While type I interferon (IFN) is best known for its key role against viral infection, accumulating preclinical and clinical data indicate that robust type I IFN production in the tumor microenvironment promotes cancer immunosurveillance and contributes to the efficacy of various antineoplastic agents, notably immunogenic cell death inducers. Here, we report that malignant blasts from patients with acute myeloid leukemia (AML) release type I IFN via a Toll-like receptor 3 (TLR3)-dependent mechanism that is not driven by treatment. While in these patients the ability of type I IFN to stimulate anticancer immune responses was abolished by immunosuppressive mechanisms elicited by malignant blasts, type I IFN turned out to exert direct cytostatic, cytotoxic and chemosensitizing activity in primary AML blasts, leukemic stem cells from AML patients and AML xenograft models. Finally, a genetic signature of type I IFN signaling was found to have independent prognostic value on relapse-free survival and overall survival in a cohort of 132 AML patients. These findings delineate a clinically relevant, therapeutically actionable and prognostically informative mechanism through which type I IFN mediates beneficial effects in patients with AML.

Biomedical Center Medical Faculty in Pilsen Charles University Pilsen Czech Republic

Caryl and Israel Englander Institute for Precision Medicine New York NY USA

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Department of Hematology and Oncology Faculty Hospital in Pilsen Pilsen Czech Republic

Department of Immunology Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Radiation Oncology Weill Cornell Medical College New York NY USA

Institute of Clinical and Experimental Hematology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Hematology and Blood Transfusion Prague Czech Republic

Laboratory of Immunological and Tumour Models Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Tumor Immunology Institute of Microbiology of the Czech Academy of Sciences Prague Czech Republic

Sandra and Edward Meyer Cancer Center New York NY USA

Sotio Biotech Prague Czech Republic

See more in PubMed

Kroemer G, Galassi C, Zitvogel L, Galluzzi L. Immunogenic cell stress and death. Nat Immunol. 2022;23:487–500. doi: 10.1038/s41590-022-01132-2. PubMed DOI

McNab F, Mayer-Barber K, Sher A, Wack A, O’Garra A. Type I interferons in infectious disease. Nat Rev Immunol. 2015;15:87–103. doi: 10.1038/nri3787. PubMed DOI PMC

Schoggins JW. Interferon-stimulated genes: what do they all do? Annu Rev Virol. 2019;6:567–84. doi: 10.1146/annurev-virology-092818-015756. PubMed DOI

Galluzzi L, Humeau J, Buque A, Zitvogel L, Kroemer G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol. 2020;17:725–41. doi: 10.1038/s41571-020-0413-z. PubMed DOI

Petroni G, Buque A, Zitvogel L, Kroemer G, Galluzzi L. Immunomodulation by targeted anticancer agents. Cancer Cell. 2021;39:310–45. doi: 10.1016/j.ccell.2020.11.009. PubMed DOI

Borden EC. Interferons alpha and beta in cancer: therapeutic opportunities from new insights. Nat Rev Drug Disco. 2019;18:219–34. doi: 10.1038/s41573-018-0011-2. PubMed DOI

Lukhele S, Boukhaled GM, Brooks DG. Type I interferon signaling, regulation and gene stimulation in chronic virus infection. Semin Immunol. 2019;43:101277. doi: 10.1016/j.smim.2019.05.001. PubMed DOI PMC

Vanpouille-Box C, Hoffmann JA, Galluzzi L. Pharmacological modulation of nucleic acid sensors - therapeutic potential and persisting obstacles. Nat Rev Drug Disco. 2019;18:845–67. doi: 10.1038/s41573-019-0043-2. PubMed DOI

Gong T, Liu L, Jiang W, Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol. 2020;20:95–112. doi: 10.1038/s41577-019-0215-7. PubMed DOI

Marchi S, Guilbaud E, Tait SWG, Yamazaki T, Galluzzi L. Mitochondrial control of inflammation. Nat Rev Immunol. 2022 doi: 10.1038/s41577-022-00760-x. PubMed DOI PMC

