlated with an overall increase in intratumoral human effector T cells. Concomitant with LIGHT-mediated vascular remodeling, we observed intratumoral high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), which resemble spontaneous TLS found in GIST patients. Thus, by overcoming the limitations of immunodeficient xenograft models, we demonstrate the therapeutic feasibility of vascular targeting and immune priming in human GIST. Since TLS positively correlate with patient prognosis and improved response to immune checkpoint inhibition, vascular LIGHT targeting in GIST is a highly translatable approach to improve immunotherapeutic outcomes.
{"title":"Immune priming and induction of tertiary lymphoid structures in a cord-blood humanized mouse model of gastrointestinal stromal tumor.","authors":"Bo He, Larissa Dymond, Kira H Wood, Edward R Bastow, Jiulia Satiaputra, Ji Li, Anna Johansson-Percival, Juliana Hamzah, M Priyanthi Kumarasinghe, Mohammed Ballal, Jonathan Foo, Mikael Johansson, Hooi C Ee, Scott W White, Louise Winteringham, Ruth Ganss","doi":"10.1080/2162402X.2024.2406576","DOIUrl":"10.1080/2162402X.2024.2406576","url":null,"abstract":"<p><p>Gastrointestinal stromal tumors (GISTs) harbor diverse immune cell populations but so far immunotherapy in patients has been disappointing. Here, we established cord blood humanized mouse models of localized and disseminated GIST to explore the remodeling of the tumor environment for improved immunotherapy. Specifically, we assessed the ability of a cancer vascular targeting peptide (VTP) to bind to mouse and patient GIST angiogenic blood vessels and deliver the TNF superfamily member LIGHT (TNFS14) into tumors. LIGHT-VTP treatment of GIST in humanized mice improved vascular function and tumor oxygenation, which correlated with an overall increase in intratumoral human effector T cells. Concomitant with LIGHT-mediated vascular remodeling, we observed intratumoral high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), which resemble spontaneous TLS found in GIST patients. Thus, by overcoming the limitations of immunodeficient xenograft models, we demonstrate the therapeutic feasibility of vascular targeting and immune priming in human GIST. Since TLS positively correlate with patient prognosis and improved response to immune checkpoint inhibition, vascular LIGHT targeting in GIST is a highly translatable approach to improve immunotherapeutic outcomes.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2406576"},"PeriodicalIF":6.5,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308843","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}
Pub Date : 2024-08-27eCollection Date: 2024-01-01DOI: 10.1080/2162402X.2024.2392897
Anaïs Jiménez-Reinoso, Magdalena Molero-Abraham, Cristina Cirauqui, Belén Blanco, Eva M Garrido-Martin, Daniel Nehme-Álvarez, Carmen Domínguez-Alonso, Ángel Ramírez-Fernández, Laura Díez-Alonso, Ángel Nuñez-Buiza, África González-Murillo, Raquel Tobes, Eduardo Pareja, Manuel Ramírez-Orellana, José Luis Rodriguez-Peralto, Irene Ferrer, Jon Zugazagoitia, Luis Paz-Ares, Luis Álvarez-Vallina
Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown remarkable results in melanoma, but only modest clinical benefits in other cancers, even after TIL have been genetically modified to improve their tumor homing, cytotoxic potential or overcome cell exhaustion. The required ex vivo TIL expansion process may induce changes in the T cell clonal composition, which could likely compromise the tumor reactivity of TIL preparations and ultimately the success of TIL therapy. A promising approach based on the production of bispecific T cell-engagers (TCE) by engineered T cells (STAb-T therapy) improves the efficacy of current T cell redirection strategies against tumor-associated antigens in hematological tumors. We studied the TCRβ repertoire in non-small cell lung cancer (NSCLC) tumors and in ex vivo expanded TIL from two unrelated patients. We generated TIL secreting anti-epidermal growth factor receptor (EGFR) × anti-CD3 TCE (TILSTAb) and tested their antitumor efficacy in vitro and in vivo using a NSCLC patient-derived xenograft (PDX) model in which tumor fragments and TIL from the same patient were transplanted into hIL-2 NOG mice. We confirmed that the standard TIL expansion protocol promotes the loss of tumor-dominant T cell clones and the overgrowth of virus-reactive TCR clonotypes that were marginally detectable in primary tumors. We demonstrated the antitumor activity of TILSTAb both in vitro and in vivo when administered intratumorally and systemically in an autologous immune-humanized PDX EGFR+ NSCLC mouse model, where tumor regression was mediated by TCE-redirected CD4+ TIL bearing non-tumor dominant clonotypes.
