Regulatory T cell depletion causes compensatory immune suppression and accelerated pancreatic carcinogenesis.

Regulatory T cells (Treg) are common in the tumor microenvironment in both human pancreatic cancer and in genetically engineered mouse models of the disease. Previous studies in orthotopic syngeneic models of pancreatic cancer -recapitulated in our own data- indicated that Treg depletion results CD8+ T cell-mediated tumor regression. In human patients and in mouse models, regulatory T cells accumulate during the onset of Pancreatic Intraepithelial Neoplasia (PanIN), the earliest steps of carcinogenesis. We thus generated a genetic model to investigate the role of regulatory T cells during the onset of pancreatic carcinogenesis. Unexpectedly, depletion of Tregs during early stages of carcinogenesis led to accelerated tumor progression. Overall design: We are using KC;Foxp3DTR mice generated by crossing KC (Ptf1a-Cre;LSL-KrasG12D) with Foxp3DTR (B6.129(Cg)-Foxp3tm3(DTR/GFP)Ayr/J, Jackson Laboratory). We depleted Foxp3-expressing Tregs by Diphtheria Toxin (DT) injection to determine the requirement of Tregs during oncogenic Kras induced Pancreatic Intraepithelial Neoplasia (PanIN) formation and maintenance. To investigate the mechanisms underlying the tumor-promoting effect of Treg depletion in KC; Foxp3DTR mice we performed RNA sequencing (RNAseq) for myeloid cells (DAPI-EpCAM-CD45+CD11b+) flow-sorted from KC and KC; Foxp3DTR pancreata.

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Zhang Y, Lazarus J, Steele NG, Yan W, Lee HJ, Nwosu ZC, Halbrook CJ, Menjivar RE, Kemp SB, Sirihorachai VR, Velez-Delgado A, Donahue K, Carpenter ES, Brown KL, Irizarry-Negron V, Nevison AC, Vinta A, Anderson MA, Crawford HC, Lyssiotis CA, Frankel TL, Bednar F, Pasca di Magliano M