Pub Date : 2024-09-07DOI: 10.1101/2024.09.05.611467
Alexandra Francian, Yevel Flores-Garcia, John R Powell, Nikolai Petrovsky, Fidel Zavala, Bryce Chackerian
Malaria is a highly lethal infectious disease caused by Plasmodium parasites. These parasites are transmitted to vertebrate hosts when mosquitoes of the Anopheles genus probe for a blood meal. Sporozoites, the infectious stage of Plasmodium, transit to the liver within hours of injection into the dermis. Vaccine efforts are hindered by the complexity of the parasite's lifecycle and the speed at which the infection is established in the liver. In an effort to enhance immunity against Plasmodium, we produced a virus-like particle (VLP)-based vaccine displaying an epitope of TRIO, an Anopheles salivary protein which has been shown to enhance mobility and dispersal of sporozoites in the dermis. Previous work demonstrated that passive immunization with TRIO offered protection from liver infection and acted synergistically with a Plasmodium targeted vaccine. Immunization of mice with TRIO VLPs resulted in high-titer and long-lasting antibody responses that did not significantly drop for over 18 months post-immunization. TRIO VLPs were similarly immunogenic when combined with an anti-malaria vaccine targeting the L9 epitope of the Plasmodium falciparum circumsporozoite protein. However, when used in a malaria challenge mouse model, TRIO VLPs only provided modest protection from infection and did not boost the protection provided by L9 VLPs.
{"title":"Virus-like particle-based vaccines targeting the Anopheles mosquito salivary protein, TRIO","authors":"Alexandra Francian, Yevel Flores-Garcia, John R Powell, Nikolai Petrovsky, Fidel Zavala, Bryce Chackerian","doi":"10.1101/2024.09.05.611467","DOIUrl":"https://doi.org/10.1101/2024.09.05.611467","url":null,"abstract":"Malaria is a highly lethal infectious disease caused by Plasmodium parasites. These parasites are transmitted to vertebrate hosts when mosquitoes of the Anopheles genus probe for a blood meal. Sporozoites, the infectious stage of Plasmodium, transit to the liver within hours of injection into the dermis. Vaccine efforts are hindered by the complexity of the parasite's lifecycle and the speed at which the infection is established in the liver. In an effort to enhance immunity against Plasmodium, we produced a virus-like particle (VLP)-based vaccine displaying an epitope of TRIO, an Anopheles salivary protein which has been shown to enhance mobility and dispersal of sporozoites in the dermis. Previous work demonstrated that passive immunization with TRIO offered protection from liver infection and acted synergistically with a Plasmodium targeted vaccine. Immunization of mice with TRIO VLPs resulted in high-titer and long-lasting antibody responses that did not significantly drop for over 18 months post-immunization. TRIO VLPs were similarly immunogenic when combined with an anti-malaria vaccine targeting the L9 epitope of the Plasmodium falciparum circumsporozoite protein. However, when used in a malaria challenge mouse model, TRIO VLPs only provided modest protection from infection and did not boost the protection provided by L9 VLPs.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211318","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 : 2024-09-07DOI: 10.1101/2024.09.03.610977
Yaqi Luan, Weiwei He, Kunmao Jiang, Shenghui Qiu, Lan Jin, Xinrui Mao, Ying Huang, Wentao Liu, Jingyuan Cao, Lai Jin, Rong Wang
Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic, but its use is limited by adverse effects in normal tissues. In particular, cisplatin administration often damages the kidneys. However, little is known about how to alleviate cisplatin-induced chronic kidney disease (CKD) specifically. Here, we found that repeated low-dose cisplatin (RLDC) recruited neutrophils to the proximal tubule, thereby promoting the progression of CKD in the mouse model. Mechanically, cisplatin destroyed the intestinal epithelium, which induced dysregulation of gut flora and intestinal leakage. It triggered Neutrophil extracellular traps (NETs) formation, accumulating in the proximal tubule and promotes chronic inflammation and fibrosis, and promotes chronic hypoxia, leading to poor regeneration that promotes CKD progression. NETs provided a scaffold for tissue factors (TF) adhesion and metalloid-matrix protease 9 (MMP-9) activation, which triggers local ischemia and hypoxia. In addition, NETs promoted inflammasome construction through NOD-like receptor thermal protein domain associated protein 3 (NLRP3) shear and secretion of mature interleukin-18 (IL18), which subsequently released interferon-γ (IFN-γ), contributing to renal interstitial fibrosis. We proposed that oligomeric procyanidins (OPC) ameliorated RLDC-induced CKD through multi-targeting damage induced by NETs. OPC ameliorated microcirculatory disorders and inhibited inflammation by protecting the intestinal mucosa barrier and subsequent bacterial endotoxin translocation. Furthermore, we found that OPC directly blocked LPS & cisplatin-induced NETs formation in vitro. In summary, NETs play a pivotal role in CKD, which OPC alleviates by inhibiting TF/MMP-9 and IL-18-NLRP3 pathways. OPCs protect the kidney by inhibiting NETs production through anti-inflammatory and antioxidant activities and restoring the balance of the intestinal flora.
