BCG priming followed by a novel interleukin combination activates Natural Killer cells to selectively proliferate and become anti-tumour long-lived effectors

• Published in: Scientific reports Vol. 14; no. 1; pp. 13133 - 16
• Main Authors: Felgueres, María-José, Esteso, Gloria, García-Jiménez, Álvaro F., Dopazo, Ana, Aguiló, Nacho, Mestre-Durán, Carmen, Martínez-Piñeiro, Luis, Pérez-Martínez, Antonio, Reyburn, Hugh T., Valés-Gómez, Mar
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/1647; 631/250; Bacillus Calmette-Guerin vaccine; BCG; BCG Vaccine - administration & dosage; BCG Vaccine - immunology; Blood cells; Bone cancer; Bone marrow; Cancer immunology; CD56 Antigen - metabolism; CD57 antigen; Cell immunotherapy; Cell proliferation; Cell Proliferation - drug effects; Cytokine activation; Cytokines; Cytotoxicity; Heterogeneity; Humanities and Social Sciences; Humans; Interleukins - metabolism; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Lymphocyte Activation - drug effects; Lymphocytes; multidisciplinary; Mycobacterium bovis - immunology; Natural killer cells; Neoplasms - drug therapy; Neoplasms - immunology; NK Cell Lectin-Like Receptor Subfamily C - metabolism; NK Cell Lectin-Like Receptor Subfamily K - metabolism; NK cells; NKG2 antigen; Peripheral blood; Phenotypes; Science; Science (multidisciplinary); Serology; Solid tumors; Tumors; Cancer immunology; NK cells; Cytokine activation; BCG; Cell immunotherapy
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-62968-2

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 (CD56 high CD16 + ), 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.