Fundamentals to therapeutics: Epigenetic modulation of CD8 T Cell exhaustion in the tumor microenvironment.

In the setting of chronic antigen exposure in the tumor microenvironment (TME), cytotoxic CD8 T cells (CTLs) lose their immune surveillance capabilities and ability to clear tumor cells as a result of their differentiation into terminally exhausted CD8 T cells. Immune checkpoint blockade (ICB) therapies reinvigorate exhausted CD8 T cells by targeting specific inhibitory receptors, thus promoting their cytolytic activity towards tumor cells. Despite exciting results with ICB therapies, many patients with solid tumors still fail to respond to such therapies and patients who initially respond can develop resistance.

SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity.

Background: Multiple sclerosis (MS) is a chronic, debilitating condition characterized by CNS autoimmunity stemming from a complex etiology involving both environmental and genetic factors. Our current understanding of MS points to dysregulation of the immune system as the pathogenic culprit, however, it remains unknown as to how the many genes associated with increased susceptibility to MS are involved. One such gene linked to MS susceptibility and known to regulate immune function is the self-ligand immune cell receptor SLAMF7.

ERAP1 is a critical regulator of inflammasome-mediated proinflammatory and ER stress responses.

Background: In addition to its role in antigen presentation, recent reports establish a new role for endoplasmic reticulum aminopeptidase 1 (ERAP1) in innate immunity; however, the mechanisms underlying these functions are not fully defined. We previously confirmed that loss of ERAP1 functions resulted in exaggerated innate immune responses in a murine in vivo model. Here, we investigated the role of ERAP1 in suppressing inflammasome pathways and their dependence on ER stress responses.

Adenoviral delivery of an immunomodulatory protein to the tumor microenvironment controls tumor growth.

Targeted modulation of the immune system against tumors can achieve responses in otherwise refractory cancers, which has spurred efforts aimed at optimizing such strategies. To this end, we have previously investigated cancer immunotherapy approaches using recombinant adenovirus vectors, as well as via modulation of the self-ligand receptor SLAMF7. Here, we present a gene transfer-based immunotherapy approach using targeted expression of a SLAMF7-Fc fusion construct directly into tumors at high concentrations via a recombinant adenoviral vector (Ad-SF7-Fc).

Absence of ERAP1 in B Cells Increases Susceptibility to Central Nervous System Autoimmunity, Alters B Cell Biology, and Mechanistically Explains Genetic Associations between ERAP1 and Multiple Sclerosis.

Hundreds of genes have been linked to multiple sclerosis (MS); yet, the underlying mechanisms behind these associations have only been investigated in a fraction of cases. Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an endoplasmic reticulum-localized aminopeptidase with important roles in trimming peptides destined for MHC class I and regulation of innate immune responses. As such, genetic polymorphisms in have been linked to multiple autoimmune diseases.

SLAMF7 Signaling Reprograms T Cells toward Exhaustion in the Tumor Microenvironment.

T cell exhaustion represents one of the most pervasive strategies tumors employ to circumvent the immune system. Although repetitive, cognate TCR signaling is recognized as the primary driving force behind this phenomenon, and it remains unknown what other forces drive T cell exhaustion in the tumor microenvironment (TME). In this study, we show that activation of the self-ligand SLAMF7 immune receptor on T cells induced STAT1 and STAT3 phosphorylation, expression of multiple inhibitory receptors, and transcription factors associated with T cell exhaustion.

SLAMF7 Is a Critical Negative Regulator of IFN-α-Mediated CXCL10 Production in Chronic HIV Infection.

Current advances in combined antiretroviral therapy have rendered HIV infection a chronic, manageable disease; however, the problem of persistent immune activation still remains despite treatment. The immune cell receptor SLAMF7 has been shown to be upregulated in diseases characterized by chronic immune activation. In this study, we studied the function of the SLAMF7 receptor in immune cells of HIV patients and the impacts of SLAMF7 signaling on peripheral immune activation.

ERAP1 deficient mice have reduced Type 1 regulatory T cells and develop skeletal and intestinal features of Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a prototypical sero-negative autoimmune disease that affects millions worldwide. Single nucleotide polymorphisms in the Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) gene have been linked to AS via GWAS studies, however, the exact mechanism as to how ERAP1 contributes to pathogenesis of AS is not understood. We undertook µCT imaging and histologic analysis to evaluate bone morphology of the axial skeletons of ERAP1 mice and discovered the hallmark skeletal features of AS in these mice, including spinal ankylosis, osteoporosis, and spinal inflammation.

Targeted inhibition of the deubiquitinating enzymes, USP14 and UCHL5, induces proteotoxic stress and apoptosis in Waldenström macroglobulinaemia tumour cells.

Deubiquitinase enzymes (DUBs) of the proteasomal 19S regulatory particle are emerging as important therapeutic targets in several malignancies. Here we demonstrate that inhibition of two proteasome-associated DUBs (USP14 and UCHL5) with the small molecule DUB inhibitor b-AP15, results in apoptosis of human Waldenström macroglobulinaemia (WM) cell lines and primary patient-derived WM tumour cells. Importantly, b-AP15 produced proteotoxic stress and apoptosis in WM cells that have acquired resistance to the proteasome inhibitor bortezomib.