Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Restoring tumor immunogenicity with dendritic cell reprogramming

Zimmermannova, Olga LU ; Ferreira, Alexandra G LU orcid ; Ascic, Ervin LU orcid ; Velasco Santiago, Marta ; Kurochkin, Ilia LU ; Hansen, Morten ; Met, Özcan ; Caiado, Inês LU ; Shapiro, Ilja E and Michaux, Justine , et al. (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
+ 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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
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
  • scopus:85164260695
  • pmid:37418548
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
2024-04-19 23:18:45
@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}},
}