NK cells shape the clonal evolution of B cell leukaemia by IFN-γ production

Abstract

AbstractThe term cancer immunoediting describes the dual role by which the immune system can suppress and promote tumour growth and is divided into three phases: elimination, equilibrium and escape. The role of NK cells has mainly been attributed to the elimination phase. Here we show that NK cells play a role in all three phases of cancer immunoediting. Extended co-culturing of DNA barcoded mouse BCR/ABLp185+B acute lymphoblastic leukaemia cells with NK cells allowed for a quantitative measure of NK cell-mediated immunoediting. Whereas most tumour cell clones were efficiently eliminated by NK cells, a certain fraction of tumour cells harboured an intrinsic resistance. Furthermore, DNA barcoding revealed tumour cell clones with secondary resistance, which stochastically acquired resistance to NK cells. We found that the production of interferon-γ (IFN-γ) rather than direct cytotoxicity by NK cells, led to the emergence of highly resistant tumour cells. Besides well-known regulators of immune evasion, our analysis of NK resistant tumour cells revealed the upregulation of novel genes, such asLy6a, which drives NK cell resistance in leukaemic cells. Our results demonstrate that tumour cells are actively edited by NK cells during the equilibrium phase and use different avenues to escape NK cell-mediated eradication.