Abstract The etiology and pathogenesis of pemphigus vulgaris (PV) entail intricate interactions between immune cells and epithelial cells. However, the specific subtypes of immune cells involved in PV, along with their respective roles, remain elusive. Likewise, the precise functions and mechanisms by which glucocorticoids affect cell types within the disease context require further elucidation. To address these knowledge gaps, we performed 5′ single-cell RNA sequencing, combined with V(D)J enrichment on buccal mucosal lesions and peripheral blood samples from treatment-naive patients with PV, in conjunction with post-treatment peripheral blood samples obtained after oral prednisone treatment. Our findings suggest that the IL-1α signaling pathway, myeloid APCs, inflammatory CD8+ resident memory T cells, and dysfunctional CD4+ regulatory T cells are involved in the pathogenesis of PV. Part of these findings were validated by immunohistochemical assays and multiplex immunofluorescence assays. Furthermore, our results highlight the significant impact of prednisone treatment on monocytes and mucosal-associated invariant T cells while revealing a limited effect on CD4+ regulatory T cells. Additionally, we present the CDR3 amino acid sequence of BCR related to PV disease and investigate the characteristics of TCR/BCR clonotypes. In conclusion, our study provides a comprehensive understanding of PV, particularly focusing on the mucosal-dominant type, and sheds light on the effects of glucocorticoids within the PV context. These insights hold promise for the development of new therapeutic strategies in this autoimmune disorder.
摘要 丘疹性荨麻疹（PV）的病因和发病机制涉及免疫细胞和上皮细胞之间错综复杂的相互作用。然而，参与丘疹性荨麻疹的免疫细胞的具体亚型及其各自的作用仍然难以确定。同样，糖皮质激素在疾病背景下影响细胞类型的确切功能和机制也需要进一步阐明。为了填补这些知识空白，我们结合 V(D)J 富集技术，对未经治疗的鼻咽癌患者的口腔黏膜病变和外周血样本进行了 5′单细胞 RNA 测序，同时还检测了口服泼尼松治疗后获得的外周血样本。我们的研究结果表明，IL-1α 信号通路、骨髓 APCs、炎症性 CD8+ 常驻记忆 T 细胞和功能失调的 CD4+ 调节性 T 细胞参与了 PV 的发病机制。部分研究结果通过免疫组化检测和多重免疫荧光检测得到了验证。此外，我们的研究结果突显了泼尼松治疗对单核细胞和粘膜相关不变性 T 细胞的重大影响，而对 CD4+ 调节性 T 细胞的影响有限。此外，我们还提出了与 PV 疾病相关的 BCR 的 CDR3 氨基酸序列，并研究了 TCR/BCR 克隆型的特征。总之，我们的研究提供了对真性红斑狼疮的全面认识，尤其是对粘膜主导型真性红斑狼疮的认识，并揭示了糖皮质激素在真性红斑狼疮中的作用。这些见解为开发治疗这种自身免疫性疾病的新策略带来了希望。
{"title":"Single-Cell Transcriptomes and Immune Repertoires Reveal the Cell State and Molecular Changes in Pemphigus Vulgaris","authors":"Shumin Duan, Qionghua Li, Fei Wang, Wenjing Kuang, Yunmei Dong, Dan Liu, Jiongke Wang, Wei Li, Qianming Chen, Xin Zeng, Taiwen Li","doi":"10.4049/jimmunol.2300312","DOIUrl":"https://doi.org/10.4049/jimmunol.2300312","url":null,"abstract":"<jats:title>Abstract</jats:title> The etiology and pathogenesis of pemphigus vulgaris (PV) entail intricate interactions between immune cells and epithelial cells. However, the specific subtypes of immune cells involved in PV, along with their respective roles, remain elusive. Likewise, the precise functions and mechanisms by which glucocorticoids affect cell types within the disease context require further elucidation. To address these knowledge gaps, we performed 5′ single-cell RNA sequencing, combined with V(D)J enrichment on buccal mucosal lesions and peripheral blood samples from treatment-naive patients with PV, in conjunction with post-treatment peripheral blood samples obtained after oral prednisone treatment. Our findings suggest that the IL-1α signaling pathway, myeloid APCs, inflammatory CD8+ resident memory T cells, and dysfunctional CD4+ regulatory T cells are involved in the pathogenesis of PV. Part of these findings were validated by immunohistochemical assays and multiplex immunofluorescence assays. Furthermore, our results highlight the significant impact of prednisone treatment on monocytes and mucosal-associated invariant T cells while revealing a limited effect on CD4+ regulatory T cells. Additionally, we present the CDR3 amino acid sequence of BCR related to PV disease and investigate the characteristics of TCR/BCR clonotypes. In conclusion, our study provides a comprehensive understanding of PV, particularly focusing on the mucosal-dominant type, and sheds light on the effects of glucocorticoids within the PV context. These insights hold promise for the development of new therapeutic strategies in this autoimmune disorder.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"114 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138823944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-20DOI: 10.4049/jimmunol.2300650
Henrique B. Abdalla, Luciano Puhl, Carla Alvarez Rivas, Yu-Chiao Wu, Paola Rojas, Carlos Antonio Trindade-da-Silva, Bruce D. Hammock, Krishna R. Maddipati, Mariana Q. S. Soares, Juliana T. Clemente-Napimoga, Alpdogan Kantarci, Marcelo H. Napimoga, Thomas E. Van Dyke
Abstract Epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids are short-acting lipids involved in resolution of inflammation. Their short half-life, due to its metabolism by soluble epoxide hydrolase (sEH), limits their effects. Specialized proresolving mediators (SPMs) are endogenous regulatory lipids insufficiently synthesized in uncontrolled and chronic inflammation. Using an experimental periodontitis model, we pharmacologically inhibited sEH, examining its impact on T cell activation and systemic SPM production. In humans, we analyzed sEH in the gingival tissue of periodontitis patients. Mice were treated with sEH inhibitor (sEHi) and/or EETs before ligature placement and treated for 14 d. Bone parameters were assessed by microcomputed tomography and methylene blue staining. Blood plasma metabololipidomics were carried out to quantify SPM levels. We also determined T cell activation by reverse transcription–quantitative PCR and flow cytometry in cervical lymph nodes. Human gingival samples were collected to analyze sEH using ELISA and electrophoresis. Data reveal that pharmacological sEHi abrogated bone resorption and preserved bone architecture. Metabololipidomics revealed that sEHi enhances lipoxin A4, lipoxin B4, resolvin E2, and resolvin D6. An increased percentage of regulatory T cells over Th17 was noted in sEHi-treated mice. Lastly, inflamed human gingival tissues presented higher levels and expression of sEH than did healthy gingivae, being positively correlated with periodontitis severity. Our findings indicate that sEHi preserves bone architecture and stimulates SPM production, associated with regulatory actions on T cells favoring resolution of inflammation. Because sEH is enhanced in human gingivae from patients with periodontitis and connected with disease severity, inhibition may prove to be an attractive target for managing osteolytic inflammatory diseases.
