Dendritic Cell Reprogramming for Cancer Immunotherapy
Ascic, Ervin LU
(2025)
In Lund University, Faculty of Medicine Doctoral Dissertation Series
- Abstract
- The success of cancer immunotherapy depends on the priming of tumor-specific T and B lymphocytes. However, tumor cells often downregulate antigen presentation and mount an immunosuppressive tumor microenvironment (TME), which excludes immunogenic cells and hinders broad success of cancer immunotherapies, including immune checkpoint blockade (ICB). Type 1 conventional dendritic cells (cDC1s) are critical for recruiting and activating tumor-specific T and B cells and correlate with response to ICB. However, their unique functional properties have not been deployed yet for immunotherapy. Cellular reprogramming provides a strategy for generating individual cell types through enforced expression of transcription factor combinations. Previous... (More)
- The success of cancer immunotherapy depends on the priming of tumor-specific T and B lymphocytes. However, tumor cells often downregulate antigen presentation and mount an immunosuppressive tumor microenvironment (TME), which excludes immunogenic cells and hinders broad success of cancer immunotherapies, including immune checkpoint blockade (ICB). Type 1 conventional dendritic cells (cDC1s) are critical for recruiting and activating tumor-specific T and B cells and correlate with response to ICB. However, their unique functional properties have not been deployed yet for immunotherapy. Cellular reprogramming provides a strategy for generating individual cell types through enforced expression of transcription factor combinations. Previous studies have shown that fibroblasts can be converted into cDC1-like cells by direct cell reprogramming employing the minimal set of transcription factors (TFs) PU.1, IRF8, and BATF3 (PIB).
In this PhD project, I hypothesized that cellular reprogramming of cancer cells into cDC1-like cells can be employed to restore their immunogenicity and endow reprogrammed cells with hallmark functions of cDC1 to elicit anti-tumor immunity. Enforced expression of PIB in cancer cell lines and patient-derived cancers was sufficient to induce hallmark phenotypic, transcriptional and functional features of cDC1. Reprogrammed cancer cells increased the presentation of tumor-associated antigens on MHC-I, acquired the capacity to secrete pro-inflammatory cytokines including IL-12 and lymphocyte-recruiting chemokines CXCL9/10 and presented endogenous and exogenous antigens on MHC-I to prime naïve CD8+ T cells and on MHC-II for CD4+ T cell activation. When injected into established ICB-resistant melanoma tumors in mice, cDC1-like cells elicited systemic tumor-specific anti-tumor immunity, and their therapeutic efficacy was further increased in combination with ICB anti-PD-1 and anti-CTLA-4. However, ex vivo cell manipulation and re-administration of reprogrammed cells pose significant challenges for clinical application. Thus, we developed an intratumoral cancer gene therapy based on adenoviral delivery of the PIB transcription factors, which endowed cancer cells within the TME to present antigens as cDC1. The in vivo cDC1 reprogramming immunotherapy remodeled the TME by recruiting T and B cells to form tertiary lymphoid structures (TLS) and expanded polyclonally cytotoxic and memory T cells. In vivo cDC1 reprogramming outperformed anti-PD-1 therapy and achieved tumor regressions and protection from re-challenges across multiple orthotopic and subcutaneous models of glioblastoma, breast, melanoma, lung, colon, and bladder cancers. Cytotoxic CD4+ T cells were critical for tumor regressions, while B cells played a supporting role through the production of tumor-specific IgM and IgG1 antibodies, which suppressed tumor growth and persisted long-term in circulation. In human tumor spheroids and xenografts, reprogramming to immunogenic cDC1-like cells progressed faster and independently of immunosuppression, which usually limits immunotherapy.
Overall, my studies demonstrated that in vivo cDC1 reprogramming can be emloyed as a tumor-agnostic gene therapy that engages both cellular and humoral arms of the immune system eliciting durable and systemic anti-tumor immunity. Furthermore, we identified tumor-specific antibodies as potential blood- based biomarkers to monitor response. Ultimately, these findings pave the way for clinical testing of a new class of immunotherapies based on the recreation of immune cell subsets in vivo to overcome current limitations of ICB. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/08339e29-f85e-4741-813c-7afe8658a423
- author
- Ascic, Ervin
LU
- supervisor
-
- Filipe Pereira LU
- William Agace LU
- opponent
-
- Professor Allison, James P., MD Anderson Cancer Center University of Texas, USA
- organization
- publishing date
- 2025
- type
- Thesis
- publication status
- published
- subject
- keywords
- Cancer immunotherapy, Cell reprogramming, Dendritic cells, Antigen presentation, Cancer, Immunology, Gene therapy
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2025:79
- pages
- 159 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- LUX Aula, hus C, Helgonavägen 3, Lund. Join by Zoom: https://lu-se.zoom.us/j/65839672545
- defense date
- 2025-09-03 15:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-732-3
- language
- English
- LU publication?
