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Eliciting Anti-Tumo...
Eliciting Anti-Tumor Immunity by Reprogramming Cancer Cells to Type 1 Conventional Dendritic Cells
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- Ascic, Ervin (författare)
- Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Cellulär omprogrammering i hematopoes och immunitet,Forskargrupper vid Lunds universitet,WCMM- Wallenberg center för molekylär medicinsk forskning,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Cell Reprogramming in Hematopoiesis and Immunity,Lund University Research Groups,WCMM-Wallenberg Centre for Molecular Medicine
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- Barros Ferreira, Alexandra Gabriela (författare)
- Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Cellulär omprogrammering i hematopoes och immunitet,Forskargrupper vid Lunds universitet,WCMM- Wallenberg center för molekylär medicinsk forskning,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Cell Reprogramming in Hematopoiesis and Immunity,Lund University Research Groups,WCMM-Wallenberg Centre for Molecular Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments,University of Coimbra
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- Benonisson, Hreinn (författare)
- Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Cellulär omprogrammering i hematopoes och immunitet,Forskargrupper vid Lunds universitet,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Cell Reprogramming in Hematopoiesis and Immunity,Lund University Research Groups
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- Kurochkin, Ilia (författare)
- Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Cellulär omprogrammering i hematopoes och immunitet,Forskargrupper vid Lunds universitet,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Cell Reprogramming in Hematopoiesis and Immunity,Lund University Research Groups,Skolkovo Institute of Science and Technology
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- Nascimento Caiado, Inês Maria (författare)
- Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Cellulär omprogrammering i hematopoes och immunitet,Forskargrupper vid Lunds universitet,WCMM- Wallenberg center för molekylär medicinsk forskning,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Cell Reprogramming in Hematopoiesis and Immunity,Lund University Research Groups,WCMM-Wallenberg Centre for Molecular Medicine,University of Coimbra
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- Zimmermannova, Olga (författare)
- Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Cellulär omprogrammering i hematopoes och immunitet,Forskargrupper vid Lunds universitet,WCMM- Wallenberg center för molekylär medicinsk forskning,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Cell Reprogramming in Hematopoiesis and Immunity,Lund University Research Groups,WCMM-Wallenberg Centre for Molecular Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Fiúza Rosa, Fábio (författare)
- Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Cellulär omprogrammering i hematopoes och immunitet,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Cell Reprogramming in Hematopoiesis and Immunity,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,University of Coimbra
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- Pires, Cristiana (författare)
- Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Cellulär omprogrammering i hematopoes och immunitet,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Cell Reprogramming in Hematopoiesis and Immunity,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,University of Coimbra
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- Pereira, Filipe (författare)
- Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Cellulär omprogrammering i hematopoes och immunitet,Forskargrupper vid Lunds universitet,WCMM- Wallenberg center för molekylär medicinsk forskning,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Cell Reprogramming in Hematopoiesis and Immunity,Lund University Research Groups,WCMM-Wallenberg Centre for Molecular Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments,University of Coimbra
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- 2022
- 2022
- Engelska.
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Abstract
Ämnesord
Stäng
- IntroductionAn important hallmark of cancer is escaping the immune system. Despite advances in immunotherapy, only a subset of patients experiences clinical benefits. It was shown that adoptive T cell or checkpoint inhibition therapy rely on the presence of conventional dendritic cells type 1 (cDC1). cDC1 excel in recruiting and priming protective CD8+ T cells through cross-presentation. However, in tumors cDC1 are often impaired in function. Recently, we demonstrated that overexpression of PU.1, IRF8 and BATF3 (PIB) imposes a cDC1 fate in fibroblasts by direct cell reprogramming. As such, we hypothesise that a similar combination of transcription factors would reprogram cancer cells into tumor-antigen presenting cells (tumor-APCs) and set in motion antigen-specific immunity.Material and Methods30 mouse tumor lines were selected to evaluate reprogramming into tumor-APCs. Reprogramming was induced by overexpression of PIB via lentiviral transduction. The phenotype was profiled by flow cytometry for cDC1 markers CD45, MHC-II, CLEC9A, XCR1 and APC markers MHC-I, CD80/86. Population mRNA-seq was applied to assess transcriptional changes. To assess cDC1 functions, cytokine secretion, cross-presentation and T cell cytotoxicity assays were performed. In vivo, ovalbumin expressing tumors were established and treated by adoptive transfer of tumor-APCs. Tumor growth and animal survival were monitored.Results and DiscussionsUpon transduction with PIB, 26 solid tumor and 4 leukemia lines initiated expression of CD45, MHC-II, at efficiencies ranging from 0.5-57.7%. Reprogramming was accompanied by CLEC9A, XCR1 and MHC-I, CD80/86 upregulation. Transcriptomic analysis of low immunogenic lines B16 and LLC, reveals that PIB overwrites the cancer transcriptome and imposes antigen presentation and cDC1 gene signatures. Importantly, tumor-APCs present endogenous antigens on MHC-I and become prone to T cell mediated killing. Functionally, reprogrammed tumor-APCs secrete inflammatory cytokines such as IL12p70 and strikingly, acquire the ability to crosspresent antigens and prime naïve CD8+ T cells. In vivo, adoptive transfer of cross-presenting tumor-APCs delays tumor growth and extends survival of animals.ConclusionThis approach combines cDC1 antigen presentation abilities with endogenous generation of tumor antigens. The induction of a cDC1 identity in tumor cells sets in motion T cell responses and makes them target for T cell mediated killing. Our study represents a pioneering contribution merging cell reprogramming with immunotherapy.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Publikations- och innehållstyp
- kon (ämneskategori)
- vet (ämneskategori)