Sammanfattning

Introduction
An important hallmark of cancer is escaping the immune system. Despite advances in immunotherapy, only a subset of patients experiences clinical benefits. It was shown that adoptive T cell or checkpoint inhibition therapy rely on the presence of conventional dendritic cells type 1 (cDC1). cDC1 excel in recruiting and priming protective CD8+ T cells through cross-presentation. However, in tumors cDC1 are often impaired in function. Recently, we demonstrated that overexpression of PU.1, IRF8 and BATF3 (PIB) imposes a cDC1 fate in fibroblasts by direct cell reprogramming. As such, we hypothesise that a similar combination of transcription factors would reprogram cancer cells into tumor-antigen presenting cells (tumor-APCs) and set in motion antigen-specific immunity.

Material and Methods
30 mouse tumor lines were selected to evaluate reprogramming into tumor-APCs. Reprogramming was induced by overexpression of PIB via lentiviral transduction. The phenotype was profiled by flow cytometry for cDC1 markers CD45, MHC-II, CLEC9A, XCR1 and APC markers MHC-I, CD80/86. Population mRNA-seq was applied to assess transcriptional changes. To assess cDC1 functions, cytokine secretion, cross-presentation and T cell cytotoxicity assays were performed. In vivo, ovalbumin expressing tumors were established and treated by adoptive transfer of tumor-APCs. Tumor growth and animal survival were monitored.

Results and Discussions
Upon transduction with PIB, 26 solid tumor and 4 leukemia lines initiated expression of CD45, MHC-II, at efficiencies ranging from 0.5-57.7%. Reprogramming was accompanied by CLEC9A, XCR1 and MHC-I, CD80/86 upregulation. Transcriptomic analysis of low immunogenic lines B16 and LLC, reveals that PIB overwrites the cancer transcriptome and imposes antigen presentation and cDC1 gene signatures. Importantly, tumor-APCs present endogenous antigens on MHC-I and become prone to T cell mediated killing. Functionally, reprogrammed tumor-APCs secrete inflammatory cytokines such as IL12p70 and strikingly, acquire the ability to crosspresent antigens and prime naïve CD8+ T cells. In vivo, adoptive transfer of cross-presenting tumor-APCs delays tumor growth and extends survival of animals.

Conclusion
This approach combines cDC1 antigen presentation abilities with endogenous generation of tumor antigens. The induction of a cDC1 identity in tumor cells sets in motion T cell responses and makes them target for T cell mediated killing. Our study represents a pioneering contribution merging cell reprogramming with immunotherapy.
Originalspråkengelska
StatusPublished - 2022 juni 22
EvenemangEuropean Association for Cancer Research 2022 - Congress: Innovative Cancer Science: Translating Biology to Medicine - Avda. Alcalde Luis Uruñuela, nº 1, Seville, Spanien
Varaktighet: 2022 juni 202022 juni 23
Konferensnummer: 28th
https://www.eacr2022.org

Konferens

KonferensEuropean Association for Cancer Research 2022 - Congress
Förkortad titelEACR2022
Land/TerritoriumSpanien
OrtSeville
Period2022/06/202022/06/23
Internetadress

Ämnesklassifikation (UKÄ)

  • Cancer och onkologi

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