T-SIGn tumor reengineering therapy and CAR T cells synergize in combination therapy to clear human lung tumor xenografts and lung metastases in NSG mice.

Although chimeric antigen receptor (CAR) T cells have emerged as highly effective treatments for patients with hematologic malignancies, similar efficacy has not been achieved in the context of solid tumors. There are several reasons for this disparity including a) fewer solid tumor target antigens, b) heterogenous target expression amongst tumor cells, c) poor trafficking of CAR T cells to the solid tumor and d) an immunosuppressive tumor microenvironment (TME). Oncolytic viruses have the potential to change this paradigm by a) directly lysing tumor cells and releasing tumor neoantigens, b) stimulating the local host innate immune response to release cytokines and recruit additional innate and adaptive immune cells, c) carrying virus-encoded transgenes to "re-program" the TME to a pro-inflammatory environment and d) promoting an adaptive immune response to the neoantigens in this newly permissive TME.

An Fc-free EGFR-specific 4-1BB-agonistic Trimerbody Displays Broad Antitumor Activity in Humanized Murine Cancer Models without Toxicity.

Purpose: The induction of 4-1BB signaling by agonistic antibodies can drive the activation and proliferation of effector T cells and thereby enhance a T-cell-mediated antitumor response. Systemic administration of anti-4-1BB-agonistic IgGs, although effective preclinically, has not advanced in clinical development due to their severe hepatotoxicity.

Experimental Design: Here, we generated a humanized EGFR-specific 4-1BB-agonistic trimerbody, which replaces the IgG Fc region with a human collagen homotrimerization domain.

A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity.

The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with FcγR interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8EGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain.

Distinct Trafficking of Cell Surface and Endosomal TIM-1 to the Immune Synapse.

The T cell costimulatory molecule TIM-1 (T cell/transmembrane, mucin and immunoglobulin domain protein 1) sorts mainly to endosomes in lymphoid cells. At difference from the cell surface protein, endosomal TIM-1 translocates to the immune synapse (IS), where it can contribute to antigen-dependent T cell costimulation. TIM-1 ligands increase the amount of cell surface protein, preventing its traffic to the IS.

APRIL promotes breast tumor growth and metastasis and is associated with aggressive basal breast cancer.

APRIL (a proliferation-inducing ligand) is a cytokine of the tumor necrosis factor family associated mainly with hematologic malignancies. APRIL is also overexpressed in breast carcinoma tissue lesions, although neither its role in breast tumorigenesis nor the underlying molecular mechanism is known. Here, we show that several breast cancer cell lines express APRIL and both its receptors, B cell maturation antigen (BCMA) and transmembrane activator and CAML-interactor (TACI), independently of luminal or basal tumor cell phenotype, and that the mitogen-activated protein kinases p38, ERK1/2, and JNK1/2 are activated in response to APRIL.

NFκB activation by modified vaccinia virus as a novel strategy to enhance neutrophil migration and HIV-specific T-cell responses.

Neutrophils are antigen-transporting cells that generate vaccinia virus (VACV)-specific T-cell responses, yet how VACV modulates neutrophil recruitment and its significance in the immune response are unknown. We generated an attenuated VACV strain that expresses HIV-1 clade C antigens but lacks three specific viral genes (A52R, K7R, and B15R). We found that these genes act together to inhibit the NFκB signaling pathway.

High-resolution live-cell imaging reveals novel cyclin A2 degradation foci involving autophagy.

Cyclin A2 is a key player in the regulation of the cell cycle. Its degradation in mid-mitosis relies on the ubiquitin-proteasome system (UPS). Using high-resolution microscopic imaging, we find that cyclin A2 persists beyond metaphase.

APRIL and BAFF proteins increase proliferation of human adipose-derived stem cells through activation of Erk1/2 MAP kinase.

Human adipose-derived stem cells (hASC) are mesenchymal stem cells with reduced immunogenicity and the ability to modulate immune responses. APRIL and BAFF proteins are overexpressed in inflammatory and autoimmune diseases for which allogeneic hASC therapy is currently under clinical investigation. Modification of hASC properties by the tissue microenvironment could be a critical factor in patient outcome and is still not well understood.