肿瘤浸润淋巴细胞(TIL)的采用性转移在黑色素瘤中取得了显著效果,但在其他癌症中的临床疗效却微乎其微,即使在对 TIL 进行基因修饰以改善其肿瘤归巢性、细胞毒性潜力或克服细胞衰竭之后也是如此。所需的体内外 TIL 扩增过程可能会引起 T 细胞克隆组成的变化,这可能会影响 TIL 制剂的肿瘤反应性,最终影响 TIL 治疗的成功。一种很有前景的方法是通过工程T细胞产生双特异性T细胞激活剂(TCE)(STAb-T疗法),这种方法提高了目前针对血液肿瘤中肿瘤相关抗原的T细胞重定向策略的疗效。我们研究了非小细胞肺癌(NSCLC)肿瘤中的 TCRβ 重排,以及来自两名非亲缘关系患者的体外扩增 TIL。我们生成了分泌抗表皮生长因子受体(EGFR)×抗CD3 TCE(TILSTAb)的TIL,并使用NSCLC患者异种移植(PDX)模型测试了它们在体外和体内的抗肿瘤疗效,该模型是将来自同一患者的肿瘤片段和TIL移植到hIL-2 NOG小鼠体内。我们证实,标准的 TIL 扩增方案会导致肿瘤主导型 T 细胞克隆的丧失和病毒反应型 TCR 克隆型的过度生长,而这些克隆型在原发性肿瘤中几乎检测不到。在自体免疫人源化 PDX EGFR+ NSCLC 小鼠模型中,我们证实了 TILSTAb 在瘤内和全身给药的体外和体内抗肿瘤活性。
{"title":"CD4<sup>+</sup> tumor-infiltrating lymphocytes secreting T cell-engagers induce regression of autologous patient-derived non-small cell lung cancer xenografts.","authors":"Anaïs Jiménez-Reinoso, Magdalena Molero-Abraham, Cristina Cirauqui, Belén Blanco, Eva M Garrido-Martin, Daniel Nehme-Álvarez, Carmen Domínguez-Alonso, Ángel Ramírez-Fernández, Laura Díez-Alonso, Ángel Nuñez-Buiza, África González-Murillo, Raquel Tobes, Eduardo Pareja, Manuel Ramírez-Orellana, José Luis Rodriguez-Peralto, Irene Ferrer, Jon Zugazagoitia, Luis Paz-Ares, Luis Álvarez-Vallina","doi":"10.1080/2162402X.2024.2392897","DOIUrl":"10.1080/2162402X.2024.2392897","url":null,"abstract":"<p><p>Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown remarkable results in melanoma, but only modest clinical benefits in other cancers, even after TIL have been genetically modified to improve their tumor homing, cytotoxic potential or overcome cell exhaustion. The required <i>ex vivo</i> TIL expansion process may induce changes in the T cell clonal composition, which could likely compromise the tumor reactivity of TIL preparations and ultimately the success of TIL therapy. A promising approach based on the production of bispecific T cell-engagers (TCE) by engineered T cells (STAb-T therapy) improves the efficacy of current T cell redirection strategies against tumor-associated antigens in hematological tumors. We studied the TCRβ repertoire in non-small cell lung cancer (NSCLC) tumors and in <i>ex vivo</i> expanded TIL from two unrelated patients. We generated TIL secreting anti-epidermal growth factor receptor (EGFR) × anti-CD3 TCE (TIL<sup>STAb</sup>) and tested their antitumor efficacy <i>in vitro</i> and <i>in vivo</i> using a NSCLC patient-derived xenograft (PDX) model in which tumor fragments and TIL from the same patient were transplanted into <i>hIL-2</i> NOG mice. We confirmed that the standard TIL expansion protocol promotes the loss of tumor-dominant T cell clones and the overgrowth of virus-reactive TCR clonotypes that were marginally detectable in primary tumors. We demonstrated the antitumor activity of TIL<sup>STAb</sup> both <i>in vitro</i> and <i>in vivo</i> when administered intratumorally and systemically in an autologous immune-humanized PDX EGFR<sup>+</sup> NSCLC mouse model, where tumor regression was mediated by TCE-redirected CD4<sup>+</sup> TIL bearing non-tumor dominant clonotypes.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2392897"},"PeriodicalIF":6.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11352715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113732","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}
Pub Date : 2024-08-26eCollection Date: 2024-01-01DOI: 10.1080/2162402X.2024.2394247
David C Montrose, Suchandrima Saha, Lorenzo Galluzzi
Disrupting mitochondrial function in malignant cells is a promising strategy to enhance anticancer immunity. We have recently demonstrated that depriving colorectal cancer cells of serine results in mitochondrial dysfunction coupled with the cytosolic accumulation of mitochondrial DNA and consequent activation of CGAS- and STING-dependent tumor-targeting immune responses.