{"title":"Modulating the sEH/EETs Axis Restrains Specialized Proresolving Mediator Impairment and Regulates T Cell Imbalance in Experimental Periodontitis","authors":"Henrique B. Abdalla, Luciano Puhl, Carla Alvarez Rivas, Yu-Chiao Wu, Paola Rojas, Carlos Antonio Trindade-da-Silva, Bruce D. Hammock, Krishna R. Maddipati, Mariana Q. S. Soares, Juliana T. Clemente-Napimoga, Alpdogan Kantarci, Marcelo H. Napimoga, Thomas E. Van Dyke","doi":"10.4049/jimmunol.2300650","DOIUrl":"https://doi.org/10.4049/jimmunol.2300650","url":null,"abstract":"<jats:title>Abstract</jats:title> Epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids are short-acting lipids involved in resolution of inflammation. Their short half-life, due to its metabolism by soluble epoxide hydrolase (sEH), limits their effects. Specialized proresolving mediators (SPMs) are endogenous regulatory lipids insufficiently synthesized in uncontrolled and chronic inflammation. Using an experimental periodontitis model, we pharmacologically inhibited sEH, examining its impact on T cell activation and systemic SPM production. In humans, we analyzed sEH in the gingival tissue of periodontitis patients. Mice were treated with sEH inhibitor (sEHi) and/or EETs before ligature placement and treated for 14 d. Bone parameters were assessed by microcomputed tomography and methylene blue staining. Blood plasma metabololipidomics were carried out to quantify SPM levels. We also determined T cell activation by reverse transcription–quantitative PCR and flow cytometry in cervical lymph nodes. Human gingival samples were collected to analyze sEH using ELISA and electrophoresis. Data reveal that pharmacological sEHi abrogated bone resorption and preserved bone architecture. Metabololipidomics revealed that sEHi enhances lipoxin A4, lipoxin B4, resolvin E2, and resolvin D6. An increased percentage of regulatory T cells over Th17 was noted in sEHi-treated mice. Lastly, inflamed human gingival tissues presented higher levels and expression of sEH than did healthy gingivae, being positively correlated with periodontitis severity. Our findings indicate that sEHi preserves bone architecture and stimulates SPM production, associated with regulatory actions on T cells favoring resolution of inflammation. Because sEH is enhanced in human gingivae from patients with periodontitis and connected with disease severity, inhibition may prove to be an attractive target for managing osteolytic inflammatory diseases.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138823859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-20DOI: 10.4049/jimmunol.2200496
Alexander David Barrow, Marina Cella, Melissa Anne Edeling, Md. Abdullah-Al-Kamran Khan, Luisa Cervantes-Barragan, Mattia Bugatti, Christian Schmedt, William Vermi, Marco Colonna
Abstract NKp44 is a human receptor originally found on activated NK cells, group 1 and group 3 innate lymphoid cells that binds dimers of platelet-derived growth factor D (PDGF-DD). NKp44 is also expressed on tissue plasmacytoid dendritic cells (PDCs), but NKp44-PDGF-DD interaction on PDCs remains unstudied. Engagement of NKp44 with PDGF-DD in vitro enhanced PDC secretion of IFN-α, TNF, and IL-6 in response to the TLR9 ligand CpG-ODN, but not TLR7/8 ligands. In tissues, PDCs were found in close contact with PDGF-DD–expressing cells in the high endothelial venules and epithelium of tonsils, melanomas, and skin lesions infected with Molluscum contagiosum. Recombinant PDGF-DD enhanced the serum IFN-α response to systemic HSV-1 infection in a humanized mouse model. We conclude that NKp44 integrates with TLR9 signaling to enhance PDC cytokine production. These findings may have bearings for immune responses to TLR9-based adjuvants, therapy for tumors expressing PDGF-DD, and infections with DNA viruses that induce PDGF-DD expression to enhance viral spread.
