Franziska Oliveri, Linda Neher, Ronja Pscheid, Isabel Sewald, Sowmya Gowdavally, Annika C Betzler, Jaqueline Hallitsch, Jens Greve, Simon Laban, Sebastian Schmid, Thomas K Hoffmann, Patrick J Schuler, Cornelia Brunner
{"title":"hpv阳性头颈部鳞状细胞癌小鼠模型中适应性免疫反应的表征及其对人类疾病的影响","authors":"Franziska Oliveri, Linda Neher, Ronja Pscheid, Isabel Sewald, Sowmya Gowdavally, Annika C Betzler, Jaqueline Hallitsch, Jens Greve, Simon Laban, Sebastian Schmid, Thomas K Hoffmann, Patrick J Schuler, Cornelia Brunner","doi":"10.1007/s00262-024-03907-y","DOIUrl":null,"url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with a poor prognosis for survival. Risk factors include alcohol and tobacco abuse and infection with human papilloma virus (HPV). To enhance anti-tumor immune responses immunotherapeutic approaches are approved for recurrent metastatic disease but only approx. 20% of patients respond to checkpoint blockade of the PD-1/PD-L1 axis. Therefore, preclinical research is needed to better understand molecular and cellular processes and to identify new therapeutic targets. Immunocompetent mouse models can serve these purposes but only few are currently available for HPV-positive HNSCC. Here, we established a mouse cell line overexpressing the oncogenes E6/E7 of the HPV16 genome as well as a constitutively active form of H-Ras and studied the anti-tumor immune response upon orthotopic tumor growth at the floor of the mouth. Moreover, we analyzed the same immunoregulatory pathways in samples of HPV-positive cancer patients. T cells in the tumor of mice and humans exhibited high expression of CD39 and CD73, two ectoenzymes involved in the production of immunosuppressive adenosine from ATP, along with increased expression of PD-1, LAG-3 and GITR. Additionally, B cell responses were elevated in tumor-bearing mice, seen as an increase of germinal center, immunoregulatory marginal zone and follicular B cell subtypes. Taken together, this study suggests that the generated mouse model shares characteristics with human disease and can thus be used as a platform to study anti-tumor responses in HPV-positive HNSCC which will help to identify novel therapeutic targets.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 2","pages":"66"},"PeriodicalIF":4.6000,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698698/pdf/","citationCount":"0","resultStr":"{\"title\":\"Characterization of the adaptive immune response in a mouse model for HPV-positive head and neck squamous cell carcinoma with implications to human disease.\",\"authors\":\"Franziska Oliveri, Linda Neher, Ronja Pscheid, Isabel Sewald, Sowmya Gowdavally, Annika C Betzler, Jaqueline Hallitsch, Jens Greve, Simon Laban, Sebastian Schmid, Thomas K Hoffmann, Patrick J Schuler, Cornelia Brunner\",\"doi\":\"10.1007/s00262-024-03907-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with a poor prognosis for survival. Risk factors include alcohol and tobacco abuse and infection with human papilloma virus (HPV). To enhance anti-tumor immune responses immunotherapeutic approaches are approved for recurrent metastatic disease but only approx. 20% of patients respond to checkpoint blockade of the PD-1/PD-L1 axis. Therefore, preclinical research is needed to better understand molecular and cellular processes and to identify new therapeutic targets. Immunocompetent mouse models can serve these purposes but only few are currently available for HPV-positive HNSCC. Here, we established a mouse cell line overexpressing the oncogenes E6/E7 of the HPV16 genome as well as a constitutively active form of H-Ras and studied the anti-tumor immune response upon orthotopic tumor growth at the floor of the mouth. Moreover, we analyzed the same immunoregulatory pathways