破坏恶性细胞的线粒体功能是一种很有前景的增强抗癌免疫力的策略。我们最近证明,剥夺结直肠癌细胞中的丝氨酸会导致线粒体功能障碍以及线粒体 DNA 的胞浆积累,从而激活依赖 CGAS 和 STING 的肿瘤靶向免疫反应。
{"title":"Metabolic regulation of the mitochondrial immune checkpoint.","authors":"David C Montrose, Suchandrima Saha, Lorenzo Galluzzi","doi":"10.1080/2162402X.2024.2394247","DOIUrl":"10.1080/2162402X.2024.2394247","url":null,"abstract":"<p><p>Disrupting mitochondrial function in malignant cells is a promising strategy to enhance anticancer immunity. We have recently demonstrated that depriving colorectal cancer cells of serine results in mitochondrial dysfunction coupled with the cytosolic accumulation of mitochondrial DNA and consequent activation of CGAS- and STING-dependent tumor-targeting immune responses.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2394247"},"PeriodicalIF":6.5,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11352702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113733","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}
Pub Date : 2024-08-26eCollection Date: 2024-01-01DOI: 10.1080/2162402X.2024.2388315
Vincenzo De Falco, Stefania Napolitano, Renato Franco, Federica Zito Marino, Luigi Formisano, Daniela Esposito, Gabriella Suarato, Rossella Napolitano, Alfonso Esposito, Francesco Caraglia, Maria Cristina Giugliano, Eleonora Cioli, Vincenzo Famiglietti, Roberto Bianco, Giuseppe Argenziano, Andrea Ronchi, Davide Ciardiello, Valerio Nardone, Emma D'Ippolito, Sara Del Tufo, Fortunato Ciardiello, Teresa Troiani
Cemiplimab has demonstrated relevant clinical activity in cutaneous squamous cell carcinoma (cSCC) but mechanisms of primary and acquired resistance to immunotherapy are still unknown. We collected clinical data from locally advanced and/or metastatic cSSC patients treated with cemiplimab in two Italian University centers. In addition, gene expression analysis by using Nanostring Technologies platform to evaluate 770 cancer- and immune-related genes on 20 tumor tissue samples (9 responders and 11 non-responders to cemiplimab) was performed. We enrolled 81 patients with a median age of 82 years. After 16.4 months of median follow-up, 12- and 24-months PFS were 53% and 42%, respectively; while 12- and 24-months OS were 71% and 61%, respectively. Treatment was well tolerated. Overall response rate (ORR) was 58%, with a disease control rate (DCR) of 77.8%. The difference between genes expressed in responder versus non-responder patient samples was substantial, particularly for genes involved in immune system regulation. Cemiplimab-resistant tumors were associated with over-expression of CCL-20 and CXCL-8. Cemiplimab confirmed efficacy and safety data in real-life cSCC patients. Overexpression of CCL-20 and CXCL-8 could represent biomarkers of lack of response to immunotherapy.