{"title":"Inhibition on neutrophil extracellular traps by oligomeric procyanidins alleviate chemotherapy-induced chronic kidney injury via gut-kidney axis","authors":"Yaqi Luan, Weiwei He, Kunmao Jiang, Shenghui Qiu, Lan Jin, Xinrui Mao, Ying Huang, Wentao Liu, Jingyuan Cao, Lai Jin, Rong Wang","doi":"10.1101/2024.09.03.610977","DOIUrl":"https://doi.org/10.1101/2024.09.03.610977","url":null,"abstract":"Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic, but its use is limited by adverse effects in normal tissues. In particular, cisplatin administration often damages the kidneys. However, little is known about how to alleviate cisplatin-induced chronic kidney disease (CKD) specifically. Here, we found that repeated low-dose cisplatin (RLDC) recruited neutrophils to the proximal tubule, thereby promoting the progression of CKD in the mouse model. Mechanically, cisplatin destroyed the intestinal epithelium, which induced dysregulation of gut flora and intestinal leakage. It triggered Neutrophil extracellular traps (NETs) formation, accumulating in the proximal tubule and promotes chronic inflammation and fibrosis, and promotes chronic hypoxia, leading to poor regeneration that promotes CKD progression. NETs provided a scaffold for tissue factors (TF) adhesion and metalloid-matrix protease 9 (MMP-9) activation, which triggers local ischemia and hypoxia. In addition, NETs promoted inflammasome construction through NOD-like receptor thermal protein domain associated protein 3 (NLRP3) shear and secretion of mature interleukin-18 (IL18), which subsequently released interferon-γ (IFN-γ), contributing to renal interstitial fibrosis. We proposed that oligomeric procyanidins (OPC) ameliorated RLDC-induced CKD through multi-targeting damage induced by NETs. OPC ameliorated microcirculatory disorders and inhibited inflammation by protecting the intestinal mucosa barrier and subsequent bacterial endotoxin translocation. Furthermore, we found that OPC directly blocked LPS & cisplatin-induced NETs formation in vitro. In summary, NETs play a pivotal role in CKD, which OPC alleviates by inhibiting TF/MMP-9 and IL-18-NLRP3 pathways. OPCs protect the kidney by inhibiting NETs production through anti-inflammatory and antioxidant activities and restoring the balance of the intestinal flora.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"79 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211322","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 : 2024-09-07DOI: 10.1101/2024.09.04.611167
Samantha G Muccilli, Bejamin Schwarz, Forrest Jessop, Jeffrey G. Shannon, Eric Bohrnsen, Byron Shue, Seon-Hui Hong, Thomas Hsu, Alison W. Ashbrook, Joseph W. Guarnieri, Justin Lack, Douglas C. Wallace, Catharine M. Bosio, Margaret R. MacDonald, Charles M Rice, Jonathan W Yewdell, Sonja M. Best
The yellow fever virus 17D (YFV-17D) live attenuated vaccine is considered one of the successful vaccines ever generated associated with high antiviral immunity, yet the signaling mechanisms that drive the response in infected cells are not understood. Here, we provide a molecular understanding of how metabolic stress and innate immune responses are linked to drive type I IFN expression in response to YFV-17D infection. Comparison of YFV-17D replication with its parental virus, YFV-Asibi, and a related dengue virus revealed that IFN expression requires RIG-I-like Receptor signaling through MAVS, as expected. However, YFV-17D uniquely induces mitochondrial respiration and major metabolic perturbations, including hyperactivation of electron transport to fuel ATP synthase. Mitochondrial hyperactivity generates reactive oxygen species (mROS) and peroxynitrite, blocking of which abrogated IFN expression in non-immune cells without reducing YFV-17D replication. Scavenging ROS in YFV-17D-infected human dendritic cells increased cell viability yet globally prevented expression of IFN signaling pathways. Thus, adaptation of YFV-17D for high growth uniquely imparts mitochondrial hyperactivity generating mROS and peroxynitrite as the critical messengers that convert a blunted IFN response into maximal activation of innate immunity essential for vaccine effectiveness.
