Pub Date : 2023-04-03eCollection Date: 2023-06-15DOI: 10.1016/j.omto.2023.03.003
Upasana Sahu, Matthew P Mullarkey, Guangsheng Pei, Zhongming Zhao, Bangxing Hong, Balveen Kaur
Longstanding evidence implicate glioma stem-like cells as the main drivers contributing toward glioblastoma (GBM) therapy resistance and tumor recurrence. Although oncolytic herpes simplex virus (oHSV) viral therapy is a promising biological therapy recently approved for melanoma (in the United States and Europe) and GBM (in Japan); however, the impact of this therapy on GBM stem-like cells (GSCs) is understudied. Here we show that post-oHSV virotherapy activated AKT signaling results in an enrichment of GSC signatures in glioma, which mimics the enrichment in GSC observed after radiation treatment. We also uncovered that a second-generation oncolytic virus armed with PTEN-L (oHSV-P10) decreases this by moderating IL6/JAK/STAT3 signaling. This ability was retained in the presence of radiation treatment and oHSV-P10-sensitized intracranial GBM to radiotherapy. Collectively, our findings uncover potential mechanisms to overcome GSC-mediated radiation resistance via oHSV-P10.
{"title":"oHSV-P10 reduces glioma stem cell enrichment after oncolytic HSV therapy.","authors":"Upasana Sahu, Matthew P Mullarkey, Guangsheng Pei, Zhongming Zhao, Bangxing Hong, Balveen Kaur","doi":"10.1016/j.omto.2023.03.003","DOIUrl":"10.1016/j.omto.2023.03.003","url":null,"abstract":"<p><p>Longstanding evidence implicate glioma stem-like cells as the main drivers contributing toward glioblastoma (GBM) therapy resistance and tumor recurrence. Although oncolytic herpes simplex virus (oHSV) viral therapy is a promising biological therapy recently approved for melanoma (in the United States and Europe) and GBM (in Japan); however, the impact of this therapy on GBM stem-like cells (GSCs) is understudied. Here we show that post-oHSV virotherapy activated AKT signaling results in an enrichment of GSC signatures in glioma, which mimics the enrichment in GSC observed after radiation treatment. We also uncovered that a second-generation oncolytic virus armed with PTEN-L (oHSV-P10) decreases this by moderating IL6/JAK/STAT3 signaling. This ability was retained in the presence of radiation treatment and oHSV-P10-sensitized intracranial GBM to radiotherapy. Collectively, our findings uncover potential mechanisms to overcome GSC-mediated radiation resistance via oHSV-P10.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c9/00/main.PMC10126842.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9364473","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 : 2023-03-16DOI: 10.1016/j.omto.2022.12.003
Jiang Lv, Le Qin, Ruocong Zhao, Di Wu, Zhiping Wu, Diwei Zheng, Siyu Li, Mintao Luo, Qiting Wu, Youguo Long, Zhaoyang Tang, Yan-Lai Tang, Xuequn Luo, Yao Yao, Li-Hua Yang, Peng Li
Tumor cells and the immunosuppressive tumor microenvironment suppress the antitumor activity of T cells through immune checkpoints, including the PD-L1/PD-1 axis. Cytokine-inducible SH2-containing protein (CISH), a member of the suppressor of cytokine signaling (SOCS) family, inhibits JAK-STAT and T cell receptor (TCR) signaling in T and natural killer (NK) cells. However, its role in the regulation of immune checkpoints in T cells remains unclear. In this study, we ablated CISH in T cells with CRISPR-Cas9 and found that the sensitivity of T cells to TCR and cytokine stimulation was increased. In addition, chimeric antigen receptor T cells with CISH deficiency exhibited longer survival and higher cytokine secretion and antitumor activity. Notably, PD-1 expression was decreased in activated CISH-deficient T cells in vitro and in vivo. The level of FBXO38, a ubiquitination-regulating protein that reduces PD-1 expression, was elevated in activated T cells after CISH ablation. Hence, this study reveals a mechanism by which CISH promotes PD-1 expression by suppressing the expression of FBXO38 and proposes a new strategy for augmenting the therapeutic effect of CAR-T cells by inhibiting CISH.