Saleiro D, Platanias LC. Interferon signaling in cancer. Non-canonical pathways and control of intracellular immune checkpoints. Semin Immunol. 2019;43:101299. doi: 10.1016/j.smim.2019.101299. PubMed DOI PMC

Rodriguez-Ruiz ME, Buque A, Hensler M, Chen J, Bloy N, Petroni G, et al. Apoptotic caspases inhibit abscopal responses to radiation and identify a new prognostic biomarker for breast cancer patients. Oncoimmunology. 2019;8:e1655964. doi: 10.1080/2162402X.2019.1655964. PubMed DOI PMC

Weichselbaum RR, Ishwaran H, Yoon T, Nuyten DS, Baker SW, Khodarev N, et al. An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proc Natl Acad Sci USA. 2008;105:18490–5. doi: 10.1073/pnas.0809242105. PubMed DOI PMC

Erdal E, Haider S, Rehwinkel J, Harris AL, McHugh PJ. A prosurvival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited by Trex1. Genes Dev. 2017;31:353–69. doi: 10.1101/gad.289769.116. PubMed DOI PMC

Boukhaled GM, Harding S, Brooks DG. Opposing roles of type I interferons in cancer immunity. Annu Rev Pathol. 2021;16:167–98. doi: 10.1146/annurev-pathol-031920-093932. PubMed DOI PMC

Vanpouille-Box C, Demaria S, Formenti SC, Galluzzi L. Cytosolic DNA sensing in organismal tumor control. Cancer Cell. 2018;34:361–78. doi: 10.1016/j.ccell.2018.05.013. PubMed DOI

McLaughlin M, Patin EC, Pedersen M, Wilkins A, Dillon MT, Melcher AA, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat Rev Cancer. 2020;20:203–17. doi: 10.1038/s41568-020-0246-1. PubMed DOI

Parker BS, Rautela J, Hertzog PJ. Antitumour actions of interferons: implications for cancer therapy. Nat Rev Cancer. 2016;16:131–44. doi: 10.1038/nrc.2016.14. PubMed DOI

Cheon H, Borden EC, Stark GR. Interferons and their stimulated genes in the tumor microenvironment. Semin Oncol. 2014;41:156–73. doi: 10.1053/j.seminoncol.2014.02.002. PubMed DOI PMC

Linsley PS, Speake C, Whalen E, Chaussabel D. Copy number loss of the interferon gene cluster in melanomas is linked to reduced T cell infiltrate and poor patient prognosis. PLoS ONE. 2014;9:e109760. doi: 10.1371/journal.pone.0109760. PubMed DOI PMC

Fucikova J, Moserova I, Urbanova L, Bezu L, Kepp O, Cremer I, et al. Prognostic and Predictive Value of DAMPs and DAMP-Associated Processes in Cancer. Front Immunol. 2015;6:402. doi: 10.3389/fimmu.2015.00402. PubMed DOI PMC

Bidwell BN, Slaney CY, Withana NP, Forster S, Cao Y, Loi S, et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat Med. 2012;18:1224–31. doi: 10.1038/nm.2830. PubMed DOI

Bi X, Hameed M, Mirani N, Pimenta EM, Anari J, Barnes BJ. Loss of interferon regulatory factor 5 (IRF5) expression in human ductal carcinoma correlates with disease stage and contributes to metastasis. Breast Cancer Res. 2011;13:R111. doi: 10.1186/bcr3053. PubMed DOI PMC

Sistigu A, Yamazaki T, Vacchelli E, Chaba K, Enot DP, Adam J, et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med. 2014;20:1301–9. doi: 10.1038/nm.3708. PubMed DOI

Schiavoni G, Sistigu A, Valentini M, Mattei F, Sestili P, Spadaro F, et al. Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res. 2011;71:768–78. doi: 10.1158/0008-5472.CAN-10-2788. PubMed DOI

Yamazaki T, Kirchmair A, Sato A, Buque A, Rybstein M, Petroni G, et al. Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy. Nat Immunol. 2020;21:1160–71. doi: 10.1038/s41590-020-0751-0. PubMed DOI

