Restoring tumor immunogenicity with dendritic cell reprogramming
(2023) In Science Immunology 8(85).- Abstract
Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen-presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce the cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surfaces of tumor cells, allowing the... (More)
Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen-presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce the cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surfaces of tumor cells, allowing the presentation of endogenous tumor antigens on MHC-I and facilitating targeted killing by CD8
(Less)
+ T cells. Functionally, tumor-APCs engulfed and processed proteins and dead cells, secreted inflammatory cytokines, and cross-presented antigens to naïve CD8
+ T cells. Human primary tumor cells could also be reprogrammed to increase their capability to present antigen and to activate patient-specific tumor-infiltrating lymphocytes. In addition to acquiring improved antigen presentation, tumor-APCs had impaired tumorigenicity in vitro and in vivo. Injection of in vitro generated melanoma-derived tumor-APCs into subcutaneous melanoma tumors delayed tumor growth and increased survival in mice. Antitumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors. Our approach serves as a platform for the development of immunotherapies that endow cancer cells with the capability to process and present endogenous tumor antigens.
- author
- organization
-
- LUCC: Lund University Cancer Centre
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Cell Reprogramming in Hematopoiesis and Immunity (research group)
- Division of Molecular Medicine and Gene Therapy
- WCMM-Wallenberg Centre for Molecular Medicine
- Stem Cell Center
- Department of Immunotechnology
- Urothelial cancer
- Urothelial Cancer Genomics (research group)
- Hepato-Pancreato-Biliary Surgery (research group)
- Surgery (Lund)
- Stem Cell Metabolism (research group)
- publishing date
- 2023-07-07
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Science Immunology
- volume
- 8
- issue
- 85
- article number
- eadd4817
- publisher
- American Association for the Advancement of Science (AAAS)
- external identifiers
-
- pmid:37418548
- scopus:85164260695
- ISSN
- 2470-9468
- DOI
- 10.1126/sciimmunol.add4817
- language
- English
- LU publication?
- yes
- id
- 58eed6b0-e2ea-4d8e-a7f5-11e0d80ab52e
- date added to LUP
- 2023-07-10 21:25:54
- date last changed
- 2024-08-11 09:35:12
@article{58eed6b0-e2ea-4d8e-a7f5-11e0d80ab52e, abstract = {{<p>Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen-presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce the cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surfaces of tumor cells, allowing the presentation of endogenous tumor antigens on MHC-I and facilitating targeted killing by CD8<br> + T cells. Functionally, tumor-APCs engulfed and processed proteins and dead cells, secreted inflammatory cytokines, and cross-presented antigens to naïve CD8<br> + T cells. Human primary tumor cells could also be reprogrammed to increase their capability to present antigen and to activate patient-specific tumor-infiltrating lymphocytes. In addition to acquiring improved antigen presentation, tumor-APCs had impaired tumorigenicity in vitro and in vivo. Injection of in vitro generated melanoma-derived tumor-APCs into subcutaneous melanoma tumors delayed tumor growth and increased survival in mice. Antitumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors. Our approach serves as a platform for the development of immunotherapies that endow cancer cells with the capability to process and present endogenous tumor antigens.<br> </p>}}, author = {{Zimmermannova, Olga and Ferreira, Alexandra G and Ascic, Ervin and Velasco Santiago, Marta and Kurochkin, Ilia and Hansen, Morten and Met, Özcan and Caiado, Inês and Shapiro, Ilja E and Michaux, Justine and Humbert, Marion and Soto-Cabrera, Diego and Benonisson, Hreinn and Silvério-Alves, Rita and Gomez-Jimenez, David and Bernardo, Carina and Bauden, Monika and Andersson, Roland and Höglund, Mattias and Miharada, Kenichi and Nakamura, Yukio and Hugues, Stephanie and Greiff, Lennart and Lindstedt, Malin and Rosa, Fábio F and Pires, Cristiana F and Bassani-Sternberg, Michal and Svane, Inge Marie and Pereira, Carlos-Filipe}}, issn = {{2470-9468}}, language = {{eng}}, month = {{07}}, number = {{85}}, publisher = {{American Association for the Advancement of Science (AAAS)}}, series = {{Science Immunology}}, title = {{Restoring tumor immunogenicity with dendritic cell reprogramming}}, url = {{http://dx.doi.org/10.1126/sciimmunol.add4817}}, doi = {{10.1126/sciimmunol.add4817}}, volume = {{8}}, year = {{2023}}, }