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Abstract
The short-lived nature and heterogeneity of Natural Killer (NK) cells limit the development of NK cell-based therapies, despite their proven safety and efficacy against cancer. Here, we describe the biological basis, detailed phenotype and function of long-lived anti-tumour human NK cells (CD56highCD16+), obtained without cell sorting or feeder cells, after priming of peripheral blood cells with Bacillus Calmette-Guérin (BCG). Further, we demonstrate that survival doses of a cytokine combination, excluding IL18, administered just weekly to BCG-primed NK cells avoids innate lymphocyte exhaustion and leads to specific long-term proliferation of innate cells that exert potent cytotoxic function against a broad range of solid tumours, mainly through NKG2D. Strikingly, a NKG2C+CD57-FcεRIγ+ NK cell population expands after BCG and cytokine stimulation, independently of HCMV serology. This strategy was exploited to rescue anti-tumour NK cells even from the suppressor environment of cancer patients’ bone marrow, demonstrating that BCG confers durable anti-tumour features to NK cells.
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Details
1 Spanish National Research Council (CNB-CSIC), Department of Immunology and Oncology, National Centre for Biotechnology, Madrid, Spain (GRID:grid.428469.5) (ISNI:0000 0004 1794 1018)
2 Centro Nacional de Investigaciones Cardiovasculares (CNIC), Genomics Unit, Madrid, Spain (GRID:grid.467824.b) (ISNI:0000 0001 0125 7682); CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain (GRID:grid.510932.c)
3 IIS Aragon, CIBER de Enfermedades Respiratorias, Department of Microbiology, Pediatrics, Radiology and Public Health of the University of Zaragoza, Zaragoza, Spain (GRID:grid.488737.7) (ISNI:0000000463436020)
4 Hospital Universitario La Paz, Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, and Pediatric Hemato-Oncology, Madrid, Spain (GRID:grid.81821.32) (ISNI:0000 0000 8970 9163); Spanish National Cancer Research Centre (CNIO), IdiPAZ-CNIO Pediatric Onco-Hematology Clinical Research Unit, Madrid, Spain (GRID:grid.7719.8) (ISNI:0000 0000 8700 1153)
5 La Paz University Hospital, Urology Department and Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain (GRID:grid.440081.9)
6 Hospital Universitario La Paz, Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, and Pediatric Hemato-Oncology, Madrid, Spain (GRID:grid.81821.32) (ISNI:0000 0000 8970 9163); Spanish National Cancer Research Centre (CNIO), IdiPAZ-CNIO Pediatric Onco-Hematology Clinical Research Unit, Madrid, Spain (GRID:grid.7719.8) (ISNI:0000 0000 8700 1153); Autonomous University of Madrid, Pediatric Department, Madrid, Spain (GRID:grid.5515.4) (ISNI:0000 0001 1957 8126)