Supplementary Figures S1-8 from An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer
Supplementary Figures S1-8. Fig. S1: CD11b+CD11c+MHC-II+ cells exhibit DC phenotype and accumulate at multiple metastatic sites. Fig. S2: PDAC cells produce large amounts of GM-CSF and stimulate Mo-DC differentiation. Fig. S3: Liver DC from tumor-bearing mice efficiently activate T cells in conventional assays. Fig. S4: Metastasis-associated DC stimulate nTreg proliferation while suppressing CD8 T cells through PD-1 ligand expression. Fig. S5: MGL2+ cells exhibit DC phenotype and their depletion activates multiple lymphocyte populations. Fig. S6: Blocking PD-L2 reduces metastasis without affecting primary tumor burden. Fig. S7: PD-L2+ and MGL+ cells are present in human PDAC tissues. Fig. S8: Development and function of CD11b+ DC in PDAC metastasis.
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ARTICLE ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) after complete surgical resection is often followed by distant metastatic relapse for reasons that remain unclear. In this study, we investigated how the immune response at secondary sites affects tumor spread in murine models of metastatic PDAC. Early metastases were associated with dense networks of CD11b+CD11c+MHC-II+CD24+CD64lowF4/80low dendritic cells (DC), which developed from monocytes in response to tumor-released GM-CSF. These cells uniquely expressed MGL2 and PD-L2 in the metastatic microenvironment and preferentially induced the expansion of T regulatory cells (Treg) in vitro and in vivo. Targeted depletion of this DC population in Mgl2DTR hosts activated cytotoxic lymphocytes, reduced Tregs, and inhibited metastasis development. Moreover, blocking PD-L2 selectively activated CD8 T cells at secondary sites and suppressed metastasis, suggesting that the DCs use this particular pathway to inhibit CD8 T-cell–mediated tumor immunity. Phenotypically similar DCs accumulated at primary and secondary sites in other models and in human PDAC. These studies suggest that a discrete DC subset both expands Tregs and suppresses CD8 T cells to establish an immunosuppressive microenvironment conducive to metastasis formation. Therapeutic strategies to block the accumulation and immunosuppressive activity of such cells may help prevent PDAC progression and metastatic relapse after surgical resection. Cancer Res; 77(15); 4158–70. ©2017 AACR.Usage metrics