{"title":"Overexpression of CCL-20 and CXCL-8 genes enhances tumor escape and resistance to cemiplimab, a programmed cell death protein-1 (PD-1) inhibitor, in patients with locally advanced and metastatic cutaneous squamous cell carcinoma.","authors":"Vincenzo De Falco, Stefania Napolitano, Renato Franco, Federica Zito Marino, Luigi Formisano, Daniela Esposito, Gabriella Suarato, Rossella Napolitano, Alfonso Esposito, Francesco Caraglia, Maria Cristina Giugliano, Eleonora Cioli, Vincenzo Famiglietti, Roberto Bianco, Giuseppe Argenziano, Andrea Ronchi, Davide Ciardiello, Valerio Nardone, Emma D'Ippolito, Sara Del Tufo, Fortunato Ciardiello, Teresa Troiani","doi":"10.1080/2162402X.2024.2388315","DOIUrl":"10.1080/2162402X.2024.2388315","url":null,"abstract":"<p><p>Cemiplimab has demonstrated relevant clinical activity in cutaneous squamous cell carcinoma (cSCC) but mechanisms of primary and acquired resistance to immunotherapy are still unknown. We collected clinical data from locally advanced and/or metastatic cSSC patients treated with cemiplimab in two Italian University centers. In addition, gene expression analysis by using Nanostring Technologies platform to evaluate 770 cancer- and immune-related genes on 20 tumor tissue samples (9 responders and 11 non-responders to cemiplimab) was performed. We enrolled 81 patients with a median age of 82 years. After 16.4 months of median follow-up, 12- and 24-months PFS were 53% and 42%, respectively; while 12- and 24-months OS were 71% and 61%, respectively. Treatment was well tolerated. Overall response rate (ORR) was 58%, with a disease control rate (DCR) of 77.8%. The difference between genes expressed in responder versus non-responder patient samples was substantial, particularly for genes involved in immune system regulation. Cemiplimab-resistant tumors were associated with over-expression of CCL-20 and CXCL-8. Cemiplimab confirmed efficacy and safety data in real-life cSCC patients. Overexpression of CCL-20 and CXCL-8 could represent biomarkers of lack of response to immunotherapy.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2388315"},"PeriodicalIF":6.5,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11352706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113734","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}
Pub Date : 2024-08-22eCollection Date: 2024-01-01DOI: 10.1080/2162402X.2024.2395067
Francois Xavier Rwandamuriye, Tao Wang, Hanfu Zhang, Omar Elaskalani, Jorren Kuster, Xueting Ye, Breana Vitali, Juliët Schreurs, M Lizeth Orozco Morales, Marck Norret, Cameron W Evans, Rachael M Zemek, K Swaminathan Iyer, W Joost Lesterhuis, Ben Wylie
Toll-like receptor (TLR) agonists are being developed as anti-cancer therapeutics due to their potent immunostimulatory properties. However, clinical trials testing TLR agonists as monotherapy have often failed to demonstrate significant improvement over standard of care. We hypothesized that the anti-cancer efficacy of TLR agonist immunotherapy could be improved by combinatorial approaches. To prevent increased toxicity, often seen with systemic combination therapies, we developed a hydrogel to deliver TLR agonist combinations at low doses, locally, during cancer debulking surgery. Using tumor models of WEHI 164 and bilateral M3-9-M sarcoma and CT26 colon carcinoma, we assessed the efficacy of pairwise combinations of poly(I:C), R848, and CpG in controlling local and distant tumor growth. We show that combination of the TLR3 agonist poly(I:C) and TLR7/8 agonist R848 drives anti-tumor immunity against local and distant tumors. In addition, combination of local poly(I:C) and R848 sensitized tumors to systemic immune checkpoint blockade, improving tumor control. Mechanistically, we demonstrate that local therapy with poly(I:C) and R848 recruits inflammatory monocytes to the tumor draining lymph nodes early in the anti-tumor response. Finally, we provide proof of concept for intraoperative delivery of poly(I:C) and R848 together via a surgically applicable biodegradable hydrogel.