{"title":"Cutting Edge: PDGF-DD Binding to NKp44 Costimulates TLR9 Signaling and Proinflammatory Cytokine Secretion in Human Plasmacytoid Dendritic Cells","authors":"Alexander David Barrow, Marina Cella, Melissa Anne Edeling, Md. Abdullah-Al-Kamran Khan, Luisa Cervantes-Barragan, Mattia Bugatti, Christian Schmedt, William Vermi, Marco Colonna","doi":"10.4049/jimmunol.2200496","DOIUrl":"https://doi.org/10.4049/jimmunol.2200496","url":null,"abstract":"<jats:title>Abstract</jats:title> NKp44 is a human receptor originally found on activated NK cells, group 1 and group 3 innate lymphoid cells that binds dimers of platelet-derived growth factor D (PDGF-DD). NKp44 is also expressed on tissue plasmacytoid dendritic cells (PDCs), but NKp44-PDGF-DD interaction on PDCs remains unstudied. Engagement of NKp44 with PDGF-DD in vitro enhanced PDC secretion of IFN-α, TNF, and IL-6 in response to the TLR9 ligand CpG-ODN, but not TLR7/8 ligands. In tissues, PDCs were found in close contact with PDGF-DD–expressing cells in the high endothelial venules and epithelium of tonsils, melanomas, and skin lesions infected with Molluscum contagiosum. Recombinant PDGF-DD enhanced the serum IFN-α response to systemic HSV-1 infection in a humanized mouse model. We conclude that NKp44 integrates with TLR9 signaling to enhance PDC cytokine production. These findings may have bearings for immune responses to TLR9-based adjuvants, therapy for tumors expressing PDGF-DD, and infections with DNA viruses that induce PDGF-DD expression to enhance viral spread.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138823756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-15DOI: 10.4049/jimmunol.2300063
Jennifer Peil, Christian Vossen, Felix Bock, Thomas Clahsen, Petra Schiller, Ludwig M. Heindl, Jacobus J. Bosch, F. Thomas Wunderlich, Claus Cursiefen, Simona L. Schlereth
Abstract Angiogenesis and immune protection are essential at the onset of tumorigenesis. Angiogenesis serves to nourish the tumor, and prevention of immune defenses, for example, by dendritic cells (DCs), allows tumor growth. In this study, we investigated whether there are factors with dual functions that are both angiogenic and immunomodulatory and represent a therapeutic target. We analyzed 1) innate immune responses intratumorally and in draining lymph nodes and 2) angiogenic factors in conjunctival melanoma (CM), a potentially lethal malignant tumor at the ocular surface whose immune and vascular responses are largely unknown. For this purpose, an HGF-Cdk4R24C model in immunocompetent C57BL/6 mice was used and revealed that CD103− type 2 classical DC (cDC2s) were the most abundant DC subtype in healthy conjunctiva, whereas in CM, CD103− cDC2s, CD103+ type 1 cDCs, monocyte-derived DCs, and plasmacytoid DCs were significantly increased. In our analysis of angiogenic factors in CM, the examination of 53 angiogenesis-related factors that might interact with DCs identified osteopontin (OPN) as a major tumor-derived protein that interacts with DCs. Consistent with these findings, 3) a dual therapeutic strategy that inhibited tumor cell function by an OPN blocking Ab while enhancing the immune response by cDC2 vaccination resulted in 35% failure of tumor development. Moreover, tumor progression, monocyte-derived DC infiltration, and intratumoral angiogenesis were significantly reduced, whereas survival and CD8+ T cell infiltration were increased in treated mice compared with the control group. Therefore, we identified OPN blockade in combination with cDC2 vaccination as a potential future therapeutic intervention for early stages of CM by combining antiangiogenic and host immune stimulating effects.
摘要 血管生成和免疫保护在肿瘤发生之初至关重要。血管生成为肿瘤提供营养，而树突状细胞（DCs）等免疫防御机制的阻碍则会使肿瘤生长。在这项研究中，我们探讨了是否存在具有双重功能的因子，它们既能促进血管生成，又能调节免疫，并成为治疗靶点。我们分析了：1）瘤内和引流淋巴结的先天性免疫反应；2）结膜黑色素瘤（CM）的血管生成因子，这是一种潜在的致命性眼表恶性肿瘤，其免疫和血管反应在很大程度上是未知的。为此，我们在免疫功能正常的 C57BL/6 小鼠中使用了 HGF-Cdk4R24C 模型，结果发现 CD103- 2 型经典 DC（cDC2s）是健康结膜中最丰富的 DC 亚型，而在 CM 中，CD103- cDC2s、CD103+ 1 型 cDCs、单核细胞衍生 DCs 和类浆细胞 DCs 显著增加。在我们对 CM 中血管生成因子的分析中，对 53 种可能与 DCs 相互作用的血管生成相关因子的研究发现，骨生成素（OPN）是一种与 DCs 相互作用的主要肿瘤衍生蛋白。与这些研究结果相一致，3) 通过 OPN 阻断抗体抑制肿瘤细胞功能，同时通过接种 cDC2 疫苗增强免疫反应的双重治疗策略导致 35% 的肿瘤发展失败。此外，与对照组相比，治疗组小鼠的肿瘤进展、单核细胞衍生 DC 浸润和瘤内血管生成明显减少，而存活率和 CD8+ T 细胞浸润增加。因此，我们将 OPN 阻断与 cDC2 疫苗接种结合起来，通过结合抗血管生成和宿主免疫刺激效应，确定为未来治疗 CM 早期阶段的一种潜在干预措施。
{"title":"Combined Osteopontin Blockade and Type 2 Classical Dendritic Cell Vaccination as Effective Synergetic Therapy for Conjunctival Melanoma","authors":"Jennifer Peil, Christian Vossen, Felix Bock, Thomas Clahsen, Petra Schiller, Ludwig M. Heindl, Jacobus J. Bosch, F. Thomas Wunderlich, Claus Cursiefen, Simona L. Schlereth","doi":"10.4049/jimmunol.2300063","DOIUrl":"https://doi.org/10.4049/jimmunol.2300063","url":null,"abstract":"<jats:title>Abstract</jats:title> Angiogenesis and immune protection are essential at the onset of tumorigenesis. Angiogenesis serves to nourish the tumor, and prevention of immune defenses, for example, by dendritic cells (DCs), allows tumor growth. In this study, we investigated whether there are factors with dual functions that are both angiogenic and immunomodulatory and represent a therapeutic target. We analyzed 1) innate immune responses intratumorally and in draining lymph nodes and 2) angiogenic factors in conjunctival melanoma (CM), a potentially lethal malignant tumor at the ocular surface whose immune and vascular responses are largely unknown. For this purpose, an HGF-Cdk4R24C model in immunocompetent C57BL/6 mice was used and revealed that CD103− type 2 classical DC (cDC2s) were the most abundant DC subtype in healthy conjunctiva, whereas in CM, CD103− cDC2s, CD103+ type 1 cDCs, monocyte-derived DCs, and plasmacytoid DCs were significantly increased. In our analysis of angiogenic factors in CM, the examination of 53 angiogenesis-related factors that might interact with DCs identified osteopontin (OPN) as a major tumor-derived protein that interacts with DCs. Consistent with these findings, 3) a dual therapeutic strategy that inhibited tumor cell function by an OPN blocking Ab while enhancing the immune response by cDC2 vaccination resulted in 35% failure of tumor development. Moreover, tumor progression, monocyte-derived DC infiltration, and intratumoral angiogenesis were significantly reduced, whereas survival and CD8+ T cell infiltration were increased in treated mice compared with the control group. Therefore, we identified OPN blockade in combination with cDC2 vaccination as a potential future therapeutic intervention for early stages of CM by combining antiangiogenic and host immune stimulating effects.