title: IL15RA drives antagonistic mechanisms of cancer development and immune control in lymphocyte-enriched triple-negative breast cancers.
abstract: Despite its aggressive nature, triple-negative breast cancer (TNBC) often exhibits leucocyte infiltrations that correlate with favorable prognosis. In this study, we offer an explanation for this apparent conundrum by defining TNBC cell subsets that overexpress the IL15 immune receptor IL15RA. This receptor usually forms a heterotrimer with the IL2 receptors IL2RB and IL2RG, which regulates the proliferation and differentiation of cytotoxic T cells and NK cells. However, unlike IL15RA, the IL2RB and IL2RG receptors are not upregulated in basal-like TNBC breast cancer cells that express IL15RA. Mechanistic investigations indicated that IL15RA signaling activated JAK1, STAT1, STAT2, AKT, PRAS40, and ERK1/2 in the absence of IL2RB and IL2RG, whereas neither STAT5 nor JAK2 were activated. RNAi-mediated attenuation of IL15RA established its role in cell growth, apoptosis, and migration, whereas expression of the IL15 cytokine in IL15RA-expressing cells stimulated an autocrine signaling cascade that promoted cell proliferation and migration and blocked apoptosis. Notably, coexpression of IL15RA and IL15 was also sufficient to activate peripheral blood mononuclear cells upon coculture in a paracrine signaling manner. Overall, our findings offer a mechanistic explanation for the paradoxical association of some high-grade breast tumors with better survival outcomes, due to engagement of the immune stroma.
authors: Breakthrough Breast Cancer Research Unit, Department of Research Oncology, Guy's Hospital, King's College London School of Medicine, London, United Kingdom.
authors: Pierfrancesco
authors: P
authors: Marra
authors: Breakthrough Breast Cancer Research Unit, Department of Research Oncology, Guy's Hospital, King's College London School of Medicine, London, United Kingdom.
authors: Sumi
authors: S
authors: Mathew
authors: Breakthrough Breast Cancer Research Unit, Department of Research Oncology, Guy's Hospital, King's College London School of Medicine, London, United Kingdom.
authors: Anita
authors: A
authors: Grigoriadis
authors: Peter Gorer Department of Immunobiology, King's College of London, London, United Kingdom.
authors: Yin
authors: Y
authors: Wu
authors: Peter Gorer Department of Immunobiology, King's College of London, London, United Kingdom.
authors: Fernanda
authors: F
authors: Kyle-Cezar
authors: Breakthrough Breast Cancer Research Unit, Department of Research Oncology, Guy's Hospital, King's College London School of Medicine, London, United Kingdom.
authors: Johnathan
authors: J
authors: Watkins
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom.
authors: Mamunur
authors: M
authors: Rashid
authors: NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College of London, London, United Kingdom.
authors: Emanuele
authors: E
authors: De Rinaldis
authors: Breakthrough Breast Cancer Research Unit, Department of Research Oncology, Guy's Hospital, King's College London School of Medicine, London, United Kingdom.
authors: Sonya
authors: S
authors: Hessey
authors: Breakthrough Breast Cancer Research Unit, Department of Research Oncology, Guy's Hospital, King's College London School of Medicine, London, United Kingdom.
authors: Patrycja
authors: P
authors: Gazinska
authors: Peter Gorer Department of Immunobiology, King's College of London, London, United Kingdom.
authors: Adrian
authors: A
authors: Hayday
authors: Breakthrough Breast Cancer Research Unit, Department of Research Oncology, Guy's Hospital, King's College London School of Medicine, London, United Kingdom. andrew.tutt@kcl.ac.uk.
authors: Andrew
authors: A
authors: Tutt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D019899:Paracrine Communication / Q000235:genetics / Q000276:immunology; D053647:Receptors, Interleukin-15 / Q000235:genetics* / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000276:immunology*
chemical_list: C569274:IL15 protein, human; C508024:IL15RA protein, human; D019409:Interleukin-15; D053647:Receptors, Interleukin-15