{"title":"Mitochondrial Hyperactivity and Reactive Oxygen Species Drive Innate Immunity to the Yellow Fever Virus-17D Live-Attenuated Vaccine","authors":"Samantha G Muccilli, Bejamin Schwarz, Forrest Jessop, Jeffrey G. Shannon, Eric Bohrnsen, Byron Shue, Seon-Hui Hong, Thomas Hsu, Alison W. Ashbrook, Joseph W. Guarnieri, Justin Lack, Douglas C. Wallace, Catharine M. Bosio, Margaret R. MacDonald, Charles M Rice, Jonathan W Yewdell, Sonja M. Best","doi":"10.1101/2024.09.04.611167","DOIUrl":"https://doi.org/10.1101/2024.09.04.611167","url":null,"abstract":"The yellow fever virus 17D (YFV-17D) live attenuated vaccine is considered one of the successful vaccines ever generated associated with high antiviral immunity, yet the signaling mechanisms that drive the response in infected cells are not understood. Here, we provide a molecular understanding of how metabolic stress and innate immune responses are linked to drive type I IFN expression in response to YFV-17D infection. Comparison of YFV-17D replication with its parental virus, YFV-Asibi, and a related dengue virus revealed that IFN expression requires RIG-I-like Receptor signaling through MAVS, as expected. However, YFV-17D uniquely induces mitochondrial respiration and major metabolic perturbations, including hyperactivation of electron transport to fuel ATP synthase. Mitochondrial hyperactivity generates reactive oxygen species (mROS) and peroxynitrite, blocking of which abrogated IFN expression in non-immune cells without reducing YFV-17D replication. Scavenging ROS in YFV-17D-infected human dendritic cells increased cell viability yet globally prevented expression of IFN signaling pathways. Thus, adaptation of YFV-17D for high growth uniquely imparts mitochondrial hyperactivity generating mROS and peroxynitrite as the critical messengers that convert a blunted IFN response into maximal activation of innate immunity essential for vaccine effectiveness.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211320","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 : 2024-09-06DOI: 10.1101/2024.09.03.610908
Justin E Johnson, Kriti Agrawal, Rafia S Al-Lamki, Fengrui Zhang, Wang D Xi, Samuel Liburd, Zsuzsanna Zsuzsanna, Leonel Rodriguez, Andrew J Martins, Esen Sefik, Richard Flavell, Marie E. Robert, Jordan S Pober
We identified molecular interactions between duodenal enterocytes and intraepithelial T cells in celiac disease (CeD) vs normal controls. We observed an expected increased ratio of T cells [bearing either T cell receptor (TCR) αβ and γδ ; and mostly activated cytotoxic T lymphocytes (CTLs) expressing granzyme B, CD45RO, Ki67 and Nur 77 proteins as well as IFNγ mRNA] to villous enterocytes. Few T cells (<5%) express NKG2C or DAP12 proteins. CeD villous enterocytes express an IFNγ signature (by single cell RNA sequencing and nuclear phopho-STAT1 and HLA-DR protein staining). CeD enterocytes express increased IFNγ -inducible chemokines CCL3, CCL4, CXCL10 and CXCL11 mRNA while CeD intraepithelial T cells express reduced levels of CCR5 and CXCR3 chemokine receptors, suggesting ligand-induced downregulation. CeD enterocyte HLA-E mRNA and protein are upregulated whereas HLA-B mRNA but not protein increases. Proximity ligation detected frequent interactions of αβ and γδ TCRs with HLA-E and HLA-B but not with HLA-DR and fewer NKG2C interactions with HLA-E. We suggest that CeD IFNγ-producing TCRαβ and γδ CTLs are recruited into villous epithelium by IFNγ-induced enterocyte production of CCR5 and CXCR3-binding chemokines and kill villous enterocytes primarily by TCR engagement with class I HLA molecules, including HLA-E, likely presenting gluten peptides. The IFN-γ signature of CeD villous enterocytes is a potential biomarker of active disease and a therapeutic target.