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"128 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138686810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a persistent and irreversible side effect of antineoplastic agents. Patients with CIPN usually show chronic pain and sensory deficits with glove-and-stocking distribution. However, whether spinal neuronal microRNA (miR)-124 is involved in cisplatin-induced peripheral neuropathy remains to be studied. In this study, miR-124 was significantly reduced in the spinal dorsal horn in CIPN mice. Overexpression of neuronal miR-124 induced by injecting adeno-associated virus with neuron-specific promoter into the spinal cord of mice prevented the development of mechanical allodynia, sensory deficits, and the loss of intraepidermal nerve fibers induced by cisplatin. Meanwhile, cisplatin-induced M1 microglia activation and the release of proinflammatory cytokines were significantly inhibited by overexpression of neuronal miR-124. Furthermore, electroacupuncture (EA) treatment upregulated miR-124 expression in the spinal dorsal horn of CIPN mice. Interestingly, downregulation of spinal neuronal miR-124 significantly inhibited the regulatory effect of EA on CIPN and microglia activity as well as spinal neuroinflammation induced by cisplatin. These results demonstrate that spinal neuronal miR-124 is involved in the prevention and treatment of EA on cisplatin-induced peripheral neuropathy in mice. Our findings suggest that spinal neuronal miR-124 might be a potential target for EA effect, and we provide, to our knowledge, a new experimental basis for EA prevention of CIPN.
{"title":"Spinal Neuronal miR-124 Inhibits Microglial Activation and Contributes to Preventive Effect of Electroacupuncture on Chemotherapy-Induced Peripheral Neuropathy in Mice","authors":"Xiao-Chen Li, Hui Chen, Yu Chen, Yu-Xia Chu, Wen-Li Mi, Yan-Qing Wang, Qi-Liang Mao-Ying","doi":"10.4049/jimmunol.2300539","DOIUrl":"https://doi.org/10.4049/jimmunol.2300539","url":null,"abstract":"<jats:title>Abstract</jats:title> Chemotherapy-induced peripheral neuropathy (CIPN) is a persistent and irreversible side effect of antineoplastic agents. Patients with CIPN usually show chronic pain and sensory deficits with glove-and-stocking distribution. However, whether spinal neuronal microRNA (miR)-124 is involved in cisplatin-induced peripheral neuropathy remains to be studied. In this study, miR-124 was significantly reduced in the spinal dorsal horn in CIPN mice. Overexpression of neuronal miR-124 induced by injecting adeno-associated virus with neuron-specific promoter into the spinal cord of mice prevented the development of mechanical allodynia, sensory deficits, and the loss of intraepidermal nerve fibers induced by cisplatin. Meanwhile, cisplatin-induced M1 microglia activation and the release of proinflammatory cytokines were significantly inhibited by overexpression of neuronal miR-124. Furthermore, electroacupuncture (EA) treatment upregulated miR-124 expression in the spinal dorsal horn of CIPN mice. Interestingly, downregulation of spinal neuronal miR-124 significantly inhibited the regulatory effect of EA on CIPN and microglia activity as well as spinal neuroinflammation induced by cisplatin. These results demonstrate that spinal neuronal miR-124 is involved in the prevention and treatment of EA on cisplatin-induced peripheral neuropathy in mice. Our findings suggest that spinal neuronal miR-124 might be a potential target for EA effect, and we provide, to our knowledge, a new experimental basis for EA prevention of CIPN.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138631321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-13DOI: 10.4049/jimmunol.2300263
Ruud H. Wijdeven, Sietse J. Luk, Tom A. W. Schoufour, Sabina Y. van der Zanden, Marta Cabezuelo, Mirjam H. M. Heemskerk, Jacques Neefjes
Abstract MHC class I (MHC-I) molecules are critical for CD8+ T cell responses to viral infections and malignant cells, and tumors can downregulate MHC-I expression to promote immune evasion. In this study, using a genome-wide CRISPR screen on a human melanoma cell line, we identified the polycomb repressive complex 1 (PRC1) subunit PCGF1 and the deubiquitinating enzyme BAP1 as opposite regulators of MHC-I transcription. PCGF1 facilitates deposition of ubiquitin at H2AK119 at the MHC-I promoters to silence MHC-I, whereas BAP1 removes this modification to restore MHC-I expression. PCGF1 is widely expressed in tumors and its depletion increased MHC-I expression in multiple tumor lines, including MHC-Ilow tumors. In cells characterized by poor MHC-I expression, PRC1 and PRC2 act in parallel to impinge low transcription. However, PCGF1 depletion was sufficient to increase MHC-I expression and restore T cell–mediated killing of the tumor cells. Taken together, our data provide an additional layer of regulation of MHC-I expression in tumors: epigenetic silencing by PRC1 subunit PCGF1.