肿瘤细胞和免疫抑制肿瘤微环境通过免疫检查点(包括PD-L1/PD-1轴)抑制T细胞的抗肿瘤活性。细胞因子诱导SH2-containing protein (CISH)是细胞因子信号传导抑制因子(SOCS)家族的一员,可抑制T细胞和自然杀伤细胞(NK)中的JAK-STAT和T细胞受体(TCR)信号传导。然而,它在T细胞免疫检查点调节中的作用尚不清楚。在本研究中,我们使用CRISPR-Cas9消融T细胞中的CISH,发现T细胞对TCR和细胞因子刺激的敏感性增加。此外,嵌合抗原受体T细胞CISH缺陷表现出更长的存活时间,更高的细胞因子分泌和抗肿瘤活性。值得注意的是,体内和体外活化的cish缺陷T细胞中PD-1的表达降低。FBXO38是一种泛素化调节蛋白,可降低PD-1的表达,在CISH消融后激活的T细胞中水平升高。因此,本研究揭示了CISH通过抑制FBXO38表达促进PD-1表达的机制,并提出了通过抑制CISH增强CAR-T细胞治疗效果的新策略。
{"title":"Disruption of CISH promotes the antitumor activity of human T cells and decreases PD-1 expression levels.","authors":"Jiang Lv, Le Qin, Ruocong Zhao, Di Wu, Zhiping Wu, Diwei Zheng, Siyu Li, Mintao Luo, Qiting Wu, Youguo Long, Zhaoyang Tang, Yan-Lai Tang, Xuequn Luo, Yao Yao, Li-Hua Yang, Peng Li","doi":"10.1016/j.omto.2022.12.003","DOIUrl":"https://doi.org/10.1016/j.omto.2022.12.003","url":null,"abstract":"<p><p>Tumor cells and the immunosuppressive tumor microenvironment suppress the antitumor activity of T cells through immune checkpoints, including the PD-L1/PD-1 axis. Cytokine-inducible SH2-containing protein (CISH), a member of the suppressor of cytokine signaling (SOCS) family, inhibits JAK-STAT and T cell receptor (TCR) signaling in T and natural killer (NK) cells. However, its role in the regulation of immune checkpoints in T cells remains unclear. In this study, we ablated CISH in T cells with CRISPR-Cas9 and found that the sensitivity of T cells to TCR and cytokine stimulation was increased. In addition, chimeric antigen receptor T cells with CISH deficiency exhibited longer survival and higher cytokine secretion and antitumor activity. Notably, PD-1 expression was decreased in activated CISH-deficient T cells <i>in vitro</i> and <i>in vivo</i>. The level of FBXO38, a ubiquitination-regulating protein that reduces PD-1 expression, was elevated in activated T cells after CISH ablation. Hence, this study reveals a mechanism by which CISH promotes PD-1 expression by suppressing the expression of FBXO38 and proposes a new strategy for augmenting the therapeutic effect of CAR-T cells by inhibiting CISH.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/11/b0/main.PMC9827364.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9100293","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 : 2023-03-16DOI: 10.1016/j.omto.2023.01.005
Valeria Guidolin, Yupeng Li, Foster C Jacobs, Margaret L MacMillan, Peter W Villalta, Stephen S Hecht, Silvia Balbo
DNA alkylating drugs have been used as cancer chemotherapy with variable outcomes. The establishment of predictive biomarkers to identify patients who will effectively respond to treatment would allow for the development of personalized therapies. As the degree of interaction of alkylating drug with DNA plays a key role in their mechanism of action, our hypothesis is that the measurement of the DNA adducts formed by alkylating drugs could be used to inform patient stratification. Beginning with busulfan, we took advantage of our DNA adductomic approach to characterize DNA adducts formed by reacting busulfan with calf-thymus DNA. Samples collected from six patients undergoing busulfan-based chemotherapy prior to allogeneic hematopoietic cell transplantation were analyzed for the presence of busulfan-derived DNA adducts. Among the 15 adducts detected in vitro, 12 were observed in the patient blood confirming the presence of a large profile of DNA adducts in vivo. Two of the detected adducts were structurally confirmed by comparison with synthetic standards and quantified in patients. These data confirm our ability to comprehensively characterize busulfan-derived DNA damage and set the stage for the development of methods to support personalized chemotherapy.
