Visual AbstractAbstract

Type I IFN is made by cells in response to stress. Cancer cells exist in a state of stress, but their IFN response is complex and not completely understood. This study investigated the role of autocrine IFN in human chronic lymphocytic leukemia (CLL) cells. CLL cells were found to make low amounts of IFN via TANK-binding kinase 1 pathways, but p-STAT1 and -STAT2 proteins along with IFN-stimulated genes that reflect IFN activation were variably downregulated in cultured CLL cells by the neutralizing IFNAR1 Ab anifrolumab. Patients with CLL were segregated into two groups based on the response of their leukemia cells to anifrolumab. Samples associated with more aggressive clinical behavior indicated by unmutated IGHV genes along with high CD38 and p-Bruton’s tyrosine kinase expression exhibited responses to low amounts of IFN that were blocked by anifrolumab. Samples with more indolent behavior were unaffected by anifrolumab. Hypersensitivity to IFN was associated with higher expression of IFNAR1, MX1, STAT1, and STAT2 proteins and lower activity of negative regulatory tyrosine phosphatases. Autocrine IFN protected responsive CLL cells from stressful tissue culture environments and therapeutic drugs such as ibrutinib and venetoclax in vitro, in part by upregulating Mcl-1 expression. These findings suggest hypersensitivity to IFN may promote aggressive clinical behavior. Specific blockade of IFN signaling may improve outcomes for patients with CLL with higher-risk disease.

Footnotes

This work was supported by Institute of Cancer Research Grant 374817 and Joint Canada-Israel Research Program International Development Research Centre Project 108594-001.

The online version of this article contains supplemental material.

Abbreviations used in this article:

BTKBruton’s tyrosine kinaseCK1casein kinase 1CLLchronic lymphocytic leukemiaGSEAgene set enrichment analysisIRAKIL-1R–associated kinaseISGIFN-stimulated geneM-CLLchronic lymphocytic leukemia cells with mutated IGHV genesSHPSrc homology region 2 domain-containing phosphataseSOCSsuppressor of cytokine signalingSTINGstimulator of IFN genesTBKTANK-binding kinase 1U-CLLchronic lymphocytic leukemia cell with unmutated IGHV genesReceived March 14, 2022.Accepted August 18, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.