{"title":"Local therapy with combination TLR agonists stimulates systemic anti-tumor immunity and sensitizes tumors to immune checkpoint blockade.","authors":"Francois Xavier Rwandamuriye, Tao Wang, Hanfu Zhang, Omar Elaskalani, Jorren Kuster, Xueting Ye, Breana Vitali, Juliët Schreurs, M Lizeth Orozco Morales, Marck Norret, Cameron W Evans, Rachael M Zemek, K Swaminathan Iyer, W Joost Lesterhuis, Ben Wylie","doi":"10.1080/2162402X.2024.2395067","DOIUrl":"10.1080/2162402X.2024.2395067","url":null,"abstract":"<p><p>Toll-like receptor (TLR) agonists are being developed as anti-cancer therapeutics due to their potent immunostimulatory properties. However, clinical trials testing TLR agonists as monotherapy have often failed to demonstrate significant improvement over standard of care. We hypothesized that the anti-cancer efficacy of TLR agonist immunotherapy could be improved by combinatorial approaches. To prevent increased toxicity, often seen with systemic combination therapies, we developed a hydrogel to deliver TLR agonist combinations at low doses, locally, during cancer debulking surgery. Using tumor models of WEHI 164 and bilateral M3-9-M sarcoma and CT26 colon carcinoma, we assessed the efficacy of pairwise combinations of poly(I:C), R848, and CpG in controlling local and distant tumor growth. We show that combination of the TLR3 agonist poly(I:C) and TLR7/8 agonist R848 drives anti-tumor immunity against local and distant tumors. In addition, combination of local poly(I:C) and R848 sensitized tumors to systemic immune checkpoint blockade, improving tumor control. Mechanistically, we demonstrate that local therapy with poly(I:C) and R848 recruits inflammatory monocytes to the tumor draining lymph nodes early in the anti-tumor response. Finally, we provide proof of concept for intraoperative delivery of poly(I:C) and R848 together via a surgically applicable biodegradable hydrogel.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2395067"},"PeriodicalIF":6.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074255","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}
Pub Date : 2024-08-22eCollection Date: 2024-01-01DOI: 10.1080/2162402X.2024.2392898
Suzanne M Castenmiller, Nandhini Kanagasabesan, Aurélie Guislain, Benoît P Nicolet, Marleen M van Loenen, Kim Monkhorst, Alexander A F A Veenhof, Egbert F Smit, Koen J Hartemink, John B A G Haanen, Rosa de Groot, Monika C Wolkers
Adoptive transfer of tumor infiltrating lymphocytes (TIL therapy) has proven highly effective for treating solid cancers, including non-small cell lung cancer (NSCLC). However, not all patients benefit from this therapy for yet unknown reasons. Defining markers that correlate with high tumor-reactivity of the autologous TIL products is thus key for achieving better tailored immunotherapies. We questioned whether the composition of immune cell infiltrates correlated with the tumor-reactivity of expanded TIL products. Unbiased flow cytometry analysis of immune cell infiltrates of 26 early-stage and 20 late-stage NSCLC tumor lesions was used for correlations with the T cell differentiation and activation status, and with the expansion rate and anti-tumor response of generated TIL products. The composition of tumor immune infiltrates was highly variable between patients. Spearman's Rank Correlation revealed that high B cell infiltration negatively correlated with the tumor-reactivity of the patient's expanded TIL products, as defined by cytokine production upon exposure to autologous tumor digest. In-depth analysis revealed that tumor lesions with high B cell infiltrates contained tertiary lymphoid structure (TLS)-related immune infiltrates, including BCL6+ antibody-secreting B cells, IgD+BCL6+ B cells and CXCR5+BLC6+ CD4+ T cells, and higher percentages of naïve CD8+ T cells. In conclusion, the composition of immune cell infiltrates in NSCLC tumors associates with the functionality of the expanded TIL product. Our findings may thus help improve patient selection for TIL therapy.
