11 research outputs found
NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer
No full textSingle-cell RNA sequencing data used in the following article:NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancerhttps://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00369-5Authors:Bérengère Salomé, John P. Sfakianos, Daniel Ranti, Jorge Daza, Christine Bieber, Andrew Charap, Christian Hammer, Romain Banchereau, Adam M. Farkas, Dan Fu Ruan, Sudeh Izadmehr, Daniel Geanon, Geoffrey Kelly, Ronaldo M. de Real, Brian Lee, Kristin G. Beaumont, Sanjana Shroff, Yuan Shuo A. Wang, Ying-chih Wang, Tin Htwe Thin, Monica Garcia-Barros, Everardo Hegewisch-Solloa, Emily M. Mace, Li Wang, Timothy O’Donnell, Diego Chowell, Ruben Fernandez-Rodriguez, Mihaela Skobe, Nicole Taylor, Seunghee Kim-Schulze, Robert P. Sebra, Doug Palmer, Eleanor Clancy-Thompson, Scott Hammond, Alice O. Kamphorst, Karl-Johan Malmberg, Emanuela Marcenaro, Pedro Romero, Rachel Brody, Mathias Viard, Yuko Yuki, Maureen Martin, Mary Carrington, Reza Mehrazin, Peter Wiklund, Ira Mellman, Sanjeev Mariathasan, Jun Zhu, Matthew D. Galsky, Nina Bhardwaj*, Amir Horowitz*SummaryPD-1/PD-L1-blockade immunotherapies have limited efficacy in the treatment of bladder cancer. Here,we show that NKG2A associates with improved survival and responsiveness to PD-L1 blockadeimmunotherapy in bladder tumors that have high abundance of CD8+ T cells. In bladder tumors, NKG2Ais acquired on CD8+ T cells later than PD-1 as well as other well-established immune checkpoints.NKG2A+ PD-1+ CD8+ T cells diverge from classically defined exhausted T cells through their ability toreact to HLA class I-deficient tumors using TCR-independent innate-like mechanisms. HLA-ABCexpression by bladder tumors is progressively diminished as disease progresses, framing the importanceof targeting TCR-independent anti-tumor functions. Notably, NKG2A+ CD8+ T cells are inhibited whenHLA-E is expressed by tumors and partly restored upon NKG2A blockade in an HLA-E-dependentmanner. Overall, our study provides a framework for subsequent clinical trials combining NKG2Ablockade with other T cell-targeted immunotherapies, where tumors express higher levels of HLA-E
NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer
No full textSingle-cell RNA sequencing data used in the following article:NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancerhttps://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00369-5Authors:Bérengère Salomé, John P. Sfakianos, Daniel Ranti, Jorge Daza, Christine Bieber, Andrew Charap, Christian Hammer, Romain Banchereau, Adam M. Farkas, Dan Fu Ruan, Sudeh Izadmehr, Daniel Geanon, Geoffrey Kelly, Ronaldo M. de Real, Brian Lee, Kristin G. Beaumont, Sanjana Shroff, Yuan Shuo A. Wang, Ying-chih Wang, Tin Htwe Thin, Monica Garcia-Barros, Everardo Hegewisch-Solloa, Emily M. Mace, Li Wang, Timothy O’Donnell, Diego Chowell, Ruben Fernandez-Rodriguez, Mihaela Skobe, Nicole Taylor, Seunghee Kim-Schulze, Robert P. Sebra, Doug Palmer, Eleanor Clancy-Thompson, Scott Hammond, Alice O. Kamphorst, Karl-Johan Malmberg, Emanuela Marcenaro, Pedro Romero, Rachel Brody, Mathias Viard, Yuko Yuki, Maureen Martin, Mary Carrington, Reza Mehrazin, Peter Wiklund, Ira Mellman, Sanjeev Mariathasan, Jun Zhu, Matthew D. Galsky, Nina Bhardwaj*, Amir Horowitz*SummaryPD-1/PD-L1-blockade immunotherapies have limited efficacy in the treatment of bladder cancer. Here,we show that NKG2A associates with improved survival and responsiveness to PD-L1 blockadeimmunotherapy in bladder tumors that have high abundance of CD8+ T cells. In bladder tumors, NKG2Ais acquired on CD8+ T cells later than PD-1 as well as other well-established immune checkpoints.NKG2A+ PD-1+ CD8+ T cells diverge from classically defined exhausted T cells through their ability toreact to HLA class I-deficient tumors using TCR-independent innate-like mechanisms. HLA-ABCexpression by bladder tumors is progressively diminished as disease progresses, framing the importanceof targeting TCR-independent anti-tumor functions. Notably, NKG2A+ CD8+ T cells are inhibited whenHLA-E is expressed by tumors and partly restored upon NKG2A blockade in an HLA-E-dependentmanner. Overall, our study provides a framework for subsequent clinical trials combining NKG2Ablockade with other T cell-targeted immunotherapies, where tumors express higher levels of HLA-E.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV
NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer
No full textProgrammed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-blockade immunotherapies have limited efficacy in the treatment of bladder cancer. Here, we show that NKG2A associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in bladder tumors that have high abundance of CD8(+) T cells. In bladder tumors, NKG2A is acquired on CD8(+) T cells later than PD-1 as well as other well -established immune checkpoints. NKG2A(+) PD-1+ CD8(+) T cells diverge from classically defined exhausted T cells through their ability to react to human leukocyte antigen (HLA) class I-deficient tumors using T cell receptor (TCR)-independent innate-like mechanisms. HLA-ABC expression by bladder tumors is progressively diminished as disease progresses, framing the importance of targeting TCR-independent anti-tumor functions. Notably, NKG2A(+) CD8(+ )T cells are inhibited when HLA-E is expressed by tumors and partly restored upon NKG2A blockade in an HLA-E-dependent manner. Overall, our study provides a framework for subsequent clinical trials combining NKG2A blockade with other T cell-targeted immunotherapies, where tumors express higher levels of HLA-E