{"title":"The Multiple Roles of Gamma Interferon in Intraepithelial T Cell-Villous Enterocyte Interactions in Active Celiac Disease","authors":"Justin E Johnson, Kriti Agrawal, Rafia S Al-Lamki, Fengrui Zhang, Wang D Xi, Samuel Liburd, Zsuzsanna Zsuzsanna, Leonel Rodriguez, Andrew J Martins, Esen Sefik, Richard Flavell, Marie E. Robert, Jordan S Pober","doi":"10.1101/2024.09.03.610908","DOIUrl":"https://doi.org/10.1101/2024.09.03.610908","url":null,"abstract":"We identified molecular interactions between duodenal enterocytes and intraepithelial T cells in celiac disease (CeD) vs normal controls. We observed an expected increased ratio of T cells [bearing either T cell receptor (TCR) αβ and γδ ; and mostly activated cytotoxic T lymphocytes (CTLs) expressing granzyme B, CD45RO, Ki67 and Nur 77 proteins as well as IFNγ mRNA] to villous enterocytes. Few T cells (<5%) express NKG2C or DAP12 proteins. CeD villous enterocytes express an IFNγ signature (by single cell RNA sequencing and nuclear phopho-STAT1 and HLA-DR protein staining). CeD enterocytes express increased IFNγ -inducible chemokines CCL3, CCL4, CXCL10 and CXCL11 mRNA while CeD intraepithelial T cells express reduced levels of CCR5 and CXCR3 chemokine receptors, suggesting ligand-induced downregulation. CeD enterocyte HLA-E mRNA and protein are upregulated whereas HLA-B mRNA but not protein increases. Proximity ligation detected frequent interactions of αβ and γδ TCRs with HLA-E and HLA-B but not with HLA-DR and fewer NKG2C interactions with HLA-E. We suggest that CeD IFNγ-producing TCRαβ and γδ CTLs are recruited into villous epithelium by IFNγ-induced enterocyte production of CCR5 and CXCR3-binding chemokines and kill villous enterocytes primarily by TCR engagement with class I HLA molecules, including HLA-E, likely presenting gluten peptides. The IFN-γ signature of CeD villous enterocytes is a potential biomarker of active disease and a therapeutic target.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226775","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 : 2024-09-06DOI: 10.1101/2024.09.05.611549
Mark Tsz Kin Cheng, Mazharul Altaf, Darren P. Martin, Christopher Ruis, Benjamin L. Sievers, Kimia Kamelian, Rebecca B. Morse, Adam Abdullahi, Bo Meng, Kata Csiba, Cambridge NIHR Bioresource, Steven A. Kemp, Ravindra K Gupta
Persistent SARS-CoV-2 infections are a likely source of new variants of concern. In a fatal infection in an immunocompromised patient, we find association between viral load and diversity, and abrupt diversification between contemporaneous nasopharyngeal and endotracheal aspirate samples following remdesivir and convalescent plasma treatment. Shared high proportion of G>T mutations suggests spread of viruses from the lower to the upper tract as the patient deteriorated. We identified the S:P812S spike mutation adjacent to the fusion peptide unique to the nasopharyngeal sample site. We find P812S reduced S1/S2 cleavage and decreased entry efficiency in cell lines with a range of ACE2 and TMPRSS2 expression levels. This reduction of infectivity contrasted with reduced susceptibility to neutralising antibodies in sera from vaccinated individuals conferred by P812S at both 37°C and 32°C (simulating upper tract). Thus, S:P812S is a specific adaptation during SARS-CoV-2 intrahost evolution, allowing immune evasion at lower temperatures observed in the upper respiratory tract at the expense of target cell entry efficiency.
{"title":"Nasopharyngeal specific selection and emergence of SARS-CoV-2 spike fusion peptide mutation P812S during chronic infection","authors":"Mark Tsz Kin Cheng, Mazharul Altaf, Darren P. Martin, Christopher Ruis, Benjamin L. Sievers, Kimia Kamelian, Rebecca B. Morse, Adam Abdullahi, Bo Meng, Kata Csiba, Cambridge NIHR Bioresource, Steven A. Kemp, Ravindra K Gupta","doi":"10.1101/2024.09.05.611549","DOIUrl":"https://doi.org/10.1101/2024.09.05.611549","url":null,"abstract":"Persistent SARS-CoV-2 infections are a likely source of new variants of concern. In a fatal infection in an immunocompromised patient, we find association between viral load and diversity, and abrupt diversification between contemporaneous nasopharyngeal and endotracheal aspirate samples following remdesivir and convalescent plasma treatment. Shared high proportion of G>T mutations suggests spread of viruses from the lower to the upper tract as the patient deteriorated. We identified the S:P812S spike mutation adjacent to the fusion peptide unique to the nasopharyngeal sample site. We find P812S reduced S1/S2 cleavage and decreased entry efficiency in cell lines with a range of ACE2 and TMPRSS2 expression levels. This reduction of infectivity contrasted with reduced susceptibility to neutralising antibodies in sera from vaccinated individuals conferred by P812S at both 37°C and 32°C (simulating upper tract). Thus, S:P812S is a specific adaptation during SARS-CoV-2 intrahost evolution, allowing immune evasion at lower temperatures observed in the upper respiratory tract at the expense of target cell entry efficiency.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"70 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211323","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 : 2024-09-06DOI: 10.1101/2024.09.03.610636
Daniel A Ruiz Torres, Jillian Wise, Brian Zhao, Joao P Oliveira-Costa, Sara Cavallaro, Peter Sadow, Jacy Fang, Osman Yilmaz, Amar Patel, Christopher Loosbroock, Moshe Sade-Feldman, Daniel L Faden, Shannon L Stott
The potent immunostimulatory effects of toll-like receptor 8 (TLR8) agonism in combination with PD-1 blockade have resulted in various preclinical investigations, yet the mechanism of action in humans remains unknown. To decipher the combinatory mode of action of TLR8 agonism and PD-1 blockade, we employed a unique, open-label, phase 1b pre-operative window of opportunity clinical trial (NCT03906526) in head and neck squamous cell carcinoma (HNSCC) patients. Matched pre- and post-treatment tumor biopsies from the same lesion were obtained. We used single-cell RNA sequencing and custom multiplex staining to leverage the unique advantage of same-lesion longitudinal sampling. Patients receiving dual TLR8 agonism and anti-PD-1 blockade exhibited marked upregulation of innate immune effector genes and cytokines, highlighted by increased CLEC9A+ dendritic cell and CLEC7A/SYK expression. This was revealed via comparison with a previous cohort from an anti-PD-1 blockade monotherapy single-cell RNA sequencing study. Furthermore, in dual therapy patients, post-treatment mature dendritic cells increased in adjacency to CD8+ T-cells. Increased tumoral cytotoxic T-lymphocyte densities and expanded CXCL13+CD8+ T-cell populations were observed in responders, with increased tertiary lymphoid structures (TLSs) across all three patients. This study provides key insights into the mode of action of TLR8 agonism and anti-PD-1 blockade immune targeting in HNSCC patients.
