3 research outputs found
A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression
Targeting immune checkpoint pathways, such as programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) or its receptor programmed cell death-1 (PD-1) has shown improved survival for patients with numerous types of cancers, not limited to lung cancer, melanoma, renal cell carcinoma, and Hodgkin lymphoma. PD-L1 is a co-inhibitory molecule whose expression on the surface of tumor cells is associated with worse prognosis in many tumors. Here we describe a splice variant (secPD-L1) that does not splice into the transmembrane domain, but instead produces a secreted form of PD-L1 that has a unique 18 amino acid tail containing a cysteine that allows it to homodimerize and more effectively inhibit lymphocyte function than monomeric soluble PD-L1. We show that recombinant secPD-L1 can dimerize and inhibit T-cell proliferation and IFN-gamma production in vitro. The secPD-L1 variant is expressed by malignant cells in vitro that also express high levels of full-length PD-L1. Transcriptomic analysis of gene expression across The Cancer Genome Atlas found the strongest association of secPD-L1 with full-length PD-L1, but also with subsets of immunologic genes, such as in myeloid-derived suppressor cells. Moreover, the splice variant is also expressed in normal tissues and within normal peripheral blood cells it is preferentially expressed in activated myeloid cells. This is the first report of a form of secreted PD-L1 that homodimerizes and is functionally active. SecPD-L1 may function as a paracrine negative immune regulator within the tumor, since secPD-L1 does not require a cell-to-cell interaction to mediate its inhibitory effect
PowerPoint Slides for: Clinical Features and Outcomes of a Racially Diverse Population with Fibrillary Glomerulonephritis
<p><b><i>Background:</i></b> Fibrillary glomerulonephritis is
characterized by randomly arranged fibrils, approximately 20 nm in
diameter by electron microscopy. Patients present with proteinuria,
hematuria and kidney insufficiency, and about half of the reported
patients progress to end-stage kidney disease within 4 years. The
dependence of patient characteristics and outcomes on race has not been
explored. In this study, we describe a cohort of patients with
fibrillary glomerulonephritis and compare their clinical characteristics
and outcomes with those of patients previously described. <b><i>Methods:</i></b>
The University of North Carolina (UNC) Nephropathology Database was
used to retrospectively identify patients diagnosed with fibrillary
glomerulonephritis between 1985 and 2015. Of these patients, those
treated at UNC were selected. Their demographic and clinical
characteristics - including signs and symptoms, comorbidities,
laboratory values, treatments and outcomes - were compared with those of
patients described earlier. <b><i>Results:</i></b> Among the 287
patients identified, 42 were treated at the UNC Kidney Center. When
compared to earlier cohorts, a higher frequency of black race, hepatitis
C virus (HCV) infection and use of hemodialysis were noted in both
black and HCV-positive patients. Autoimmune diseases, infections and
malignancies were frequently observed, present in over half of all
cases. <b><i>Conclusion:</i></b> According to this study, fibrillary
glomerulonephritis represents a secondary glomerular disease process
(associated with autoimmune disease, infection or malignancy) in many
cases and hence screening is essential. As the screening for
comorbidities increased over time, more underlying causes were
identified. We noted a high frequency of HCV among black patients,
suggesting a possible causative association. Treatment of underlying
disease is essential for patients for the best outcome.</p
Supplementary Material for: Clinical Features and Outcomes of a Racially Diverse Population with Fibrillary Glomerulonephritis
<p><b><i>Background:</i></b> Fibrillary glomerulonephritis is
characterized by randomly arranged fibrils, approximately 20 nm in
diameter by electron microscopy. Patients present with proteinuria,
hematuria and kidney insufficiency, and about half of the reported
patients progress to end-stage kidney disease within 4 years. The
dependence of patient characteristics and outcomes on race has not been
explored. In this study, we describe a cohort of patients with
fibrillary glomerulonephritis and compare their clinical characteristics
and outcomes with those of patients previously described. <b><i>Methods:</i></b>
The University of North Carolina (UNC) Nephropathology Database was
used to retrospectively identify patients diagnosed with fibrillary
glomerulonephritis between 1985 and 2015. Of these patients, those
treated at UNC were selected. Their demographic and clinical
characteristics - including signs and symptoms, comorbidities,
laboratory values, treatments and outcomes - were compared with those of
patients described earlier. <b><i>Results:</i></b> Among the 287
patients identified, 42 were treated at the UNC Kidney Center. When
compared to earlier cohorts, a higher frequency of black race, hepatitis
C virus (HCV) infection and use of hemodialysis were noted in both
black and HCV-positive patients. Autoimmune diseases, infections and
malignancies were frequently observed, present in over half of all
cases. <b><i>Conclusion:</i></b> According to this study, fibrillary
glomerulonephritis represents a secondary glomerular disease process
(associated with autoimmune disease, infection or malignancy) in many
cases and hence screening is essential. As the screening for
comorbidities increased over time, more underlying causes were
identified. We noted a high frequency of HCV among black patients,
suggesting a possible causative association. Treatment of underlying
disease is essential for patients for the best outcome.</p