事实证明,肿瘤浸润淋巴细胞的采纳转移(TIL疗法)对治疗包括非小细胞肺癌(NSCLC)在内的实体瘤非常有效。然而,并非所有患者都能从这种疗法中获益,原因尚不清楚。因此,确定与自体 TIL 产物的高肿瘤反应性相关的标记物是实现更好的定制免疫疗法的关键。我们对免疫细胞浸润的组成是否与扩增 TIL 产物的肿瘤反应性相关提出了疑问。我们对 26 例早期和 20 例晚期 NSCLC 肿瘤病灶的免疫细胞浸润进行了无偏流式细胞术分析,以确定其与 T 细胞分化和活化状态、扩增率以及生成的 TIL 产物的抗肿瘤反应之间的相关性。不同患者的肿瘤免疫浸润组成差异很大。斯皮尔曼等级相关性显示,高B细胞浸润与患者扩增的TIL产物的肿瘤反应性呈负相关,其定义是暴露于自体肿瘤消化液时产生的细胞因子。深入分析发现,B细胞浸润较高的肿瘤病灶含有三级淋巴结构(TLS)相关的免疫浸润,包括分泌抗体的BCL6+ B细胞、IgD+BCL6+ B细胞和CXCR5+BLC6+ CD4+ T细胞,以及较高比例的幼稚CD8+ T细胞。总之,NSCLC 肿瘤中免疫细胞浸润的组成与扩增的 TIL 产物的功能有关。因此,我们的发现可能有助于改善TIL疗法的患者选择。
{"title":"Tertiary lymphoid structure-related immune infiltrates in NSCLC tumor lesions correlate with low tumor-reactivity of TIL products.","authors":"Suzanne M Castenmiller, Nandhini Kanagasabesan, Aurélie Guislain, Benoît P Nicolet, Marleen M van Loenen, Kim Monkhorst, Alexander A F A Veenhof, Egbert F Smit, Koen J Hartemink, John B A G Haanen, Rosa de Groot, Monika C Wolkers","doi":"10.1080/2162402X.2024.2392898","DOIUrl":"10.1080/2162402X.2024.2392898","url":null,"abstract":"<p><p>Adoptive transfer of tumor infiltrating lymphocytes (TIL therapy) has proven highly effective for treating solid cancers, including non-small cell lung cancer (NSCLC). However, not all patients benefit from this therapy for yet unknown reasons. Defining markers that correlate with high tumor-reactivity of the autologous TIL products is thus key for achieving better tailored immunotherapies. We questioned whether the composition of immune cell infiltrates correlated with the tumor-reactivity of expanded TIL products. Unbiased flow cytometry analysis of immune cell infiltrates of 26 early-stage and 20 late-stage NSCLC tumor lesions was used for correlations with the T cell differentiation and activation status, and with the expansion rate and anti-tumor response of generated TIL products. The composition of tumor immune infiltrates was highly variable between patients. Spearman's Rank Correlation revealed that high B cell infiltration negatively correlated with the tumor-reactivity of the patient's expanded TIL products, as defined by cytokine production upon exposure to autologous tumor digest. In-depth analysis revealed that tumor lesions with high B cell infiltrates contained tertiary lymphoid structure (TLS)-related immune infiltrates, including BCL6<sup>+</sup> antibody-secreting B cells, IgD<sup>+</sup>BCL6<sup>+</sup> B cells and CXCR5<sup>+</sup>BLC6<sup>+</sup> CD4<sup>+</sup> T cells, and higher percentages of naïve CD8<sup>+</sup> T cells. In conclusion, the composition of immune cell infiltrates in NSCLC tumors associates with the functionality of the expanded TIL product. Our findings may thus help improve patient selection for TIL therapy.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2392898"},"PeriodicalIF":6.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074256","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}
Pub Date : 2024-08-21eCollection Date: 2024-01-01DOI: 10.1080/2162402X.2024.2393442
Kirsi Kainulainen, Einari A Niskanen, Johanna Kinnunen, Kaisa Mäki-Mantila, Kiia Hartikainen, Ville Paakinaho, Marjo Malinen, Kirsi Ketola, Sanna Pasonen-Seppänen
The inflammatory tumor microenvironment (TME) is a key driver for tumor-promoting processes. Tumor-associated macrophages are one of the main immune cell types in the TME and their increased density is related to poor prognosis in prostate cancer. Here, we investigated the influence of pro-inflammatory (M1) and immunosuppressive (M2) macrophages on prostate cancer lineage plasticity. Our findings reveal that M1 macrophage secreted factors upregulate genes related to stemness while downregulating genes associated with androgen response in prostate cancer cells. The expression of cancer stem cell (CSC) plasticity markers NANOG, KLF4, SOX2, OCT4, and CD44 was stimulated by the secreted factors from M1 macrophages. Moreover, AR and its target gene PSA were observed to be suppressed in LNCaP cells treated with secreted factors from M1 macrophages. Inhibition of NFκB signaling using the IKK16 inhibitor resulted in downregulation of NANOG, SOX2, and CD44 and CSC plasticity. Our study highlights that the secreted factors from M1 macrophages drive prostate cancer cell plasticity by upregulating the expression of CSC plasticity markers through NFκB signaling pathway.