{"title":"Balanced Epigenetic Regulation of MHC Class I Expression in Tumor Cells by the Histone Ubiquitin Modifiers BAP1 and PCGF1","authors":"Ruud H. Wijdeven, Sietse J. Luk, Tom A. W. Schoufour, Sabina Y. van der Zanden, Marta Cabezuelo, Mirjam H. M. Heemskerk, Jacques Neefjes","doi":"10.4049/jimmunol.2300263","DOIUrl":"https://doi.org/10.4049/jimmunol.2300263","url":null,"abstract":"<jats:title>Abstract</jats:title> MHC class I (MHC-I) molecules are critical for CD8+ T cell responses to viral infections and malignant cells, and tumors can downregulate MHC-I expression to promote immune evasion. In this study, using a genome-wide CRISPR screen on a human melanoma cell line, we identified the polycomb repressive complex 1 (PRC1) subunit PCGF1 and the deubiquitinating enzyme BAP1 as opposite regulators of MHC-I transcription. PCGF1 facilitates deposition of ubiquitin at H2AK119 at the MHC-I promoters to silence MHC-I, whereas BAP1 removes this modification to restore MHC-I expression. PCGF1 is widely expressed in tumors and its depletion increased MHC-I expression in multiple tumor lines, including MHC-Ilow tumors. In cells characterized by poor MHC-I expression, PRC1 and PRC2 act in parallel to impinge low transcription. However, PCGF1 depletion was sufficient to increase MHC-I expression and restore T cell–mediated killing of the tumor cells. Taken together, our data provide an additional layer of regulation of MHC-I expression in tumors: epigenetic silencing by PRC1 subunit PCGF1.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"287 2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138631333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-13DOI: 10.4049/jimmunol.2300689
Shubhra Singh, Zhilan Xiao, Karishma Bavisi, Jason Roszik, Brenda D Melendez, Zhiqiang Wang, Mark J Cantwell, Richard E Davis, Greg Lizee, Patrick Hwu, Sattva S Neelapu, Willem W Overwijk, Manisha Singh
Abstract Singh, S., Z. Xiao, K. Bavisi, J. Roszik, B. D. Melendez, Z. Wang, M. J. Cantwell, R. E. Davis, G. Lizee, P. Hwu, S. S. Neelapu, W. W. Overwijk, and M. Singh. 2021. IL-1α mediates innate and acquired resistance to immunotherapy in melanoma. J. Immunol. 206: 1966–1975. The Materials and Methods section erroneously omitted the manufacturer and clone of one of the Ab reagents used under the heading “Tumor induction, treatment, and monitoring.” The second sentence in this section reads “Three days after tumor inoculation, mice were treated with i.p. injection of 200 μg of anti–CTLA-4 (9H10), anti-mouse Ly6G (1A8), anti–IL-1α (ALF-161), anti–IL-1β (B122), anti–IL-1R1 (JAMA-147), and/or 200 μg of anti–PD-L1 (10F.9G2) (all from Bio X Cell) or their isotype control Abs.” It should have read “Three days after tumor inoculation, mice were treated with i.p. injection of 200 μg of anti–CTLA-4 (9H10, Bio X Cell), anti-mouse Ly6G (1A8, Bio X Cell), anti–IL-1α (Flo1-2a, XBiotech), anti–IL-1β (B122, Bio X Cell), anti–IL-1R1 (JAMA-147, Bio X Cell), and/or 200 μg of anti–PD-L1 (10F.9G2, Bio X Cell) or their isotype control Abs.”