- yes
- id
- 08339e29-f85e-4741-813c-7afe8658a423
- date added to LUP
- 2025-08-08 09:40:37
- date last changed
- 2025-08-12 19:59:20
@phdthesis{08339e29-f85e-4741-813c-7afe8658a423,
abstract = {{The success of cancer immunotherapy depends on the priming of tumor-specific T and B lymphocytes. However, tumor cells often downregulate antigen presentation and mount an immunosuppressive tumor microenvironment (TME), which excludes immunogenic cells and hinders broad success of cancer immunotherapies, including immune checkpoint blockade (ICB). Type 1 conventional dendritic cells (cDC1s) are critical for recruiting and activating tumor-specific T and B cells and correlate with response to ICB. However, their unique functional properties have not been deployed yet for immunotherapy. Cellular reprogramming provides a strategy for generating individual cell types through enforced expression of transcription factor combinations. Previous studies have shown that fibroblasts can be converted into cDC1-like cells by direct cell reprogramming employing the minimal set of transcription factors (TFs) PU.1, IRF8, and BATF3 (PIB).<br/>In this PhD project, I hypothesized that cellular reprogramming of cancer cells into cDC1-like cells can be employed to restore their immunogenicity and endow reprogrammed cells with hallmark functions of cDC1 to elicit anti-tumor immunity. Enforced expression of PIB in cancer cell lines and patient-derived cancers was sufficient to induce hallmark phenotypic, transcriptional and functional features of cDC1. Reprogrammed cancer cells increased the presentation of tumor-associated antigens on MHC-I, acquired the capacity to secrete pro-inflammatory cytokines including IL-12 and lymphocyte-recruiting chemokines CXCL9/10 and presented endogenous and exogenous antigens on MHC-I to prime naïve CD8+ T cells and on MHC-II for CD4+ T cell activation. When injected into established ICB-resistant melanoma tumors in mice, cDC1-like cells elicited systemic tumor-specific anti-tumor immunity, and their therapeutic efficacy was further increased in combination with ICB anti-PD-1 and anti-CTLA-4. However, ex vivo cell manipulation and re-administration of reprogrammed cells pose significant challenges for clinical application. Thus, we developed an intratumoral cancer gene therapy based on adenoviral delivery of the PIB transcription factors, which endowed cancer cells within the TME to present antigens as cDC1. The in vivo cDC1 reprogramming immunotherapy remodeled the TME by recruiting T and B cells to form tertiary lymphoid structures (TLS) and expanded polyclonally cytotoxic and memory T cells. In vivo cDC1 reprogramming outperformed anti-PD-1 therapy and achieved tumor regressions and protection from re-challenges across multiple orthotopic and subcutaneous models of glioblastoma, breast, melanoma, lung, colon, and bladder cancers. Cytotoxic CD4+ T cells were critical for tumor regressions, while B cells played a supporting role through the production of tumor-specific IgM and IgG1 antibodies, which suppressed tumor growth and persisted long-term in circulation. In human tumor spheroids and xenografts, reprogramming to immunogenic cDC1-like cells progressed faster and independently of immunosuppression, which usually limits immunotherapy.<br/>Overall, my studies demonstrated that in vivo cDC1 reprogramming can be emloyed as a tumor-agnostic gene therapy that engages both cellular and humoral arms of the immune system eliciting durable and systemic anti-tumor immunity. Furthermore, we identified tumor-specific antibodies as potential blood- based biomarkers to monitor response. Ultimately, these findings pave the way for clinical testing of a new class of immunotherapies based on the recreation of immune cell subsets in vivo to overcome current limitations of ICB.}},
author = {{Ascic, Ervin}},
isbn = {{978-91-8021-732-3}},
issn = {{1652-8220}},
keywords = {{Cancer immunotherapy; Cell reprogramming; Dendritic cells; Antigen presentation; Cancer; Immunology; Gene therapy}},
language = {{eng}},
number = {{2025:79}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Dendritic Cell Reprogramming for Cancer Immunotherapy}},
url = {{https://lup.lub.lu.se/search/files/224950751/Doctoral_Thesis_Ervin_Ascic_Dendritic_Cell_Reprogramming_for_Cancer_Immunotherapy.pdf}},
year = {{2025}},
}