High-dimensional analysis of NK cells in kidney transplantation uncovers subsets associated with antibody-independent graft dysfunction
No full textNatural killer (NK) cells respond to diseased and allogeneic cells through NKG2A/HLA-E or killer cell immunoglobulin-like receptor (KIR)/HLA-ABC interactions. Correlations between HLA/KIR disparities and kidney transplant pathology suggest an antibody-independent pathogenic role for NK cells in transplantation, but the mechanisms remain unclear. Using CyTOF to characterize recipient peripheral NK cell phenotypes and function, we observed diverse NK cell subsets among participants who responded heterogeneously to allo-stimulators. NKG2A+KIR+ NK cells responded more vigorously than other subsets, and this heightened response persisted after kidney transplantation despite immunosuppression. In test and validation sets from 2 clinical trials, pretransplant donor-induced release of cytotoxicity mediator Ksp37 by NKG2A+ NK cells correlated with reduced long-term allograft function. Separate analyses showed that Ksp37 gene expression in allograft biopsies lacking histological rejection correlated with death-censored graft loss. Our findings support an antibody-independent role for NK cells in transplant injury and support further testing of pretransplant, donor-reactive, NK cell–produced Ksp37 as a risk-assessing, transplantation biomarker
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Limited Extent and Consequences of Pancreatic SARS-CoV-2 Infection
No full textLimited extent and consequences of pancreatic SARS-CoV-2 infection
No full textConcerns that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), may cause new-onset diabetes persist in an evolving research landscape, and precise risk assessment is hampered by, at times, conflicting evidence. Here, leveraging comprehensive single-cell analyses of in vitro SARS-CoV-2-infected human pancreatic islets, we demonstrate that productive infection is strictly dependent on the SARS-CoV-2 entry receptor ACE2 and targets practically all pancreatic cell types. Importantly, the infection remains highly circumscribed and largely non-cytopathic and, despite a high viral burden in infected subsets, promotes only modest cellular perturbations and inflammatory responses. Similar experimental outcomes are also observed after islet infection with endemic coronaviruses. Thus, the limits of pancreatic SARS-CoV-2 infection, even under in vitro conditions of enhanced virus exposure, challenge the proposition that in vivo targeting of β cells by SARS-CoV-2 precipitates new-onset diabetes. Whether restricted pancreatic damage and immunological alterations accrued by COVID-19 increase cumulative diabetes risk, however, remains to be evaluated.
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•SARS-CoV-2 infection targets practically all human pancreatic cell types in vitro•Productive SARS-CoV-2 infection of islet cells is strictly dependent on ACE2•Extent and consequences of pancreatic SARS-CoV-2 infection are notably restrained•Islets are also permissive to in vitro infection with endemic human coronaviruses
Assessing the risk of SARS-CoV-2-induced new-onset diabetes requires integration of multiple complementary lines of investigation. Here, van der Heide et al. demonstrate that the specific limits of in vitro pancreatic SARS-CoV-2 infection suggest at best a minor, if any, role of virus-induced β cell damage directly promoting new-onset diabetes
Type I Interferon Autoantibodies Correlate With Cellular Immune Alterations in Severe COVID-19
No full textBackground:Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe disease with increased morbidity and mortality among certain risk groups. The presence of autoantibodies against type I interferons (aIFN-Abs) is one mechanism that contributes to severe coronavirus disease 2019 (COVID-19).Methods:This study aimed to investigate the presence of aIFN-Abs in relation to the soluble proteome, circulating immune cell numbers, and cellular phenotypes, as well as development of adaptive immunity.Results:aIFN-Abs were more prevalent in critical compared to severe COVID-19 but largely absent in the other viral and bacterial infections studied here. The antibody and T-cell response to SARS-CoV-2 remained largely unaffected by the presence aIFN-Abs. Similarly, the inflammatory response in COVID-19 was comparable in individuals with and without aIFN-Abs. Instead, presence of aIFN-Abs had an impact on cellular immune system composition and skewing of cellular immune pathways.Conclusions:Our data suggest that aIFN-Abs do not significantly influence development of adaptive immunity but covary with alterations in immune cell numbers
Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C)
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