{"title":"Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade","authors":"Daniel A Ruiz Torres, Jillian Wise, Brian Zhao, Joao P Oliveira-Costa, Sara Cavallaro, Peter Sadow, Jacy Fang, Osman Yilmaz, Amar Patel, Christopher Loosbroock, Moshe Sade-Feldman, Daniel L Faden, Shannon L Stott","doi":"10.1101/2024.09.03.610636","DOIUrl":"https://doi.org/10.1101/2024.09.03.610636","url":null,"abstract":"The potent immunostimulatory effects of toll-like receptor 8 (TLR8) agonism in combination with PD-1 blockade have resulted in various preclinical investigations, yet the mechanism of action in humans remains unknown. To decipher the combinatory mode of action of TLR8 agonism and PD-1 blockade, we employed a unique, open-label, phase 1b pre-operative window of opportunity clinical trial (NCT03906526) in head and neck squamous cell carcinoma (HNSCC) patients. Matched pre- and post-treatment tumor biopsies from the same lesion were obtained. We used single-cell RNA sequencing and custom multiplex staining to leverage the unique advantage of same-lesion longitudinal sampling. Patients receiving dual TLR8 agonism and anti-PD-1 blockade exhibited marked upregulation of innate immune effector genes and cytokines, highlighted by increased CLEC9A+ dendritic cell and CLEC7A/SYK expression. This was revealed via comparison with a previous cohort from an anti-PD-1 blockade monotherapy single-cell RNA sequencing study. Furthermore, in dual therapy patients, post-treatment mature dendritic cells increased in adjacency to CD8+ T-cells. Increased tumoral cytotoxic T-lymphocyte densities and expanded CXCL13+CD8+ T-cell populations were observed in responders, with increased tertiary lymphoid structures (TLSs) across all three patients. This study provides key insights into the mode of action of TLR8 agonism and anti-PD-1 blockade immune targeting in HNSCC patients.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211326","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 : 2024-09-06DOI: 10.1101/2024.09.03.610810
Rute Salvador, Bruna Filipa Correia, Daniela Grosa, Telma Martins, Suelen C Soares Baal, Diana Pereira Saraiva, Sofia Cristovao-Ferreira, Isabel Lopes Pereira, Catia Rebelo de Almeida, Rita Fior, Antonio Jacinto, Carolina Mathias, Sofia Braga, Maria de guadalupe Cabral
Background: Despite advances in breast cancer (BC) therapies, more effective interventions are needed, especially for chemotherapy-resistant tumors. Immune checkpoint inhibitors show promise for triple-negative breast cancer, but their effectiveness across all BC subtypes remains challenging. Therefore, novel strategies, including adoptive cellular therapy, employing patients own T lymphocytes expanded ex vivo, are under investigation. Previously, we demonstrated that cytotoxic T lymphocytes (CTLs) expressing high HLA-DR levels in the tumor microenvironment are associated with a good response to neoadjuvant chemotherapy (NACT), due to their pronounced anti-tumor properties compared to CTLs with low or no HLA-DR expression. In this paper, we demonstrated that HLA-DR expression in CTLs is crucial for efficient T lymphocytes-based therapies. Methods: To clarify the role of HLA-DR in CTLs anti-tumor abilities, we performed in vitro and in vivo experiments. We also improved a protocol to expand ex vivo HLA-DR-expressing CTLs and employed a 3D co-culture platform to test the potential of different immune agents, namely an anti-PD1, anti-OX40, anti-VEGF and anti-CD137, on CTLs cytotoxicity against BC cells. Additionally, we conducted a bioinformatic analysis of scRNA-seq data of BC patients to better understand the modulation of HLA-DR expression in CTLs. Results: Our findings revealed that CTLs require HLA-DR expression to eliminate tumor cells. Additionally, we unveiled that blocking HLA-DR or depleting CD4+ T cells compromised CTLs activation and cytotoxicity, suggesting antigen presentation by CTLs through HLA-DR, and CD4+ T cells, as probable mechanisms for CTLs increased anti-tumor immune response and treatment efficacy. We refined an ex vivo stimulation and cytokine supplementation protocol, observing that short-term stimulation increases HLA-DR expression while boosting CTLs functionality, unlike prolonged expansion. This result highlights the importance of prioritizing cell quality, over quantity, for therapy efficiency. Additionally, we verified that anti-PD-1 further increases HLA-DR levels in CTLs, enhancing their anti-tumor efficiency. Notably, an in silico analysis revealed that PD-1 in CTLs shares 34 co-expressed genes with HLA-DR, including several non-coding RNAs, suggesting a PD-1-mediated regulation of HLA-DR expression. Conclusions: Globally, our findings underscore that heightening HLA-DR expression in CTLs, by combining anti-PD-1 with short-term stimulation, offers promise for improving T lymphocyte-based therapies for BC.