[摘要]Singh, S.， Z. Xiao, K. Bavisi, J. Roszik, B. D. Melendez, Z. Wang, M. J. Cantwell, R. E. Davis, G. Lizee, P. Hwu, S. S. Neelapu, W. W. Overwijk, M. Singh。2021。IL-1α介导黑色素瘤免疫治疗的先天和获得性耐药。[j] .中华医学杂志，2006(6):389 - 398。材料和方法部分错误地省略了标题“肿瘤诱导、治疗和监测”下使用的一种Ab试剂的制造商和克隆。本节第二句应该是“肿瘤接种3天后，小鼠腹腔注射200 μg抗ctla -4 (9H10)，抗小鼠Ly6G (1A8)，抗il -1α (ALF-161)，抗il -1β (B122)，抗il - 1r1 (JAMA-147)，和/或200 μg抗pd - l1 (10F.9G2)(全部来自Bio X细胞)或其同型对照抗体。”应该是“肿瘤接种3天后，小鼠腹腔注射200 μg抗ctla -4 (9H10, Bio X细胞)，抗小鼠Ly6G (1A8, Bio X细胞)。Bio X Cell)、抗il -1α (Flo1-2a, XBiotech)、抗il -1β (B122, Bio X Cell)、抗il - 1r1 (JAMA-147, Bio X Cell)和/或200 μg抗pd - l1 (10F。9G2, Bio X Cell)或其同型对照抗体。
{"title":"Corrections: IL-1α mediates innate and acquired resistance to immunotherapy in melanoma.","authors":"Shubhra Singh, Zhilan Xiao, Karishma Bavisi, Jason Roszik, Brenda D Melendez, Zhiqiang Wang, Mark J Cantwell, Richard E Davis, Greg Lizee, Patrick Hwu, Sattva S Neelapu, Willem W Overwijk, Manisha Singh","doi":"10.4049/jimmunol.2300689","DOIUrl":"https://doi.org/10.4049/jimmunol.2300689","url":null,"abstract":"<jats:title>Abstract</jats:title> Singh, S., Z. Xiao, K. Bavisi, J. Roszik, B. D. Melendez, Z. Wang, M. J. Cantwell, R. E. Davis, G. Lizee, P. Hwu, S. S. Neelapu, W. W. Overwijk, and M. Singh. 2021. IL-1α mediates innate and acquired resistance to immunotherapy in melanoma. J. Immunol. 206: 1966–1975. The Materials and Methods section erroneously omitted the manufacturer and clone of one of the Ab reagents used under the heading “Tumor induction, treatment, and monitoring.” The second sentence in this section reads “Three days after tumor inoculation, mice were treated with i.p. injection of 200 μg of anti–CTLA-4 (9H10), anti-mouse Ly6G (1A8), anti–IL-1α (ALF-161), anti–IL-1β (B122), anti–IL-1R1 (JAMA-147), and/or 200 μg of anti–PD-L1 (10F.9G2) (all from Bio X Cell) or their isotype control Abs.” It should have read “Three days after tumor inoculation, mice were treated with i.p. injection of 200 μg of anti–CTLA-4 (9H10, Bio X Cell), anti-mouse Ly6G (1A8, Bio X Cell), anti–IL-1α (Flo1-2a, XBiotech), anti–IL-1β (B122, Bio X Cell), anti–IL-1R1 (JAMA-147, Bio X Cell), and/or 200 μg of anti–PD-L1 (10F.9G2, Bio X Cell) or their isotype control Abs.”","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138631485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-13DOI: 10.4049/jimmunol.2300462
Bowen Hou, Yanyan Hu, Yuzhen Zhu, Xiaocui Wang, Wanyun Li, Jian Tang, Xian Jia, Jiayu Wang, Yu Cong, Minxue Quan, Hongying Yang, Haiping Zheng, Yuzhou Bao, Xiao Lei Chen, Hong-Rui Wang, Bing Xu, Nicholas R. J. Gascoigne, Guo Fu
Abstract SHP-1 (Src homology region 2 domain-containing phosphatase 1) is a well-known negative regulator of T cells, whereas its close homolog SHP-2 is the long-recognized main signaling mediator of the PD-1 inhibitory pathway. However, recent studies have challenged the requirement of SHP-2 in PD-1 signaling, and follow-up studies further questioned the alternative idea that SHP-1 may replace SHP-2 in its absence. In this study, we systematically investigate the role of SHP-1 alone or jointly with SHP-2 in CD8+ T cells in a series of gene knockout mice. We show that although SHP-1 negatively regulates CD8+ T cell effector function during acute lymphocytic choriomeningitis virus (LCMV) infection, it is dispensable for CD8+ T cell exhaustion during chronic LCMV infection. Moreover, in contrast to the mortality of PD-1 knockout mice upon chronic LCMV infection, mice double deficient for SHP-1 and SHP-2 in CD8+ T cells survived without immunopathology. Importantly, CD8+ T cells lacking both phosphatases still differentiate into exhausted cells and respond to PD-1 blockade. Finally, we found that SHP-1 and SHP-2 suppressed effector CD8+ T cell expansion at the early and late stages, respectively, during chronic LCMV infection.