{"title":"Characterization and quantitation of busulfan DNA adducts in the blood of patients receiving busulfan therapy.","authors":"Valeria Guidolin, Yupeng Li, Foster C Jacobs, Margaret L MacMillan, Peter W Villalta, Stephen S Hecht, Silvia Balbo","doi":"10.1016/j.omto.2023.01.005","DOIUrl":"https://doi.org/10.1016/j.omto.2023.01.005","url":null,"abstract":"<p><p>DNA alkylating drugs have been used as cancer chemotherapy with variable outcomes. The establishment of predictive biomarkers to identify patients who will effectively respond to treatment would allow for the development of personalized therapies. As the degree of interaction of alkylating drug with DNA plays a key role in their mechanism of action, our hypothesis is that the measurement of the DNA adducts formed by alkylating drugs could be used to inform patient stratification. Beginning with busulfan, we took advantage of our DNA adductomic approach to characterize DNA adducts formed by reacting busulfan with calf-thymus DNA. Samples collected from six patients undergoing busulfan-based chemotherapy prior to allogeneic hematopoietic cell transplantation were analyzed for the presence of busulfan-derived DNA adducts. Among the 15 adducts detected <i>in vitro</i>, 12 were observed in the patient blood confirming the presence of a large profile of DNA adducts <i>in vivo</i>. Two of the detected adducts were structurally confirmed by comparison with synthetic standards and quantified in patients. These data confirm our ability to comprehensively characterize busulfan-derived DNA damage and set the stage for the development of methods to support personalized chemotherapy.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6e/2a/main.PMC9938526.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9493813","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 : 2023-03-16DOI: 10.1016/j.omto.2022.12.007
Saru Basnet, Joao M Santos, Dafne C A Quixabeira, James H A Clubb, Susanna A M Grönberg-Vähä-Koskela, Victor Arias, Santeri Pakola, Tatiana V Kudling, Camilla Heiniö, Riikka Havunen, Victor Cervera-Carrascon, Suvi Sorsa, Marjukka Anttila, Anna Kanerva, Akseli Hemminki
Immunotherapy with bispecific T cell engagers has shown efficacy in patients with hematologic malignancies and uveal melanoma. Antitumor effects of bispecific T cell engagers in most solid tumors are limited due to their short serum half-life and insufficient tumor concentration. We designed a novel serotype 5/3 oncolytic adenovirus encoding a human mucin1 antibody and the human CD3 receptor, Ad5/3-E2F-d24-aMUC1aCD3 (TILT-321). TILT-321 is engineered to replicate only in cancer cells, leading to a high concentration of the aMUC1aCD3 molecule in the tumor microenvironment. Infection and cell viability assays were performed to determine the oncolytic potential of the novel construct. The functionality of the virus-derived aMUC1aCD3 was evaluated in vitro. When TILT-321 was combined with allogeneic T cells, rapid tumor cell lysis was observed. TILT-321-infected cells secreted functional aMUC1aCD3, as shown by increased T cell activity and its binding to MUC1 and CD3. In vivo, TILT-321 treatment led to effective antitumor efficacy mediated by increased intratumoral T cell activity in an A549 and patient-derived ovarian cancer xenograft mouse model humanized with peripheral blood mononuclear cells (PBMC). This study provides a proof of concept for an effective strategy to overcome the key limitations of recombinant bispecific T cell engager delivery for solid tumor treatment.
{"title":"Oncolytic adenovirus coding for bispecific T cell engager against human MUC-1 potentiates T cell response against solid tumors.","authors":"Saru Basnet, Joao M Santos, Dafne C A Quixabeira, James H A Clubb, Susanna A M Grönberg-Vähä-Koskela, Victor Arias, Santeri Pakola, Tatiana V Kudling, Camilla Heiniö, Riikka Havunen, Victor Cervera-Carrascon, Suvi Sorsa, Marjukka Anttila, Anna Kanerva, Akseli Hemminki","doi":"10.1016/j.omto.2022.12.007","DOIUrl":"https://doi.org/10.1016/j.omto.2022.12.007","url":null,"abstract":"<p><p>Immunotherapy with bispecific T cell engagers has shown efficacy in patients with hematologic malignancies and uveal melanoma. Antitumor effects of bispecific T cell engagers in most solid tumors are limited due to their short serum half-life and insufficient tumor concentration. We designed a novel serotype 5/3 oncolytic adenovirus encoding a human mucin1 antibody and the human CD3 receptor, Ad5/3-E2F-d24-aMUC1aCD3 (TILT-321). TILT-321 is engineered to replicate only in cancer cells, leading to a high