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tumor, cancer, fig, response, exhausted, tcells, pdl, patients, cells, ovarian, data, immune, samples, article, clinical, tumors, score, hrd, sig, macrophages, cell, supplementary, expression, positive, compared, analysis, performed, responders, google, scholar, microenvironment, sequencing, test, nature, higher, celltype, mutational, brca, imaging, spatial, significantly, study, singlecell, trial, combination, positivity, pdlpositive, interactions, research, cas,

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nature portfolio exhausted cd8 + t-cell/cd8 + t-cell score exhausted cd8 + t-cell/cd8t-cell score privacy policy relative exhausted cd8 + t-cell-scores /farkkilab/pubs/tree/master/farkkila multiple sage libraries interferon-primed exhausted cd8 + t-cells exhibited pd-l1/pd-l2 amplification dcc data portal editing exhausted cd8 + t-cell preferentially advertising exhausted cd8 + t-cells involved cd8-exhausted effector t-cells pd-1+ exhausted cd8 + t-cells anti-pd-1/pd-l1 agents4 activated effector cd8 + t-cells scientific partner picard tools total cd8 + t-cell score pd-l1/pd-l2 amplification nature 500 nature received research funding pd-l1-positive cancer cells social media exhausted cd8 + t-cells associate exhausted cd8 + t-cell compared pd-1/pd-l1 checkpoint blockade exhausted cd8 + t-cells compared sample-wise z-score normalization pd-1/pd-l1 spatial interactions reprints pd-l1-positive tumor cells exhausted cd8 + t-cell platinum-resistant ovarian cancer cd8 + t-cell exhaustion exhausted cd8 + t-cells effector cd8 + t-cells cd8 + effector t-cells library small-cell lung cancer receives research funding cd8+ cytotoxic t-cells cd8 + t-cell compartment large-scale state transitions single-cell imaging data total cd8 + t-cells peak emission/half-width

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         headline:Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer
         description:Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second. A Phase I/II trial previously revealed variable anti-tumor efficacy of the PARP inhibitor niraparib in combination with the PD-1 inhibitor pembrolizumab in platinum-resistant ovarian cancer patients. Here, the authors perform an integrated genomic and immunomics analysis of tumor samples from the same patients and find potential predictive biomarkers of response to such combination therapy.
         datePublished:2020-03-19T00:00:00Z
         dateModified:2020-05-18T00:00:00Z
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      headline:Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer
      description:Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second. A Phase I/II trial previously revealed variable anti-tumor efficacy of the PARP inhibitor niraparib in combination with the PD-1 inhibitor pembrolizumab in platinum-resistant ovarian cancer patients. Here, the authors perform an integrated genomic and immunomics analysis of tumor samples from the same patients and find potential predictive biomarkers of response to such combination therapy.
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      dateModified:2020-05-18T00:00:00Z
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         Cancer microenvironment
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