التفاصيل البيبلوغرافية
| العنوان: |
Restoring tumor immunogenicity with dendritic cell reprogramming. |
| المؤلفون: |
Zimmermannova, Olga, Ferreira, Alexandra G., Ascic, Ervin, Velasco Santiago, Marta, Kurochkin, Ilia, Hansen, Morten, Met, Özcan, Caiado, Inês, Shapiro, Ilja E., Michaux, Justine, Humbert, Marion, Soto-Cabrera, Diego, Benonisson, Hreinn, Silvério-Alves, Rita, Gomez-Jimenez, David, Bernardo, Carina, Bauden, Monika, Andersson, Roland, Höglund, Mattias, Miharada, Kenichi |
| المصدر: |
Science Immunology; 2023, Vol. 8 Issue 85, p1-20, 20p |
| مستخلص: |
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. Editor's summary: Cancer cells down-regulate antigen presentation to evade recognition by the immune system. Zimmermannova et al. investigated the ability to reprogram cancer cells into tumor-derived antigen-presenting cells (tumor-APCs). Mouse or primary human cancer cells transduced with the transcription factors PU.1, IRF8, and BATF3 acquired a stable dendritic cell phenotype, could present endogenous tumor antigens to stimulate the effector function of CD8+ T cells, and showed decreased tumorigenicity. In mouse models, intratumoral injection of tumor-APCs decreased tumor growth, increased the survival of tumor-bearing mice, and enhanced responses to immune checkpoint inhibitors. This study highlights that future immunotherapies aimed at reprogramming cancer cells in situ could combine reversing malignancy with mobilizing the cellular antigen-presenting machinery to enhance the activity of CD8+ T cells toward tumors. —Sarah H. Ross [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