{"title":"Enhancing HLA-DR in Cytotoxic T Lymphocytes is crucial for the development of efficient adoptive T cell Therapies for Breast Cancer","authors":"Rute Salvador, Bruna Filipa Correia, Daniela Grosa, Telma Martins, Suelen C Soares Baal, Diana Pereira Saraiva, Sofia Cristovao-Ferreira, Isabel Lopes Pereira, Catia Rebelo de Almeida, Rita Fior, Antonio Jacinto, Carolina Mathias, Sofia Braga, Maria de guadalupe Cabral","doi":"10.1101/2024.09.03.610810","DOIUrl":"https://doi.org/10.1101/2024.09.03.610810","url":null,"abstract":"Background: Despite advances in breast cancer (BC) therapies, more effective interventions are needed, especially for chemotherapy-resistant tumors. Immune checkpoint inhibitors show promise for triple-negative breast cancer, but their effectiveness across all BC subtypes remains challenging. Therefore, novel strategies, including adoptive cellular therapy, employing patients own T lymphocytes expanded ex vivo, are under investigation. Previously, we demonstrated that cytotoxic T lymphocytes (CTLs) expressing high HLA-DR levels in the tumor microenvironment are associated with a good response to neoadjuvant chemotherapy (NACT), due to their pronounced anti-tumor properties compared to CTLs with low or no HLA-DR expression. In this paper, we demonstrated that HLA-DR expression in CTLs is crucial for efficient T lymphocytes-based therapies.\u0000Methods: To clarify the role of HLA-DR in CTLs anti-tumor abilities, we performed in vitro and in vivo experiments. We also improved a protocol to expand ex vivo HLA-DR-expressing CTLs and employed a 3D co-culture platform to test the potential of different immune agents, namely an anti-PD1, anti-OX40, anti-VEGF and anti-CD137, on CTLs cytotoxicity against BC cells. Additionally, we conducted a bioinformatic analysis of scRNA-seq data of BC patients to better understand the modulation of HLA-DR expression in CTLs.\u0000Results: Our findings revealed that CTLs require HLA-DR expression to eliminate tumor cells. Additionally, we unveiled that blocking HLA-DR or depleting CD4+ T cells compromised CTLs activation and cytotoxicity, suggesting antigen presentation by CTLs through HLA-DR, and CD4+ T cells, as probable mechanisms for CTLs increased anti-tumor immune response and treatment efficacy. We refined an ex vivo stimulation and cytokine supplementation protocol, observing that short-term stimulation increases HLA-DR expression while boosting CTLs functionality, unlike prolonged expansion. This result highlights the importance of prioritizing cell quality, over quantity, for therapy efficiency. Additionally, we verified that anti-PD-1 further increases HLA-DR levels in CTLs, enhancing their anti-tumor efficiency. Notably, an in silico analysis revealed that PD-1 in CTLs shares 34 co-expressed genes with HLA-DR, including several non-coding RNAs, suggesting a PD-1-mediated regulation of HLA-DR expression.\u0000Conclusions: Globally, our findings underscore that heightening HLA-DR expression in CTLs, by combining anti-PD-1 with short-term stimulation, offers promise for improving T lymphocyte-based therapies for BC.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211379","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 : 2024-09-06DOI: 10.1101/2024.09.03.608755
Ines C Osma-Garcia, Orlane Maloudi, Mailys Mouysset, Dunja Capitan-Sobrino, Trang-My M Nguyen, Yann Aubert, Manuel D. Diaz-Munoz
Immune protection against new and recurrent infections relies on long-term maintenance of a highly diversified T-cell repertoire. Transcription factors cooperate to enforce T-cell metabolic quiescence and maintenance. However, less is known about the post-transcriptional networks that preserve peripheral naive T cells. Here we describe the RNA binding proteins TIA1 and TIAL1 as key promoters of CD4 and CD8 T cell quiescence. T cells deficient in TIA1 and TIAL1 undergo uncontrolled cell proliferation in the absence of cognate antigens, leading this to a premature T-cell activation, exhaustion and death. Mechanistically, TIA1 and TIAL1 control the expression of master regulatory transcription factors, FOXP1, LEF1 and TCF1, that restrain homeostatic T-cell proliferation. In summary, our study highlights a previously unrecognised dependency on post-transcriptional gene regulation by TIA1 and TIAL1 for implementing the quiescent transcriptional programs for long survival of T cells.