{"title":"SHP-1 Regulates CD8+ T Cell Effector Function but Plays a Subtle Role with SHP-2 in T Cell Exhaustion Due to a Stage-Specific Nonredundant Functional Relay","authors":"Bowen Hou, Yanyan Hu, Yuzhen Zhu, Xiaocui Wang, Wanyun Li, Jian Tang, Xian Jia, Jiayu Wang, Yu Cong, Minxue Quan, Hongying Yang, Haiping Zheng, Yuzhou Bao, Xiao Lei Chen, Hong-Rui Wang, Bing Xu, Nicholas R. J. Gascoigne, Guo Fu","doi":"10.4049/jimmunol.2300462","DOIUrl":"https://doi.org/10.4049/jimmunol.2300462","url":null,"abstract":"<jats:title>Abstract</jats:title> SHP-1 (Src homology region 2 domain-containing phosphatase 1) is a well-known negative regulator of T cells, whereas its close homolog SHP-2 is the long-recognized main signaling mediator of the PD-1 inhibitory pathway. However, recent studies have challenged the requirement of SHP-2 in PD-1 signaling, and follow-up studies further questioned the alternative idea that SHP-1 may replace SHP-2 in its absence. In this study, we systematically investigate the role of SHP-1 alone or jointly with SHP-2 in CD8+ T cells in a series of gene knockout mice. We show that although SHP-1 negatively regulates CD8+ T cell effector function during acute lymphocytic choriomeningitis virus (LCMV) infection, it is dispensable for CD8+ T cell exhaustion during chronic LCMV infection. Moreover, in contrast to the mortality of PD-1 knockout mice upon chronic LCMV infection, mice double deficient for SHP-1 and SHP-2 in CD8+ T cells survived without immunopathology. Importantly, CD8+ T cells lacking both phosphatases still differentiate into exhausted cells and respond to PD-1 blockade. Finally, we found that SHP-1 and SHP-2 suppressed effector CD8+ T cell expansion at the early and late stages, respectively, during chronic LCMV infection.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138631261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-11DOI: 10.4049/jimmunol.2200691
Jing Chen, Chao Liu, Anna V. Chernatynskaya, Brittney Newby, Todd M. Brusko, Yuan Xu, Jessie M. Barra, Nadine Morgan, Christopher Santarlas, Westley H. Reeves, Hubert M. Tse, Jennifer W. Leiding, Clayton E. Mathews
Abstract Oxidants participate in lymphocyte activation and function. We previously demonstrated that eliminating the activity of NADPH oxidase 2 (NOX2) significantly impaired the effectiveness of autoreactive CD8+ CTLs. However, the molecular mechanisms impacting CD8+ T cell function remain unknown. In the present study, we examined the role of NOX2 in both NOD mouse and human CD8+ T cell function. Genetic ablation or chemical inhibition of NOX2 in CD8+ T cells significantly suppressed activation-induced expression of the transcription factor T-bet, the master transcription factor of the Tc1 cell lineage, and T-bet target effector genes such as IFN-γ and granzyme B. Inhibition of NOX2 in both human and mouse CD8+ T cells prevented target cell lysis. We identified that superoxide generated by NOX2 must be converted into hydrogen peroxide to transduce the redox signal in CD8+ T cells. Furthermore, we show that NOX2-generated oxidants deactivate the tumor suppressor complex leading to activation of RheB and subsequently mTOR complex 1. These results indicate that NOX2 plays a nonredundant role in TCR-mediated CD8+ T cell effector function.
摘要 氧化剂参与淋巴细胞的活化和功能。我们以前曾证实，消除 NADPH 氧化酶 2（NOX2）的活性会显著降低自反应 CD8+ CTL 的有效性。然而，影响 CD8+ T 细胞功能的分子机制仍然未知。在本研究中，我们考察了 NOX2 在 NOD 小鼠和人类 CD8+ T 细胞功能中的作用。基因消减或化学抑制 CD8+ T 细胞中的 NOX2 能显著抑制活化诱导的转录因子 T-bet（Tc1 细胞系的主转录因子）和 T-bet 靶效应基因（如 IFN-γ 和颗粒酶 B）的表达。我们发现，NOX2 产生的超氧化物必须转化为过氧化氢，才能在 CD8+ T 细胞中传递氧化还原信号。此外，我们还发现，NOX2 产生的氧化剂能使肿瘤抑制复合体失活，从而激活 RheB，随后激活 mTOR 复合体 1。这些结果表明，NOX2 在 TCR 介导的 CD8+ T 细胞效应器功能中发挥着非多余的作用。
{"title":"NADPH Oxidase 2–Derived Reactive Oxygen Species Promote CD8+ T Cell Effector Function","authors":"Jing Chen, Chao Liu, Anna V. Chernatynskaya, Brittney Newby, Todd M. Brusko, Yuan Xu, Jessie M. Barra, Nadine Morgan, Christopher Santarlas, Westley H. Reeves, Hubert M. Tse, Jennifer W. Leiding, Clayton E. Mathews","doi":"10.4049/jimmunol.2200691","DOIUrl":"https://doi.org/10.4049/jimmunol.2200691","url":null,"abstract":"<jats:title>Abstract</jats:title> Oxidants participate in lymphocyte activation and function. We previously demonstrated that eliminating the activity of NADPH oxidase 2 (NOX2) significantly impaired the effectiveness of autoreactive CD8+ CTLs. However, the molecular mechanisms impacting CD8+ T cell function remain unknown. In the present study, we examined the role of NOX2 in both NOD mouse and human CD8+ T cell function. Genetic ablation or chemical inhibition of NOX2 in CD8+ T cells significantly suppressed activation-induced expression of the transcription factor T-bet, the master transcription factor of the Tc1 cell lineage, and T-bet target effector genes such as IFN-γ and granzyme B. Inhibition of NOX2 in both human and mouse CD8+ T cells prevented target cell lysis. We identified that superoxide generated by NOX2 must be converted into hydrogen peroxide to transduce the redox signal in CD8+ T cells. Furthermore, we show that NOX2-generated oxidants deactivate the tumor suppressor complex leading to activation of RheB and subsequently mTOR complex 1. These results indicate that NOX2 plays a nonredundant role in TCR-mediated CD8+ T cell effector function.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138573434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-08DOI: 10.4049/jimmunol.2300038
Melisa D. Castro Eiro, Kou Hioki, Ling Li, Merel E. P. Wilmsen, Caoimhe H. Kiernan, Inge Brouwers-Haspels, Marjan van Meurs, Manzhi Zhao, Harm de Wit, Dwin G. B. Grashof, Harmen J. G. van de Werken, Yvonne M. Mueller, Christopher Schliehe, Burcu Temizoz, Kouji Kobiyama, Ken J. Ishii, Peter D. Katsikis
Abstract Immune checkpoint blockade (ICB) immunotherapies have emerged as promising strategies for the treatment of cancer; however, there remains a need to improve their efficacy. Determinants of ICB efficacy are the frequency of tumor mutations, the associated neoantigens, and the T cell response against them. Therefore, it is expected that neoantigen vaccinations that boost the antitumor T cell response would improve ICB therapy efficacy. The aim of this study was to develop a highly immunogenic vaccine using pattern recognition receptor agonists in combination with synthetic long peptides to induce potent neoantigen-specific T cell responses. We determined that the combination of the TLR9 agonist K-type CpG oligodeoxynucleotides (K3 CpG) with the STING agonist c-di-AMP (K3/c-di-AMP combination) significantly increased dendritic cell activation. We found that immunizing mice with 20-mer of either an OVA peptide, low-affinity OVA peptides, or neopeptides identified from mouse melanoma or lung mesothelioma, together with K3/c-di-AMP, induced potent Ag-specific T cell responses. The combined K3/c-di-AMP adjuvant formulation induced 10 times higher T cell responses against neopeptides than the TLR3 agonist polyinosinic:polycytidylic acid, a derivative of which is the leading adjuvant in clinical trials of neoantigen peptide vaccines. Moreover, we demonstrated that our K3/c-di-AMP vaccine formulation with 20-mer OVA peptide was capable of controlling tumor growth and improving survival in B16-F10-OVA tumor-bearing C57BL/6 mice and synergized with anti-PD-1 treatment. Together, our findings demonstrate that the K3/c-di-AMP vaccine formulation induces potent T cell immunity against synthetic long peptides and is a promising candidate to improve neoantigen vaccine platform.
