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Restoring the immunogenicity of cancer cells with dendritic cell reprogramming

Ferreira, Alexandra Gabriela LU orcid ; Ascic, Ervin LU orcid ; Caiado, Inês LU ; Zimmermannova, Olga LU ; Kurochkin, Ilia LU ; Rosa, Fábio LU ; Benonisson, Hreinn LU ; Pires, Cristiana LU and Pereira, Carlos-Filipe LU orcid (2021) In Experimental Hematology 100(Suppl). p.72-72
Abstract
An important hallmark of cancer is the ability to evade the immune system. Genetic mutations may result in the accumulation of tumor antigens, however, downregulation of antigen presentation in tumor cells results in decreased immunogenicity and immune surveillance evasion. Recently, we demonstrated that enforced expression of PU.1, IRF8 and BATF3 (PIB) imposes a conventional dendritic cell type 1 (cDC1) fate in fibroblasts by direct cell reprogramming. As such, we hypothesise that a similar combination of transcription factors can reprogram cancer cells into antigen presenting cells.

Here, we show that expression of PIB factors is sufficient to induce hematopoietic and cDC1 markers in the mouse melanoma and lung cancer cell lines... (More)
An important hallmark of cancer is the ability to evade the immune system. Genetic mutations may result in the accumulation of tumor antigens, however, downregulation of antigen presentation in tumor cells results in decreased immunogenicity and immune surveillance evasion. Recently, we demonstrated that enforced expression of PU.1, IRF8 and BATF3 (PIB) imposes a conventional dendritic cell type 1 (cDC1) fate in fibroblasts by direct cell reprogramming. As such, we hypothesise that a similar combination of transcription factors can reprogram cancer cells into antigen presenting cells.

Here, we show that expression of PIB factors is sufficient to induce hematopoietic and cDC1 markers in the mouse melanoma and lung cancer cell lines B16 and 3LL. We further show that reprogramming restores the expression of antigen presentation molecules (MHC-II, MHC-I and B2M) at cancer cell surface. This is accompanied by the activation of the co-stimulatory molecules CD80 and CD86. This reprogrammed tumor antigen presenting cell (tumor-APC) phenotype is specified gradually within the course of 9 days. PIB overwrites the cancer transcriptional program imposing global antigen presentation and cDC1 gene signatures. Functionally, tumor-APCs secrete inflammatory cytokines such as IL-12, IL-6, CXCL10 and type 1 interferons. After reprogramming they also acquire the capacity to uptake and process proteins as well as dead cells. Importantly, tumor-APCs directly prime antigen-specific naïve CD8+ T-cells after antigen loading. Finally, tumor-APCs are capable to show endogenous antigens to T cells and become prone to T cell mediated cell killing.

Our approach combines cDC1’s antigen processing and presenting abilities with the endogenous generation of tumor antigens, and serves as a platform for the development of novel immunotherapies based on endowed antigen presentation in cancer cells. (Less)
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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Hematology
volume
100
issue
Suppl
article number
3063
pages
72 - 72
publisher
Elsevier
ISSN
1873-2399
DOI
10.1016/j.exphem.2021.12.281
language
English
LU publication?
yes
id
b7beafca-8d2c-4c45-94d0-252c677b0a14
date added to LUP
2023-08-10 21:21:31
date last changed
2023-08-11 11:17:10
@misc{b7beafca-8d2c-4c45-94d0-252c677b0a14,
  abstract     = {{An important hallmark of cancer is the ability to evade the immune system. Genetic mutations may result in the accumulation of tumor antigens, however, downregulation of antigen presentation in tumor cells results in decreased immunogenicity and immune surveillance evasion. Recently, we demonstrated that enforced expression of PU.1, IRF8 and BATF3 (PIB) imposes a conventional dendritic cell type 1 (cDC1) fate in fibroblasts by direct cell reprogramming. As such, we hypothesise that a similar combination of transcription factors can reprogram cancer cells into antigen presenting cells.<br/><br/>Here, we show that expression of PIB factors is sufficient to induce hematopoietic and cDC1 markers in the mouse melanoma and lung cancer cell lines B16 and 3LL. We further show that reprogramming restores the expression of antigen presentation molecules (MHC-II, MHC-I and B2M) at cancer cell surface. This is accompanied by the activation of the co-stimulatory molecules CD80 and CD86. This reprogrammed tumor antigen presenting cell (tumor-APC) phenotype is specified gradually within the course of 9 days. PIB overwrites the cancer transcriptional program imposing global antigen presentation and cDC1 gene signatures. Functionally, tumor-APCs secrete inflammatory cytokines such as IL-12, IL-6, CXCL10 and type 1 interferons. After reprogramming they also acquire the capacity to uptake and process proteins as well as dead cells. Importantly, tumor-APCs directly prime antigen-specific naïve CD8+ T-cells after antigen loading. Finally, tumor-APCs are capable to show endogenous antigens to T cells and become prone to T cell mediated cell killing.<br/><br/>Our approach combines cDC1’s antigen processing and presenting abilities with the endogenous generation of tumor antigens, and serves as a platform for the development of novel immunotherapies based on endowed antigen presentation in cancer cells.}},
  author       = {{Ferreira, Alexandra Gabriela and Ascic, Ervin and Caiado, Inês and Zimmermannova, Olga and Kurochkin, Ilia and Rosa, Fábio and Benonisson, Hreinn and Pires, Cristiana and Pereira, Carlos-Filipe}},
  issn         = {{1873-2399}},
  language     = {{eng}},
  note         = {{Conference Abstract}},
  number       = {{Suppl}},
  pages        = {{72--72}},
  publisher    = {{Elsevier}},
  series       = {{Experimental Hematology}},
  title        = {{Restoring the immunogenicity of cancer cells with dendritic cell reprogramming}},
  url          = {{http://dx.doi.org/10.1016/j.exphem.2021.12.281}},
  doi          = {{10.1016/j.exphem.2021.12.281}},
  volume       = {{100}},
  year         = {{2021}},
}