in samples of HPV-positive cancer patients. T cells in the tumor of mice and humans exhibited high expression of CD39 and CD73, two ectoenzymes involved in the production of immunosuppressive adenosine from ATP, along with increased expression of PD-1, LAG-3 and GITR. Additionally, B cell responses were elevated in tumor-bearing mice, seen as an increase of germinal center, immunoregulatory marginal zone and follicular B cell subtypes. Taken together, this study suggests that the generated mouse model shares characteristics with human disease and can thus be used as a platform to study anti-tumor responses in HPV-positive HNSCC which will help to identify novel therapeutic targets.</p>\",\"PeriodicalId\":9595,\"journal\":{\"name\":\"Cancer Immunology, Immunotherapy\",\"volume\":\"74 2\",\"pages\":\"66\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2025-01-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698698/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Immunology, Immunotherapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00262-024-03907-y\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Immunology, Immunotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00262-024-03907-y","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
头颈部鳞状细胞癌(HNSCC)是全球第七大常见癌症,预后不良,生存率低。危险因素包括酗酒和吸烟以及感染人类乳头瘤病毒(HPV)。为增强抗肿瘤免疫反应,免疫治疗方法已被批准用于治疗复发性转移性疾病,但只有约 20% 的患者对 PD-1/PD-L1 轴的检查点阻断产生反应。因此,需要进行临床前研究,以更好地了解分子和细胞过程,并确定新的治疗靶点。免疫功能健全的小鼠模型可以达到这些目的,但目前只有少数小鼠模型可用于 HPV 阳性 HNSCC。在这里,我们建立了一种过表达 HPV16 基因组中的致癌基因 E6/E7 以及组成型活性 H-Ras 的小鼠细胞系,并研究了肿瘤在口腔底部正位生长时的抗肿瘤免疫反应。此外,我们还分析了 HPV 阳性癌症患者样本中的相同免疫调节途径。小鼠和人类肿瘤中的 T 细胞表现出 CD39 和 CD73 的高表达,CD39 和 CD73 是两种参与从 ATP 生成免疫抑制腺苷的外酶,同时 PD-1、LAG-3 和 GITR 的表达也有所增加。此外,肿瘤小鼠的 B 细胞反应增强,表现为生殖中心、免疫调节边缘区和滤泡 B 细胞亚型的增加。综上所述,这项研究表明所生成的小鼠模型与人类疾病具有相同的特征,因此可用作研究 HPV 阳性 HNSCC 抗肿瘤反应的平台,这将有助于确定新的治疗靶点。
Characterization of the adaptive immune response in a mouse model for HPV-positive head and neck squamous cell carcinoma with implications to human disease.
Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with a poor prognosis for survival. Risk factors include alcohol and tobacco abuse and infection with human papilloma virus (HPV). To enhance anti-tumor immune responses immunotherapeutic approaches are approved for recurrent metastatic disease but only approx. 20% of patients respond to checkpoint blockade of the PD-1/PD-L1 axis. Therefore, preclinical research is needed to better understand molecular and cellular processes and to identify new therapeutic targets. Immunocompetent mouse models can serve these purposes but only few are currently available for HPV-positive HNSCC. Here, we established a mouse cell line overexpressing the oncogenes E6/E7 of the HPV16 genome as well as a constitutively active form of H-Ras and studied the anti-tumor immune response upon orthotopic tumor growth at the floor of the mouth. Moreover, we analyzed the same immunoregulatory pathways in samples of HPV-positive cancer patients. T cells in the tumor of mice and humans exhibited high expression of CD39 and CD73, two ectoenzymes involved in the production of immunosuppressive adenosine from ATP, along with increased expression of PD-1, LAG-3 and GITR. Additionally, B cell responses were elevated in tumor-bearing mice, seen as an increase of germinal center, immunoregulatory marginal zone and follicular B cell subtypes. Taken together, this study suggests that the generated mouse model shares characteristics with human disease and can thus be used as a platform to study anti-tumor responses in HPV-positive HNSCC which will help to identify novel therapeutic targets.
期刊介绍:
Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions.
The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.