炎性肿瘤微环境(TME)是肿瘤促发过程的关键驱动因素。肿瘤相关巨噬细胞是肿瘤微环境中的主要免疫细胞类型之一,其密度的增加与前列腺癌的不良预后有关。在这里,我们研究了促炎性(M1)和免疫抑制性(M2)巨噬细胞对前列腺癌血统可塑性的影响。我们的研究结果表明,M1巨噬细胞分泌的因子会上调前列腺癌细胞中与干性相关的基因,同时下调与雄激素反应相关的基因。癌症干细胞(CSC)可塑性标志物NANOG、KLF4、SOX2、OCT4和CD44的表达受到M1巨噬细胞分泌因子的刺激。此外,在使用 M1 巨噬细胞分泌因子处理的 LNCaP 细胞中,还观察到 AR 及其靶基因 PSA 受到抑制。使用IKK16抑制剂抑制NFκB信号传导会导致NANOG、SOX2和CD44的下调以及CSC的可塑性。我们的研究强调,M1巨噬细胞分泌的因子通过NFκB信号通路上调CSC可塑性标志物的表达,从而驱动前列腺癌细胞的可塑性。
{"title":"Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, <i>SOX2</i>, and <i>CD44</i> through NFκB-signaling.","authors":"Kirsi Kainulainen, Einari A Niskanen, Johanna Kinnunen, Kaisa Mäki-Mantila, Kiia Hartikainen, Ville Paakinaho, Marjo Malinen, Kirsi Ketola, Sanna Pasonen-Seppänen","doi":"10.1080/2162402X.2024.2393442","DOIUrl":"10.1080/2162402X.2024.2393442","url":null,"abstract":"<p><p>The inflammatory tumor microenvironment (TME) is a key driver for tumor-promoting processes. Tumor-associated macrophages are one of the main immune cell types in the TME and their increased density is related to poor prognosis in prostate cancer. Here, we investigated the influence of pro-inflammatory (M1) and immunosuppressive (M2) macrophages on prostate cancer lineage plasticity. Our findings reveal that M1 macrophage secreted factors upregulate genes related to stemness while downregulating genes associated with androgen response in prostate cancer cells. The expression of cancer stem cell (CSC) plasticity markers NANOG, KLF4, <i>SOX2, OCT4</i>, and CD44 was stimulated by the secreted factors from M1 macrophages. Moreover, AR and its target gene <i>PSA</i> were observed to be suppressed in LNCaP cells treated with secreted factors from M1 macrophages. Inhibition of NFκB signaling using the IKK16 inhibitor resulted in downregulation of NANOG, <i>SOX2</i>, and <i>CD44</i> and CSC plasticity. Our study highlights that the secreted factors from M1 macrophages drive prostate cancer cell plasticity by upregulating the expression of CSC plasticity markers through NFκB signaling pathway.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2393442"},"PeriodicalIF":6.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034397","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}
Pub Date : 2024-08-18eCollection Date: 2024-01-01DOI: 10.1080/2162402X.2024.2388306
Michaël Constantinides, Nicolas Robert, Caroline Multrier, Loïs Coënon, Mauricio Campos-Mora, Carine Jacquard, Fei Gao, Sara Zemiti, Jessy Presumey, Guillaume Cartron, Jérome Moreaux, Martin Villalba
FCGR3A presents a single nucleotide polymorphism at location 158 (V/F), which affects its binding to the fragment crystallizable (Fc) of antibodies (Abs). FcγRIIIa-158 V allotype has the highest affinity and is associated with a better clinical response to IgG1 monoclonal Abs (mAb) treatment. We compared the allele frequency of FCGR3A-F158V polymorphism in cohorts of patients with B-cell lymphoproliferative disorders, including multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), non-Hodgkin lymphoma (NHL), and B-cell chronic leukemia (B-CLL). FCGR3A-158F homozygous were enriched and tended to be in MM and MGUS patients, respectively; but neither in B-CLL nor in NHL patients. We identified a significantly lower concentration of CD8 T-cells and resting memory CD4 T-cells in MM patients bone marrow with the F/F genotype, associated with an increase in the macrophage percentage. In contrast, natural killer cells increased in V/V homozygous patients. This suggests a deregulation of the immune microenvironment in FCGR3A-F/F homozygous patients. However, we did not observe difference in response following treatment combining chemotherapy associated or not with daratumumab, an IgG1 mAb direct against CD38. Our findings suggest that FCGR3A F158V polymorphism can regulate the immune environment and affect the development of tumor plasma cells.