针对新感染和复发性感染的免疫保护依赖于高度多样化的 T 细胞库的长期保持。转录因子通力合作，强制T细胞代谢静止和维持。然而，人们对维持外周幼稚 T 细胞的转录后网络知之甚少。在这里，我们描述了作为 CD4 和 CD8 T 细胞静止的关键启动子的 RNA 结合蛋白 TIA1 和 TIAL1。缺乏 TIA1 和 TIAL1 的 T 细胞在缺乏同源抗原的情况下会发生不受控制的细胞增殖，导致 T 细胞过早活化、衰竭和死亡。从机理上讲，TIA1 和 TIAL1 可控制主调节转录因子 FOXP1、LEF1 和 TCF1 的表达，从而抑制同源性 T 细胞增殖。总之，我们的研究强调了以前未认识到的 TIA1 和 TIAL1 对转录后基因调控的依赖性，TIA1 和 TIAL1 可实施静息转录程序，使 T 细胞长期存活。
{"title":"Post-transcriptional regulation by TIA1 and TIAL1 controls the transcriptional program enforcing T cell quiescence.","authors":"Ines C Osma-Garcia, Orlane Maloudi, Mailys Mouysset, Dunja Capitan-Sobrino, Trang-My M Nguyen, Yann Aubert, Manuel D. Diaz-Munoz","doi":"10.1101/2024.09.03.608755","DOIUrl":"https://doi.org/10.1101/2024.09.03.608755","url":null,"abstract":"Immune protection against new and recurrent infections relies on long-term maintenance of a highly diversified T-cell repertoire. Transcription factors cooperate to enforce T-cell metabolic quiescence and maintenance. However, less is known about the post-transcriptional networks that preserve peripheral naive T cells. Here we describe the RNA binding proteins TIA1 and TIAL1 as key promoters of CD4 and CD8 T cell quiescence. T cells deficient in TIA1 and TIAL1 undergo uncontrolled cell proliferation in the absence of cognate antigens, leading this to a premature T-cell activation, exhaustion and death. Mechanistically, TIA1 and TIAL1 control the expression of master regulatory transcription factors, FOXP1, LEF1 and TCF1, that restrain homeostatic T-cell proliferation. In summary, our study highlights a previously unrecognised dependency on post-transcriptional gene regulation by TIA1 and TIAL1 for implementing the quiescent transcriptional programs for long survival of T cells.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211382","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 : 2024-09-06DOI: 10.1101/2024.09.04.611250
Han Jiao, Jarne Jermei, Xian Liang, Felipe Correa-da-Silva, Milan Dorscheidt, Valentina Sophia Rumanova, Delaram Poormoghadam, Ewout Foppen, Nikita Korpel, Dirk Jan Stenvers, Alberto Pereira Arias, Tiemin Liu, Zhang Zhi, Andries Kalsbeek, Chun-Xia Yi
Time-restricted eating has shown promise for improving metabolic health in obese humans. In this study, we investigated how time-restricted feeding (TRF) at different times of the day affects the microglial brain immune function using Wistar rats. We found that in high-fat diet (HFD)-induced obesity, TRF during the active phase of rats is effective in reducing fat mass, enhancing the rhythmicity of the microglial transcriptome, and preventing an increase in microglial cell number. These effects are not seen with TRF during the resting phase. However, the HFD-induced activation of microglial metabolic pathways was not reversed by TRF in either the active or resting phase, indicating that the reprogrammed microglial metabolism in obesity is a persistent cellular functional change that might form a metabolic memory and play a role in body weight regain upon discontinuation of restricted eating.
