Checkpoint inhibitors (CPIs) targeting programmed death-1(PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications including CPI-induced diabetes (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induces diabetes rapidly. RNA sequencing revealed that cytolytic IFNγ+ CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFNγ and TNFα and included induction of a potentially novel β cell population with transcriptional changes suggesting dedifferentiation. IFNγ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFNγ and anti-TNFα prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.
Ana Luisa Perdigoto, Songyan Deng, Katherine C. Du, Manik Kuchroo, Daniel B. Burkhardt, Alexander Tong, Gary Israel, Marie E. Robert, Stuart P. Weisberg, Nancy Kirkiles-Smith, Angeliki M. Stamatouli, Harriet M. Kluger, Zoe Quandt, Arabella Young, Mei-Ling Yang, Mark J. Mamula, Jordan S. Pober, Mark S. Anderson, Smita Krishnaswamy, Kevan C. Herold
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) efficacy is complicated by graft-versus-host disease (GVHD), a leading cause of morbidity and mortality after transplant. Despite GVHD prophylaxis, 30-70% of patients develop GVHD resulting in susceptibility to infections, relapse and secondary malignancies. Regulatory T-cells (Tregs) have shown efficacy in preventing GVHD, but variably suppressive at high doses. To enhance in vivo suppressor function, murine Treg were transduced to express an anti-human CD19 chimeric antigen receptor (hCAR19) and infused into lethally irradiated hCD19 transgenic recipients for allo-HSCT. As compared to recipients receiving controlled transduced Tregs, those receiving hCAR19 Tregs had a significant decrease in acute GVHD lethality. GVHD amelioration was accomplished with not only maintenance but potentiation of the graft-versus tumor (GVT) response, as recipient hCD19 B-cells and murine hCD19TBL12luc lymphoma cells were both cleared by allogeneic hCAR19 Tregs. Mechanistically, hCAR19 Tregs killed syngeneic hCD19+ but not hCD19- murine TBL12luc cells in vitro in a perforin-dependent, granzyme B-independent manner. Importantly, cyclophosphamide treated hCD19 transgenic mice given hCAR19 cytotoxic T-lymphocytes without allo-HSCT experienced rapid lethality due to systemic toxicity, whereas hCAR19 Tregs avoided this severe complication. In conclusion, CAR19 Tregs are a novel and effective strategy to suppress GVHD without loss of GVT responses.
Sara Bolivar-Wagers, Michael L. Loschi, Sujeong Jin, Govindarajan Thangavelu, Jemma H. Larson, Cameron S. McDonald-Hyman, Ethan A. Aguilar, Asim Saha, Brent H. Koehn, Mehrdad Hefazi, Mark J. Osborn, Michael C. Jensen, John E. Wagner, Christopher A. Pennell, Bruce R. Blazar.
Lysosomal acid lipase (LAL) is a key enzyme in the metabolic pathway of neutral lipids. In the blood of LAL deficient (lal-/-) mice, increased CD11c+ cells were accompanied by up-regulated PD-L1 expression. Single cell RNA sequencing of lal-/- CD11c+ cells identified two distinctive clusters with a major metabolic shift towards glucose utilization and reactive oxygen species (ROS) over-production. Pharmacologically blocking pyruvate dehydrogenase in glycolysis not only reduced CD11c+ cells and their PD-L1 expression, but also reversed their capabilities of T cell suppression and tumor growth stimulation. Colony-stimulating factor 1 receptor (CSF1R) plays an essential role in controlling lal-/- CD11c+ cell homeostasis and function and PD-L1 expression. Inhibition of LAL activity by pharmacological inhibitor increased CD11c, PD-L1 and CSF1R levels in both normal murine myeloid cells and human blood cells. Tumor-bearing mice and human non-small-cell lung cancer (NSCLC) patients also showed CD11c+ cell expansion with PD-L1 and CSF1R up-regulation and immunosuppression. There were positive correlations among CD11c, PD-L1 and CSF1R expression and negative correlations with LAL expression in lung cancer and melanoma patients using the TCGA database and patient samples. Therefore, CD11c+ cells switched their functions to immune suppression and tumor growth stimulation through CSF1R/PD-L1 upregulation and metabolic reprogramming.
Ting Zhao, Sheng Liu, Xinchun Ding, Erica M. Johnson, Nasser H. Hanna, Kanhaiya Singh, Chandan K. Sen, Jun Wan, Hong Du, Cong Yan
Pneumocystis is the most common fungal pulmonary infection in children under 5. In children with primary immunodeficiency, Pneumocystis often presents at 3-6 months that coincides with the nadir of maternal IgG and where IgM is the dominant immunoglobulin isotype. Since B cells are the dominant antigen-presenting cells for Pneumocystis, we hypothesized the presence of fungal specific IgMs in human and mice and that these IgM specificities would predict T cell antigens. We detected fungal specific IgMs in human and mouse serum and utilized immunoprecipitation to determine if any antigens were similar across donors. We then assessed T cell responses to these antigens. We found anti-Pneumocystis IgM in wild-type mice as well as Aicda-/- mice and in human cord blood. Immunoprecipitation of Pneumocystis murina with human cord blood identified shared antigens among these donors. Using class II MHC binding prediction, we designed peptides with these antigens and identified robust peptide specific lung T cell responses after P. murina infection. After mice were immunized with two of the antigens, adoptive transfer of vaccine elicited CD4+ T cells showed effector activity suggesting that these antigens contain protective Pneumocystis epitopes. These data support the notion that germline encoded IgM B-cell receptors are critical in antigen presentation and T cell priming in early Pneumocystis infection.
Kristin Noell, Guixiang Dai, Dora Pungan, Anna Ebacher, Janet E. McCombs, Samuel J. Landry, Jay K. Kolls
In rodent models of type 2 diabetes (T2D), central administration of fibroblast growth factor 1 (FGF1) normalizes elevated blood glucose levels in a manner that is sustained for weeks or months. Increased activity of NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of hyperglycemia in these animals, and the ARC is a key brain area for the antidiabetic action of FGF1. We therefore sought to determine whether FGF1 inhibits NPY/AgRP neurons, and if so whether this inhibitory effect is sufficiently durable to offer a feasible explanation for sustained diabetes remission induced by central administration of FGF1. Here we show that FGF1 inhibits ARC NPY/AgRP neuron activity, both after icv injection in vivo and when applied ex vivo in a slice preparation, and that the underlying mechanism involves increased input from presynaptic GABAergic neurons. Following central administration, the inhibitory effect of FGF1 on NPY/AgRP neurons is also highly durable, lasting for at least two weeks. To our knowledge, no precedent for such a prolonged inhibitory effect exists. Future studies are warranted to determine whether NPY/AgRP neuron inhibition contributes to the sustained antidiabetic action elicited by icv FGF1 injection in rodent models of T2D.
Eunsang Hwang, Jarrad M. Scarlett, Arian F. Baquero, Camdin Bennett, Yanbin Dong, Dominic Chau, Jenny M. Brown, Aaron J. Mercer, Thomas H. Meek, Kevin L. Grove, Bao Anh N. Phan, Gregory J. Morton, Kevin W. Williams, Michael W. Schwartz
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