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Harnessing Dendritic Cell Reprogramming to Elucidate Mechanisms of Tumor Immunity

Ascic, Ervin LU orcid ; Barros Ferreira, Alexandra Gabriela LU orcid ; Benonisson, Hreinn LU ; Kurochkin, Ilia LU ; Nascimento Caiado, Inês Maria LU ; Zimmermannova, Olga LU ; Alves, Rita LU ; Fiúza Rosa, Fábio LU ; Pires, Cristiana LU and Pereira, Filipe LU orcid (2022) Lund Stem Cell Center Retreat
Abstract
The presence of conventional dendritic cells type 1 (cDC1) in the tumor correlates with positive treatment outcome. The ability to cross-present neoantigens and prime protective CD8+ T-cell responses, makes cDC1s central for tumor immunity. However, in tumors cDC1 are rare and often functionally impaired. Our group reported that overexpression of the transcription factors PU.1, IRF8 and BATF3 (PIB) converts mouse and human fibroblasts into cross-presenting cDC1-like cells. We employed the minimal gene regulatory network of highly immunogenic cDC1 and restored the immunogenicity of low immunogenic lung cancer and melanoma cell lines by reprogramming into professional tumor antigen presenting cells (tumor-APCs).

Here, we report... (More)
The presence of conventional dendritic cells type 1 (cDC1) in the tumor correlates with positive treatment outcome. The ability to cross-present neoantigens and prime protective CD8+ T-cell responses, makes cDC1s central for tumor immunity. However, in tumors cDC1 are rare and often functionally impaired. Our group reported that overexpression of the transcription factors PU.1, IRF8 and BATF3 (PIB) converts mouse and human fibroblasts into cross-presenting cDC1-like cells. We employed the minimal gene regulatory network of highly immunogenic cDC1 and restored the immunogenicity of low immunogenic lung cancer and melanoma cell lines by reprogramming into professional tumor antigen presenting cells (tumor-APCs).

Here, we report that upon transduction with PIB, 23 solid syngeneic cancer lines initiate reprogramming into cDC1-like cells expressing CD45 and MHC-II at efficiencies ranging from 0.5-57.7%. Functionally, PIB overexpression endows tumor cells with the capacity to cross-present exogenous antigen and prime naïve CD8+ T-cells. Adoptive transfer of ovalbumin cross-presenting B16 tumor-APCs into established ovalbumin expressing B16 tumors (B16-OVA) elicits tumor growth control and extends animal survival. Treated animals show a systemic antigen-specific T cell response against ovalbumin and endogenous tumor-associated antigen MuLV p15E. Intratumoral injection of reprogrammed B2905 and LLC into tumors shows differential response, correlating with their cross-presentation capacity.

This approach combines cDC1 antigen cross-presentation abilities with the generation of tumor antigens. The induction of a cDC1 identity in tumor cells sets in motion T cell responses in vitro and in vivo. In the future of this project, dendritic cell reprogramming will be object in a 2-cell CRISPR/Cas9 screen using induced cDC1-like tumor cells and reporter T-cells to explore mechanistically cross-presentation regulators. The generation of cross-presenting tumor-APCs will be also used to map and characterize presented and cross-presented neoantigens. Finally, dendritic cell reprogramming of tumor cells will be explored in vivo by replenishing cDC1 within the tumor microenvironment through in vivo reprogramming. Ultimately, this project will provide insight into mechanisms of cross-presentation and pave the way for the development of novel cDC1-centric therapies. (Less)
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; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to conference
publication status
published
subject
conference name
Lund Stem Cell Center Retreat
conference location
Båstad, Sweden
conference dates
2022-05-23 - 2022-05-24
project
Harnessing Dendritic Cell Reprogramming to Elucidate Mechanisms of Tumor Immunity
language
English
LU publication?
yes
id
6de3378e-92d5-4cc7-8722-a6a5dbcd493b
date added to LUP
2022-09-18 20:51:41
date last changed
2022-09-19 13:58:35
@misc{6de3378e-92d5-4cc7-8722-a6a5dbcd493b,
  abstract     = {{The presence of conventional dendritic cells type 1 (cDC1) in the tumor correlates with positive treatment outcome. The ability to cross-present neoantigens and prime protective CD8+ T-cell responses, makes cDC1s central for tumor immunity. However, in tumors cDC1 are rare and often functionally impaired. Our group reported that overexpression of the transcription factors PU.1, IRF8 and BATF3 (PIB) converts mouse and human fibroblasts into cross-presenting cDC1-like cells. We employed the minimal gene regulatory network of highly immunogenic cDC1 and restored the immunogenicity of low immunogenic lung cancer and melanoma cell lines by reprogramming into professional tumor antigen presenting cells (tumor-APCs). <br/><br/>Here, we report that upon transduction with PIB, 23 solid syngeneic cancer lines initiate reprogramming into cDC1-like cells expressing CD45 and MHC-II at efficiencies ranging from 0.5-57.7%. Functionally, PIB overexpression endows tumor cells with the capacity to cross-present exogenous antigen and prime naïve CD8+ T-cells. Adoptive transfer of ovalbumin cross-presenting B16 tumor-APCs into established ovalbumin expressing B16 tumors (B16-OVA) elicits tumor growth control and extends animal survival. Treated animals show a systemic antigen-specific T cell response against ovalbumin and endogenous tumor-associated antigen MuLV p15E. Intratumoral injection of reprogrammed B2905 and LLC into tumors shows differential response, correlating with their cross-presentation capacity. <br/><br/>This approach combines cDC1 antigen cross-presentation abilities with the generation of tumor antigens. The induction of a cDC1 identity in tumor cells sets in motion T cell responses in vitro and in vivo. In the future of this project, dendritic cell reprogramming will be object in a 2-cell CRISPR/Cas9 screen using induced cDC1-like tumor cells and reporter T-cells to explore mechanistically cross-presentation regulators. The generation of cross-presenting tumor-APCs will be also used to map and characterize presented and cross-presented neoantigens. Finally, dendritic cell reprogramming of tumor cells will be explored in vivo by replenishing cDC1 within the tumor microenvironment through in vivo reprogramming. Ultimately, this project will provide insight into mechanisms of cross-presentation and pave the way for the development of novel cDC1-centric therapies.}},
  author       = {{Ascic, Ervin and Barros Ferreira, Alexandra Gabriela and Benonisson, Hreinn and Kurochkin, Ilia and Nascimento Caiado, Inês Maria and Zimmermannova, Olga and Alves, Rita and Fiúza Rosa, Fábio and Pires, Cristiana and Pereira, Filipe}},
  language     = {{eng}},
  month        = {{05}},
  title        = {{Harnessing Dendritic Cell Reprogramming to Elucidate Mechanisms of Tumor Immunity}},
  url          = {{https://lup.lub.lu.se/search/files/124226155/Poster_SCC_2022_Ervin.pdf}},
  year         = {{2022}},
}