{"title":"Limited microglial metabolic improvement with time-restricted feeding in diet-induced obesity","authors":"Han Jiao, Jarne Jermei, Xian Liang, Felipe Correa-da-Silva, Milan Dorscheidt, Valentina Sophia Rumanova, Delaram Poormoghadam, Ewout Foppen, Nikita Korpel, Dirk Jan Stenvers, Alberto Pereira Arias, Tiemin Liu, Zhang Zhi, Andries Kalsbeek, Chun-Xia Yi","doi":"10.1101/2024.09.04.611250","DOIUrl":"https://doi.org/10.1101/2024.09.04.611250","url":null,"abstract":"Time-restricted eating has shown promise for improving metabolic health in obese humans. In this study, we investigated how time-restricted feeding (TRF) at different times of the day affects the microglial brain immune function using Wistar rats. We found that in high-fat diet (HFD)-induced obesity, TRF during the active phase of rats is effective in reducing fat mass, enhancing the rhythmicity of the microglial transcriptome, and preventing an increase in microglial cell number. These effects are not seen with TRF during the resting phase. However, the HFD-induced activation of microglial metabolic pathways was not reversed by TRF in either the active or resting phase, indicating that the reprogrammed microglial metabolism in obesity is a persistent cellular functional change that might form a metabolic memory and play a role in body weight regain upon discontinuation of restricted eating.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211380","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}
Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections and can profoundly affect the host antiviral innate immune response, although the mechanisms by which these changes occur are largely unknown. Here we report that chicken-specific ERVs exert genetic resistance to exogenous retrovirus infection. Mechanistically, chicken-specific ERVs activated the scavenger receptor MARCO (macrophage receptor with collagenous structure)-mediated TLR3-IL-1β inflammatory response in macrophages. Under the presence of MARCO, macrophages response to viral infection through inducing TLR3-IL-1β inflammatory response. Conversely, lack of MARCO increased the viral replication levels and attenuated the antiviral inflammatory response. MARCO-mediated ligand delivery enhances TLR3-IL-1β antiviral response, and IL-1β expression is responsible for viral inhibition. Restoring MARCO or IL-1β expression overcomes viral infection in macrophages. Our study provides new insights into the molecular mechanisms underlying the host defense against exogenous retroviruses infection and may have important implications for the development of novel therapeutic strategies against retroviruses infection.
内源性逆转录病毒（ERVs）是古老逆转录病毒感染的残留物，可对宿主的抗病毒先天免疫反应产生深远影响，但这些变化发生的机制大多尚不清楚。在这里，我们报告了鸡特异性ERV对外源逆转录病毒感染的遗传抗性。从机制上讲，鸡特异性 ERV 激活了巨噬细胞中清道夫受体 MARCO（具有胶原结构的巨噬细胞受体）介导的 TLR3-IL-1β 炎症反应。在 MARCO 存在的情况下，巨噬细胞通过诱导 TLR3-IL-1β 炎症反应来应对病毒感染。相反，缺乏 MARCO 会增加病毒复制水平，削弱抗病毒炎症反应。MARCO介导的配体传递增强了TLR3-IL-1β抗病毒反应，而IL-1β的表达是抑制病毒的原因。恢复 MARCO 或 IL-1β 的表达可克服巨噬细胞中的病毒感染。我们的研究为宿主防御外源性逆转录病毒感染的分子机制提供了新的见解，并可能对逆转录病毒感染的新型治疗策略的开发具有重要意义。
{"title":"Endogenous retroviruses activate MARCO-mediated inflammatory response to block retroviral infection","authors":"Hu Xuming, Wang Guo, Huixian Wu, Jinlu Liu, Xujing Chen, Xiao Han, Yu Zhang, Yang Zhang, Zhengfeng Cao, Qiang Bao, Wenxian Chai, Shihao Chen, Wenming Zhao, Guohong Chen, Hengmi Cui, Xu Qi","doi":"10.1101/2024.09.03.610969","DOIUrl":"https://doi.org/10.1101/2024.09.03.610969","url":null,"abstract":"Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections and can profoundly affect the host antiviral innate immune response, although the mechanisms by which these changes occur are largely unknown. Here we report that chicken-specific ERVs exert genetic resistance to exogenous retrovirus infection. Mechanistically, chicken-specific ERVs activated the scavenger receptor MARCO (macrophage receptor with collagenous structure)-mediated TLR3-IL-1β inflammatory response in macrophages. Under the presence of MARCO, macrophages response to viral infection through inducing TLR3-IL-1β inflammatory response. Conversely, lack of MARCO increased the viral replication levels and attenuated the antiviral inflammatory response. MARCO-mediated ligand delivery enhances TLR3-IL-1β antiviral response, and IL-1β expression is responsible for viral inhibition. Restoring MARCO or IL-1β expression overcomes viral infection in macrophages. Our study provides new insights into the molecular mechanisms underlying the host defense against exogenous retroviruses infection and may have important implications for the development of novel therapeutic strategies against retroviruses infection.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211381","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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