RESUMO
To systematically define molecular features in human tumor cells that determine their degree of sensitivity to human allogeneic natural killer (NK) cells, we quantified the NK cell responsiveness of hundreds of molecularly annotated 'DNA-barcoded' solid tumor cell lines in multiplexed format and applied genome-scale CRISPR-based gene-editing screens in several solid tumor cell lines, to functionally interrogate which genes in tumor cells regulate the response to NK cells. In these orthogonal studies, NK cell-sensitive tumor cells tend to exhibit 'mesenchymal-like' transcriptional programs; high transcriptional signature for chromatin remodeling complexes; high levels of B7-H6 (NCR3LG1); and low levels of HLA-E/antigen presentation genes. Importantly, transcriptional signatures of NK cell-sensitive tumor cells correlate with immune checkpoint inhibitor (ICI) resistance in clinical samples. This study provides a comprehensive map of mechanisms regulating tumor cell responses to NK cells, with implications for future biomarker-driven applications of NK cell immunotherapies.
Assuntos
Citotoxicidade Imunológica/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Inibidores de Checkpoint Imunológico/farmacologia , Células Matadoras Naturais/fisiologia , Células Alógenas/fisiologia , Animais , Antígenos B7/genética , Linhagem Celular Tumoral , Montagem e Desmontagem da Cromatina/fisiologia , Testes Imunológicos de Citotoxicidade/métodos , Citotoxicidade Imunológica/fisiologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Genoma Humano , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Camundongos Endogâmicos NOD , Ensaios Antitumorais Modelo de Xenoenxerto , Antígenos HLA-ERESUMO
BACKGROUND: Critical limb ischaemia (CLI) is a life threatening condition with a considerable risk of major amputation and death. Besides revascularisation, no treatment has been proven to reduce the risks. Therapeutic angiogenesis by gene or cell therapy has not demonstrated definitive evidence in randomised controlled trials. PLX-PAD is an "off the shelf" allogeneic placental derived, mesenchymal like cell therapy, which, in preclinical studies, has shown pro-angiogenic, anti-inflammatory, and regenerative properties. Favourable one year amputation free survival (AFS), and trends in reduction of pain scores and increase of tissue perfusion have been shown in two small, open label, phase I trials. METHODS: The PACE study is a phase III randomised, double blind, multicentre, multinational placebo controlled, parallel group study to evaluate the efficacy, tolerability, and safety of intramuscular injections of PLX-PAD cells to treat patients with atherosclerotic CLI with minor tissue loss (Rutherford Category 5) up to the ankle level, who are unsuitable for revascularisation or carry an unfavourable risk benefit for that treatment. The study will enroll 246 patients, who after screening are randomised in a ratio of 2:1 to treatment with intramuscular injections of PLX-PAD 300 × 106 cells or placebo on two occasions, eight weeks apart. The primary efficacy endpoint is time to major amputation or death (amputation free survival), which will be assessed in follow up of at least 12 months and up to 36 months. CONCLUSIONS: Based on favourable pre-clinical and initial clinical study results, the PACE phase III randomised controlled trial will evaluate placenta derived PLX-PAD cell treatment in patients with critical limb ischaemia, with an unfavourable risk benefit for revascularisation. Clinicaltrials.gov: NCT03006770.