Allogeneic stem cells engineered to release interferon β and scFv-PD1 target glioblastoma and alter the tumor microenvironment.

Highly malignant brain tumors, glioblastomas (GBM), are immunosuppressive, thereby limiting current promising immunotherapeutic approaches. In this study, we created interferon receptor 1 knockout allogeneic mesenchymal stem cells (MSC) to secrete dual-function pro-apoptotic and immunomodulatory interferon (IFN) β (MSC-IFNβ) using a single lentiviral vector CRISPR/Cas9 system. We show that MSC-IFNβ induces apoptosis in GBM cells and upregulates the cell surface expression of programmed death ligand-1 in tumor cells.

Engineered cell-based therapies in ex vivo ready-made CellDex capsules have therapeutic efficacy in solid tumors.

Encapsulated cell-based therapies for solid tumors have shown promising results in pre-clinical settings. However, the inability to culture encapsulated therapeutic cells prior to their transplantation has limited their translation into clinical settings. In this study, we created a wide variety of engineered therapeutic cells (ThC) loaded in micropore-forming gelatin methacryloyl (GelMA) hydrogel (CellDex) capsules that can be cultured in vitro prior to their transplantation in surgically debulked solid tumors.

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies.

Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 are enzymes which post-translationally modify proteins through poly(ADP-ribosyl)ation (PARylation)-the transfer of ADP-ribose chains onto amino acid residues-with a resultant modulation of protein function. Many targets of PARP-1/2-dependent PARylation are involved in the DNA damage response and hence, the loss of these proteins disrupts a wide range of biological processes, from DNA repair and epigenetics to telomere and centromere regulation. The central role of these PARPs in DNA metabolism in cancer cells has led to the development of PARP inhibitors as new cancer therapeutics, both as adjuvant treatment potentiating chemo-, radio-, and immuno-therapies and as monotherapy exploiting cancer-specific defects in DNA repair.

Coordinated signals from PARP-1 and PARP-2 are required to establish a proper T cell immune response to breast tumors in mice.

Poly(ADP-ribose)-polymerase (PARP)-1 and PARP-2 play an essential role in the DNA damage response. Based on this effect of PARP in the tumor cell itself, PARP inhibitors have emerged as new therapeutic tools both approved and in clinical trials. However, the interactome of multiple other cell types, particularly T cells, within the tumor microenvironment are known to either favor or limit tumorigenesis.

Coordinated signals from the DNA repair enzymes PARP-1 and PARP-2 promotes B-cell development and function.

Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 regulate the function of various DNA-interacting proteins by transferring ADP-ribose emerging from catalytic cleavage of cellular β-NAD. Hence, mice lacking PARP-1 or PARP-2 show DNA perturbations ranging from altered DNA integrity to impaired DNA repair. These effects stem from the central role that PARP-1 and PARP-2 have on the cellular response to DNA damage.