Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma DOI Creative Commons
Lewis Au, Emine Hatipoglu, Marc Robert de Massy

et al.

Cancer Cell, Journal Year: 2021, Volume and Issue: 39(11), P. 1497 - 1518.e11

Published: Oct. 28, 2021

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates clinical T receptor (TCR) analysis reveals significantly higher number expanded TCR clones pre-treatment responders suggesting pre-existing immunity. Maintenance highly similar clusters TCRs post-treatment predict ongoing antigen engagement survival families cells likely recognizing same antigens. In responders, nivolumab-bound CD8

Language: Английский

Inter- and intra-tumor heterogeneity of metastatic prostate cancer determined by digital spatial gene expression profiling DOI Creative Commons
Lauren Brady, Michelle Kriner, Ilsa M. Coleman

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: March 3, 2021

Abstract Metastatic prostate cancer (mPC) comprises a spectrum of diverse phenotypes. However, the extent inter- and intra-tumor heterogeneity is not established. Here we use digital spatial profiling (DSP) technology to quantitate transcript protein abundance in spatially-distinct regions mPCs. By assessing multiple discrete areas across metastases, find high level intra-patient homogeneity with respect tumor phenotype. there are notable exceptions including tumors comprised low androgen receptor (AR) neuroendocrine activity. While vast majority metastases examined devoid significant inflammatory infiltrates lack PD1, PD-L1 CTLA4, B7-H3/CD276 immune checkpoint highly expressed, particularly mPCs AR Our results demonstrate utility DSP for accurately classifying phenotype, heterogeneity, identifying aspects biology involving immunological composition metastases.

Language: Английский

Citations

228
Spatial profiling technologies illuminate the tumor microenvironment DOI Creative Commons
Ofer Elhanani, Raz Ben-Uri, Leeat Keren

et al.

Cancer Cell, Journal Year: 2023, Volume and Issue: 41(3), P. 404 - 420

Published: Feb. 16, 2023

Language: Английский

Citations

219
Advances in mixed cell deconvolution enable quantification of cell types in spatial transcriptomic data DOI Creative Commons
Patrick Danaher, Young‐Mi Kim,

Brenn Nelson

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Jan. 19, 2022

Mapping cell types across a tissue is central concern of spatial biology, but type abundance difficult to extract from gene expression data. We introduce SpatialDecon, an algorithm for quantifying populations defined by single sequencing within the regions studies. SpatialDecon incorporates several advancements in deconvolution. propose harnessing log-normal regression and modelling background, outperforming classical least-squares methods. compile profile matrices 75 types. identify genes whose minimal cancer cells makes them suitable immune deconvolution tumors. Using lung tumors, we create dataset benchmarking methods against marker proteins. simple flexible tool mapping It obtains estimates that are spatially resolved, granular, paired with highly multiplexed

Language: Английский

Citations

208
The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2 DOI Creative Commons
Susanne Krasemann, Undine Haferkamp, Susanne Pfefferle

et al.

Stem Cell Reports, Journal Year: 2022, Volume and Issue: 17(2), P. 307 - 320

Published: Jan. 20, 2022

Neurological complications are common in COVID-19. Although SARS-CoV-2 has been detected patients' brain tissues, its entry routes and resulting consequences not well understood. Here, we show a pronounced upregulation of interferon signaling pathways the neurovascular unit fatal By investigating susceptibility human induced pluripotent stem cell (hiPSC)-derived capillary endothelial-like cells (BCECs) to infection, found that BCECs were infected recapitulated transcriptional changes vivo. While compromised their paracellular tightness, basolateral compartment transwell assays after apical suggesting active replication transcellular transport virus across blood-brain barrier (BBB) vitro. Moreover, into could be reduced by anti-spike-, anti-angiotensin-converting enzyme 2 (ACE2)-, anti-neuropilin-1 (NRP1)-specific antibodies or transmembrane protease serine subtype (TMPRSS2) inhibitor nafamostat. Together, our data provide strong support for BBB increased signaling.

Language: Английский

Citations

201
Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma DOI Creative Commons
Lewis Au, Emine Hatipoglu, Marc Robert de Massy

et al.

Cancer Cell, Journal Year: 2021, Volume and Issue: 39(11), P. 1497 - 1518.e11

Published: Oct. 28, 2021

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates clinical T receptor (TCR) analysis reveals significantly higher number expanded TCR clones pre-treatment responders suggesting pre-existing immunity. Maintenance highly similar clusters TCRs post-treatment predict ongoing antigen engagement survival families cells likely recognizing same antigens. In responders, nivolumab-bound CD8

Language: Английский

Citations

187