concentration of the aMUC1aCD3 molecule in the tumor microenvironment. Infection and cell viability assays were performed to determine the oncolytic potential of the novel construct. The functionality of the virus-derived aMUC1aCD3 was evaluated <i>in vitro</i>. When TILT-321 was combined with allogeneic T cells, rapid tumor cell lysis was observed. TILT-321-infected cells secreted functional aMUC1aCD3, as shown by increased T cell activity and its binding to MUC1 and CD3. <i>In vivo</i>, TILT-321 treatment led to effective antitumor efficacy mediated by increased intratumoral T cell activity in an A549 and patient-derived ovarian cancer xenograft mouse model humanized with peripheral blood mononuclear cells (PBMC). This study provides a proof of concept for an effective strategy to overcome the key limitations of recombinant bispecific T cell engager delivery for solid tumor treatment.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a3/00/main.PMC9842968.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9178066","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}
Breast cancer is the leading cause of cancer-related deaths in females worldwide, and the liver is one of the most common sites of distant metastases in breast cancer patients. Patients with breast cancer liver metastases face limited treatment options, and drug resistance is highly prevalent, leading to a poor prognosis and a short survival. Liver metastases respond extremely poorly to immunotherapy and have shown resistance to treatments such as chemotherapy and targeted therapies. Therefore, to develop and to optimize treatment strategies as well as to explore potential therapeutic approaches, it is crucial to understand the mechanisms of drug resistance in breast cancer liver metastases patients. In this review, we summarize recent advances in the research of drug resistance mechanisms in breast cancer liver metastases and discuss their therapeutic potential for improving patient prognoses and outcomes.
{"title":"Mechanisms of drug resistance in breast cancer liver metastases: Dilemmas and opportunities.","authors":"Chun-Yan Yan, Meng-Lu Zhao, Ya-Nan Wei, Xi-He Zhao","doi":"10.1016/j.omto.2023.02.001","DOIUrl":"https://doi.org/10.1016/j.omto.2023.02.001","url":null,"abstract":"<p><p>Breast cancer is the leading cause of cancer-related deaths in females worldwide, and the liver is one of the most common sites of distant metastases in breast cancer patients. Patients with breast cancer liver metastases face limited treatment options, and drug resistance is highly prevalent, leading to a poor prognosis and a short survival. Liver metastases respond extremely poorly to immunotherapy and have shown resistance to treatments such as chemotherapy and targeted therapies. Therefore, to develop and to optimize treatment strategies as well as to explore potential therapeutic approaches, it is crucial to understand the mechanisms of drug resistance in breast cancer liver metastases patients. In this review, we summarize recent advances in the research of drug resistance mechanisms in breast cancer liver metastases and discuss their therapeutic potential for improving patient prognoses and outcomes.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/80/70/main.PMC9969274.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10625881","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}
Endogenous microRNAs (miRNA) in tumors are currently under exhaustive investigation as potential therapeutic agents for cancer treatment. Nevertheless, RNase degradation, inefficient and untargeted delivery, limited biological effect, and currently unclear side effects remain unsettled issues that frustrate clinical application. To address this, a versatile targeted delivery system for multiple therapeutic and diagnostic agents should be adapted for miRNA. In this study, we developed membrane-coated PLGA-b-PEG DC-chol nanoparticles (m-PPDCNPs) co-encapsulating doxorubicin (Dox) and miRNA-190-Cy7. Such a system showed low biotoxicity, high loading efficiency, and superior targeting ability. Systematic delivery of m-PPDCNPs in mouse models showed exceptionally specific tumor accumulation. Sustained release of miR-190 inhibited tumor angiogenesis, tumor growth, and migration by regulating a large group of angiogenic effectors. Moreover, m-PPDCNPs also enhanced the sensitivity of Dox by suppressing TGF-β signal in colorectal cancer cell lines and mouse models. Together, our results demonstrate a stimulating and promising m-PPDCNPs nanoplatform for colorectal cancer theranostics.
