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Sökning: onr:"swepub:oai:lup.lub.lu.se:8a36f9bd-50f7-4510-b88b-12d16c32cf5e" > Reprogramming prima...

  • Velasco Santiago, Marta (författare)

Reprogramming primary melanoma cells to dendritic cell fate enhances tumor immunogenicity

  • Artikel/kapitelEngelska2022

Förlag, utgivningsår, omfång ...

  • 2022

Nummerbeteckningar

  • LIBRIS-ID:oai:lup.lub.lu.se:8a36f9bd-50f7-4510-b88b-12d16c32cf5e
  • https://lup.lub.lu.se/record/8a36f9bd-50f7-4510-b88b-12d16c32cf5eURI

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  • Språk:engelska
  • Sammanfattning på:engelska

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  • Ämneskategori:kon swepub-publicationtype
  • Ämneskategori:ref swepub-contenttype

Anmärkningar

  • Background Direct cell reprogramming is characterized by the use of defined factors to rewire the transcriptional and epigenetic network of one cell-type into one of a different lineage. We have recently identified the transcription factors PU.1, IRF8, and BAFT3 (PIB) as sufficient to induce a type 1 conventional dendritic cell (cDC1) fate in both somatic and cancer cells.1,2 cDC1 is a rare dendritic cell subset with unique ability to initiate de novo T cell responses after migrating to the tumor site. Several studies have shown that higher levels of cDC1s within the tumor microenvironment strongly correlate with good prognosis and responsiveness to immunotherapy for patients with melanoma.3 Therefore, we hypothesized that PIB factors could reprogram primary melanoma cells into functional antigen presenting cDC1s capable of presenting tumor antigens and restoring anti-tumor immunity.Methods Primary melanoma cells from eight patients were reprogrammed into cDC1-like cells through transduction with lentivirus constitutively expressing PIB. Reprogrammed cells were profiled at multiple time-points to characterize reprogramming efficiency, phenotype, and functional properties including cytokine secretion and the capacity to prime T cells.Results All eight PIB-transduced melanoma cells progressively acquired a cDC1 surface phenotype characterized by the expression of CD45 and HLA-DR, marking the acquisition of hematopoietic and antigen presentation phenotype. The cell reprogramming process was consistent across all cell lines. Induced cDC1s also expressed CD11c, the cDC1-specific markers CLEC9A and CD141 as well as the costimulatory molecules CD40, CD80 and CD86. Functionally, cDC1-like melanoma cells at day 9 secreted the human cDC1-specific cytokines IL12p70 and IL-29 upon stimulation with Poly(I:C). After pulsing with a 9mer MART-1 peptide restricted to HLA-A2, cDC1-like melanoma cells were able to prime allogeneic HLA-A2 matched naïve CD8+ T cells and resulted in expansion of MART-1-specific T-cells after an eight-day co-culture with IL-2 and IL-7. Moreover, autologous tumor-infiltrating lymphocytes (TILs) were more reactive (higher expression of CD107a, CD137, IFN-gamma, and TNF-alpha) and cytotoxic towards cDC1-like melanoma cells compared to the original tumor cells.Conclusions Here, we demonstrated that melanoma cells from multiple patients can be efficiently reprogrammed into cDC1-like cells and present tumor-associated antigens. These results lay the groundwork for the development of cDC1 reprogramming as an innovative cancer immunotherapy to counteract immune escape and reactivating anti-tumor immunity.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Zimmermannova, OlgaLund University,Lunds universitet,Cellulär omprogrammering i hematopoes och immunitet,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Cell Reprogramming in Hematopoiesis and Immunity,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)ol1273zi (författare)
  • Hansen, Morten (författare)
  • Fiúza Rosa, FábioLund University,Lunds universitet,Cellulär omprogrammering i hematopoes och immunitet,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Cell Reprogramming in Hematopoiesis and Immunity,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Asgard Therapeutics AB(Swepub:lu)fa8852fi (författare)
  • Pires, CristianaLund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Cellulär omprogrammering i hematopoes och immunitet,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Cell Reprogramming in Hematopoiesis and Immunity,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Asgard Therapeutics AB(Swepub:lu)cr5211fe (författare)
  • Met, ÖzcanUniversity of Copenhagen (författare)
  • Pereira, FilipeLund University,Lunds universitet,Cellulär omprogrammering i hematopoes och immunitet,Forskargrupper vid Lunds universitet,WCMM- Wallenberg center för molekylär medicinsk forskning,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Cell Reprogramming in Hematopoiesis and Immunity,Lund University Research Groups,WCMM-Wallenberg Centre for Molecular Medicine,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)ca4155pe (författare)
  • Marie Svane, IngeUniversity of Copenhagen (författare)
  • Cellulär omprogrammering i hematopoes och immunitetForskargrupper vid Lunds universitet (creator_code:org_t)

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