摘要 免疫检查点阻断（ICB）免疫疗法已成为治疗癌症的有前途的策略，但仍需提高其疗效。决定 ICB 疗效的因素包括肿瘤突变的频率、相关的新抗原以及针对它们的 T 细胞反应。因此，新抗原疫苗可增强抗肿瘤 T 细胞的反应，从而提高 ICB 的疗效。本研究旨在开发一种高免疫原性疫苗，利用模式识别受体激动剂与合成长肽相结合，诱导有效的新抗原特异性 T 细胞反应。我们发现，TLR9 激动剂 K 型 CpG 寡脱氧核苷酸（K3 CpG）与 STING 激动剂 c-di-AMP 组合（K3/c-di-AMP 组合）能显著提高树突状细胞的活化。我们发现，用 20-mer 的 OVA 肽、低亲和力 OVA 肽或从小鼠黑色素瘤或肺间皮瘤中鉴定出的新肽与 K3/c-di-AMP 一起免疫小鼠，可诱导强效的 Ag 特异性 T 细胞反应。K3/c-di-AMP复合佐剂配方诱导的针对新肽的T细胞应答比TLR3激动剂聚肌苷酸：聚胞苷酸高10倍，后者的衍生物是新抗原肽疫苗临床试验中的主要佐剂。此外，我们还证明了含有 20-mer OVA 肽的 K3/c-di-AMP 疫苗制剂能够控制肿瘤生长，提高 B16-F10-OVA 肿瘤 C57BL/6 小鼠的存活率，并与抗 PD-1 治疗协同作用。总之，我们的研究结果表明，K3/c-di-AMP 疫苗制剂能诱导针对合成长肽的强效 T 细胞免疫，是一种有希望改进新抗原疫苗平台的候选药物。
{"title":"TLR9 plus STING Agonist Adjuvant Combination Induces Potent Neopeptide T Cell Immunity and Improves Immune Checkpoint Blockade Efficacy in a Tumor Model","authors":"Melisa D. Castro Eiro, Kou Hioki, Ling Li, Merel E. P. Wilmsen, Caoimhe H. Kiernan, Inge Brouwers-Haspels, Marjan van Meurs, Manzhi Zhao, Harm de Wit, Dwin G. B. Grashof, Harmen J. G. van de Werken, Yvonne M. Mueller, Christopher Schliehe, Burcu Temizoz, Kouji Kobiyama, Ken J. Ishii, Peter D. Katsikis","doi":"10.4049/jimmunol.2300038","DOIUrl":"https://doi.org/10.4049/jimmunol.2300038","url":null,"abstract":"<jats:title>Abstract</jats:title> Immune checkpoint blockade (ICB) immunotherapies have emerged as promising strategies for the treatment of cancer; however, there remains a need to improve their efficacy. Determinants of ICB efficacy are the frequency of tumor mutations, the associated neoantigens, and the T cell response against them. Therefore, it is expected that neoantigen vaccinations that boost the antitumor T cell response would improve ICB therapy efficacy. The aim of this study was to develop a highly immunogenic vaccine using pattern recognition receptor agonists in combination with synthetic long peptides to induce potent neoantigen-specific T cell responses. We determined that the combination of the TLR9 agonist K-type CpG oligodeoxynucleotides (K3 CpG) with the STING agonist c-di-AMP (K3/c-di-AMP combination) significantly increased dendritic cell activation. We found that immunizing mice with 20-mer of either an OVA peptide, low-affinity OVA peptides, or neopeptides identified from mouse melanoma or lung mesothelioma, together with K3/c-di-AMP, induced potent Ag-specific T cell responses. The combined K3/c-di-AMP adjuvant formulation induced 10 times higher T cell responses against neopeptides than the TLR3 agonist polyinosinic:polycytidylic acid, a derivative of which is the leading adjuvant in clinical trials of neoantigen peptide vaccines. Moreover, we demonstrated that our K3/c-di-AMP vaccine formulation with 20-mer OVA peptide was capable of controlling tumor growth and improving survival in B16-F10-OVA tumor-bearing C57BL/6 mice and synergized with anti-PD-1 treatment. Together, our findings demonstrate that the K3/c-di-AMP vaccine formulation induces potent T cell immunity against synthetic long peptides and is a promising candidate to improve neoantigen vaccine platform.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"127 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138562384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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