{"title":"A cancer cell membrane coated, doxorubicin and microRNA co-encapsulated nanoplatform for colorectal cancer theranostics.","authors":"Sihao Zhu, Ziyuan Li, Dongye Zheng, Yue Yu, Jing Xiang, Xiao Ma, Dongqing Xu, Jiajun Qiu, Ziyu Yang, Zhiyi Wang, Jun Li, Hongfang Sun, Weiqiang Chen, Xiangxi Meng, Yanye Lu, Qiushi Ren","doi":"10.1016/j.omto.2022.12.002","DOIUrl":"https://doi.org/10.1016/j.omto.2022.12.002","url":null,"abstract":"<p><p>Endogenous microRNAs (miRNA) in tumors are currently under exhaustive investigation as potential therapeutic agents for cancer treatment. Nevertheless, RNase degradation, inefficient and untargeted delivery, limited biological effect, and currently unclear side effects remain unsettled issues that frustrate clinical application. To address this, a versatile targeted delivery system for multiple therapeutic and diagnostic agents should be adapted for miRNA. In this study, we developed membrane-coated PLGA-b-PEG DC-chol nanoparticles (m-PPDCNPs) co-encapsulating doxorubicin (Dox) and miRNA-190-Cy7. Such a system showed low biotoxicity, high loading efficiency, and superior targeting ability. Systematic delivery of m-PPDCNPs in mouse models showed exceptionally specific tumor accumulation. Sustained release of miR-190 inhibited tumor angiogenesis, tumor growth, and migration by regulating a large group of angiogenic effectors. Moreover, m-PPDCNPs also enhanced the sensitivity of Dox by suppressing TGF-β signal in colorectal cancer cell lines and mouse models. Together, our results demonstrate a stimulating and promising m-PPDCNPs nanoplatform for colorectal cancer theranostics.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9937835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9317499","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}
The tumor microenvironment (TME) comprises a variety of immune cells, among which T cells exert a prominent axial role in tumor development or anti-tumor responses in patients with breast cancer (BC). High or low levels of anti-inflammatory cytokines, such as transforming growth factor β, in the absence or presence of proinflammatory cytokines, such as interleukin-6 (IL-6), delineate the fate of T cells toward either regulatory T (Treg) or T helper 17 (Th17) cells, respectively. The transitional state of RORγt+Foxp3+ Treg (IL-17-producing Treg) resides in the middle of this reciprocal polarization, which is known as Treg/IL-17-producing Treg/Th17 cell axis. TME secretome, including microRNAs, cytokines, and extracellular vesicles, can significantly affect this axis. Furthermore, immune checkpoint inhibitors may be used to reconstruct immune cells; however, some of these novel therapies may favor tumor development. Therefore, understanding secretory and cell-associated factors involved in their differentiation or polarization and functions may be targeted for BC management. This review discusses microRNAs, cytokines, and extracellular vesicles (as secretome), as well as transcription factors and immune checkpoints (as cell-associated factors), which influence the Treg/IL-17-producing Treg/Th17 cell axis in BC. Furthermore, approved or ongoing clinical trials related to the modulation of this axis in the TME of BC are described to broaden new horizons of promising therapeutic approaches.
肿瘤微环境(tumor microenvironment, TME)由多种免疫细胞组成,其中T细胞在乳腺癌(BC)患者的肿瘤发展或抗肿瘤反应中发挥着突出的轴向作用。高或低水平的抗炎细胞因子,如转化生长因子β,在缺乏或存在促炎细胞因子,如白细胞介素-6 (IL-6)的情况下,分别描绘了T细胞对调节性T (Treg)或T辅助17 (Th17)细胞的命运。rorγ - t+Foxp3+ Treg(产生il -17的Treg)的过渡状态位于这种互反极化的中间,称为Treg/ il -17产生的Treg/Th17细胞轴。TME分泌组,包括microrna、细胞因子和细胞外囊泡,可以显著影响这一轴。此外,免疫检查点抑制剂可用于重建免疫细胞;然而,其中一些新疗法可能有利于肿瘤的发展。因此,了解参与其分化或极化和功能的分泌和细胞相关因子可能是BC管理的目标。本文综述了影响BC中Treg/ il -17生成的Treg/Th17细胞轴的microrna、细胞因子、细胞外囊泡(作为分泌组)以及转录因子和免疫检查点(作为细胞相关因子)。此外,已批准或正在进行的与BC TME中该轴调节相关的临床试验为有希望的治疗方法开辟了新的视野。
{"title":"Breast cancer tumor microenvironment affects Treg/IL-17-producing Treg/Th17 cell axis: Molecular and therapeutic perspectives.","authors":"Farhad Seif, Zahra Torki, Hamidreza Zalpoor, Mehran Habibi, Majid Pornour","doi":"10.1016/j.omto.2023.01.001","DOIUrl":"https://doi.org/10.1016/j.omto.2023.01.001","url":null,"abstract":"<p><p>The tumor microenvironment (TME) comprises a variety of immune cells, among which T cells exert a prominent axial role in tumor development or anti-tumor responses in patients with breast cancer (BC). High or low levels of anti-inflammatory cytokines, such as transforming growth factor β, in the absence or presence of proinflammatory cytokines, such as interleukin-6 (IL-6), delineate the fate of T cells toward either regulatory T (Treg) or T helper 17 (Th17) cells, respectively. The