FCGR3A 在 158 位(V/F)上存在单核苷酸多态性,这会影响其与抗体(Abs)的可结晶片段(Fc)的结合。FcγRIIIa-158 V 异型具有最高的亲和力,与对 IgG1 单克隆抗体(mAb)治疗更好的临床反应相关。我们比较了多发性骨髓瘤(MM)、意义未定的单克隆性淋巴瘤(MGUS)、非霍奇金淋巴瘤(NHL)和B细胞慢性白血病(B-CLL)等B细胞淋巴组织增生性疾病患者群体中FCGR3A-F158V多态性的等位基因频率。FCGR3A-158F同源基因分别在MM和MGUS患者中富集并趋向于出现,但在B-CLL和NHL患者中均未出现。我们发现,F/F 基因型的 MM 患者骨髓中 CD8 T 细胞和静息记忆 CD4 T 细胞的浓度明显较低,这与巨噬细胞比例的增加有关。相比之下,V/V同型患者的自然杀伤细胞则有所增加。这表明FCGR3A-F/F同型患者的免疫微环境发生了失调。然而,我们没有观察到化疗联合或不联合达拉单抗(一种直接针对CD38的IgG1 mAb)治疗后的反应差异。我们的研究结果表明,FCGR3A F158V多态性可调节免疫环境并影响肿瘤浆细胞的发育。
{"title":"<i>FCGR3A</i> F158V alleles frequency differs in multiple myeloma patients from healthy population.","authors":"Michaël Constantinides, Nicolas Robert, Caroline Multrier, Loïs Coënon, Mauricio Campos-Mora, Carine Jacquard, Fei Gao, Sara Zemiti, Jessy Presumey, Guillaume Cartron, Jérome Moreaux, Martin Villalba","doi":"10.1080/2162402X.2024.2388306","DOIUrl":"10.1080/2162402X.2024.2388306","url":null,"abstract":"<p><p><i>FCGR3A</i> presents a single nucleotide polymorphism at location 158 (V/F), which affects its binding to the fragment crystallizable (Fc) of antibodies (Abs). FcγRIIIa-158 V allotype has the highest affinity and is associated with a better clinical response to IgG1 monoclonal Abs (mAb) treatment. We compared the allele frequency of <i>FCGR3A-</i>F158V polymorphism in cohorts of patients with B-cell lymphoproliferative disorders, including multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), non-Hodgkin lymphoma (NHL), and B-cell chronic leukemia (B-CLL). <i>FCGR3A</i>-158F homozygous were enriched and tended to be in MM and MGUS patients, respectively; but neither in B-CLL nor in NHL patients. We identified a significantly lower concentration of CD8 T-cells and resting memory CD4 T-cells in MM patients bone marrow with the F/F genotype, associated with an increase in the macrophage percentage. In contrast, natural killer cells increased in V/V homozygous patients. This suggests a deregulation of the immune microenvironment in <i>FCGR3A</i>-F/F homozygous patients. However, we did not observe difference in response following treatment combining chemotherapy associated or not with daratumumab, an IgG1 mAb direct against CD38. Our findings suggest that <i>FCGR3A</i> F158V polymorphism can regulate the immune environment and affect the development of tumor plasma cells.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2388306"},"PeriodicalIF":6.5,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037402","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}