Restoring the immunogenicity of cancer cells with dendritic cell reprogramming
(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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https://lup.lub.lu.se/record/b7beafca-8d2c-4c45-94d0-252c677b0a14
- author
- Ferreira, Alexandra Gabriela LU ; Ascic, Ervin LU ; Caiado, Inês LU ; Zimmermannova, Olga LU ; Kurochkin, Ilia LU ; Rosa, Fábio LU ; Benonisson, Hreinn LU ; Pires, Cristiana LU and Pereira, Carlos-Filipe LU
- organization
- publishing date
- 2021
- 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}}, }