transitional state of RORγt<sup>+</sup>Foxp3<sup>+</sup> Treg (IL-17-producing Treg) resides in the middle of this reciprocal polarization, which is known as Treg/IL-17-producing Treg/Th17 cell axis. TME secretome, including microRNAs, cytokines, and extracellular vesicles, can significantly affect this axis. Furthermore, immune checkpoint inhibitors may be used to reconstruct immune cells; however, some of these novel therapies may favor tumor development. Therefore, understanding secretory and cell-associated factors involved in their differentiation or polarization and functions may be targeted for BC management. This review discusses microRNAs, cytokines, and extracellular vesicles (as secretome), as well as transcription factors and immune checkpoints (as cell-associated factors), which influence the Treg/IL-17-producing Treg/Th17 cell axis in BC. Furthermore, approved or ongoing clinical trials related to the modulation of this axis in the TME of BC are described to broaden new horizons of promising therapeutic approaches.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9922830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10767181","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 : 2023-03-16DOI: 10.1016/j.omto.2023.01.002
Lukasz Kuryk, Anne-Sophie W Møller
Immunotherapy of metastatic melanoma (MM) has vastly improved the longevity of only a minority of patients. To broaden the repertoire of agents against MM, we investigated the effectiveness of locally interrupting tumor blood endothelial cell proliferation and angiogenesis, arginine deprivation, or both on the growth of melanoma by constructing and characterizing the effectiveness of four oncolytic adenoviruses. ONCOS-207 (which expressed tissue inhibitor of metalloprotease type 2 [TIMP2]), ONCOS-209 (which expressed peptidyl arginine deiminase [PADI1]), and ONCOS-210 and ONCOS-212 (which expressed both TIMP2 and PADI1) exhibited oncolytic activity against four melanoma cell lines in vitro. ONCOS-212 treatments significantly inhibited tumor growth in an A2058 tumor model in nude mice compared with vehicle control. The inhibitory effects of the two transgenes of ONCOS-212 on tumor growth appeared to be synergistic. These viruses also significantly inhibited tumor growth in a humanized NOG model of melanoma (A2058 xenograft). All viruses significantly increased the percentage of activated CD8+ T cells in the tumor-infiltrating lymphocytes. The abscopal effect of ONCOS-212 treatments in the A2058 tumor challenge model in hNOG mice supports the hypothesis that the human immune response contributes to the anti-tumor activity of ONCOS-212. These results support the further development of ONCOS-212 for cancer treatment.
{"title":"Next generation oncolytic viruses expressing PADI1 and TIMP2 exhibit anti-tumor activity against melanoma in nude and humanized mouse models.","authors":"Lukasz Kuryk, Anne-Sophie W Møller","doi":"10.1016/j.omto.2023.01.002","DOIUrl":"https://doi.org/10.1016/j.omto.2023.01.002","url":null,"abstract":"<p><p>Immunotherapy of metastatic melanoma (MM) has vastly improved the longevity of only a minority of patients. To broaden the repertoire of agents against MM, we investigated the effectiveness of locally interrupting tumor blood endothelial cell proliferation and angiogenesis, arginine deprivation, or both on the growth of melanoma by constructing and characterizing the effectiveness of four oncolytic adenoviruses. ONCOS-207 (which expressed tissue inhibitor of metalloprotease type 2 [TIMP2]), ONCOS-209 (which expressed peptidyl arginine deiminase [PADI1]), and ONCOS-210 and ONCOS-212 (which expressed both TIMP2 and PADI1) exhibited oncolytic activity against four melanoma cell lines <i>in vitro</i>. ONCOS-212 treatments significantly inhibited tumor growth in an A2058 tumor model in nude mice compared with vehicle control. The inhibitory effects of the two transgenes of ONCOS-212 on tumor growth appeared to be synergistic. These viruses also significantly inhibited tumor growth in a humanized NOG model of melanoma (A2058 xenograft). All viruses significantly increased the percentage of activated CD8+ T cells in the tumor-infiltrating lymphocytes. The abscopal effect of ONCOS-212 treatments in the A2058 tumor challenge model in hNOG mice supports the hypothesis that the human immune response contributes to the anti-tumor activity of ONCOS-212. These results support the further development of ONCOS-212 for cancer treatment.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9922816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10755257","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}