Rodriguez-Ruiz ME, Vitale I, Harrington KJ, Melero I, Galluzzi L. Immunological impact of cell death signaling driven by radiation on the tumor microenvironment. Nat Immunol. 2020;21:120–34. doi: 10.1038/s41590-019-0561-4. PubMed DOI

Petroni G, Buque A, Coussens LM, Galluzzi L. Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment. Nat Rev Drug Disco. 2022;21:440–62. doi: 10.1038/s41573-022-00415-5. PubMed DOI

Bald T, Landsberg J, Lopez-Ramos D, Renn M, Glodde N, Jansen P, et al. Immune cell-poor melanomas benefit from PD-1 blockade after targeted type I IFN activation. Cancer Disco. 2014;4:674–87. doi: 10.1158/2159-8290.CD-13-0458. PubMed DOI

Kepp O, Marabelle A, Zitvogel L, Kroemer G. Oncolysis without viruses - inducing systemic anticancer immune responses with local therapies. Nat Rev Clin Oncol. 2020;17:49–64. doi: 10.1038/s41571-019-0272-7. PubMed DOI

Zhou H, Forveille S, Sauvat A, Yamazaki T, Senovilla L, Ma Y, et al. The oncolytic peptide LTX-315 triggers immunogenic cell death. Cell Death Dis. 2016;7:e2134. doi: 10.1038/cddis.2016.47. PubMed DOI PMC

Yamazaki T, Wennerberg E, Hensler M, Buque A, Kraynak J, Fucikova J, et al. LTX-315-enabled, radiotherapy-boosted immunotherapeutic control of breast cancer by NK cells. Oncoimmunology. 2021;10:1962592. doi: 10.1080/2162402X.2021.1962592. PubMed DOI PMC

Talpaz M, Mercer J, Hehlmann R. The interferon-alpha revival in CML. Ann Hematol. 2015;94:S195–207. doi: 10.1007/s00277-015-2326-y. PubMed DOI

Jiang H, Liu XH, Kong J, Wang J, Jia JS, Lu SY, et al. Interferon-alpha as maintenance therapy can significantly reduce relapse in patients with favorable-risk acute myeloid leukemia. Leuk Lymphoma. 2021;62:2949–56. doi: 10.1080/10428194.2021.1948027. PubMed DOI

Magenau JM, Peltier D, Riwes M, Pawarode A, Parkin B, Braun T, et al. Type 1 interferon to prevent leukemia relapse after allogeneic transplantation. Blood Adv. 2021;5:5047–56. doi: 10.1182/bloodadvances.2021004908. PubMed DOI PMC

Swatler J, Turos-Korgul L, Kozlowska E, Piwocka K. Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias. Cancers (Basel) 2021;13. 10.3390/cancers13061203. PubMed PMC

Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol. 2004;5:738–43. doi: 10.1038/ni1080. PubMed DOI

Anguille S, Lion E, Willemen Y, Van Tendeloo VF, Berneman ZN, Smits EL. Interferon-alpha in acute myeloid leukemia: an old drug revisited. Leukemia. 2011;25:739–48. doi: 10.1038/leu.2010.324. PubMed DOI

Bernard JJ, Cowing-Zitron C, Nakatsuji T, Muehleisen B, Muto J, Borkowski AW, et al. Ultraviolet radiation damages self noncoding RNA and is detected by TLR3. Nat Med. 2012;18:1286–90. doi: 10.1038/nm.2861. PubMed DOI PMC

Baessler T, Charton JE, Schmiedel BJ, Grunebach F, Krusch M, Wacker A, et al. CD137 ligand mediates opposite effects in human and mouse NK cells and impairs NK-cell reactivity against human acute myeloid leukemia cells. Blood. 2010;115:3058–69. doi: 10.1182/blood-2009-06-227934. PubMed DOI

Baessler T, Krusch M, Schmiedel BJ, Kloss M, Baltz KM, Wacker A, et al. Glucocorticoid-induced tumor necrosis factor receptor-related protein ligand subverts immunosurveillance of acute myeloid leukemia in humans. Cancer Res. 2009;69:1037–45. doi: 10.1158/0008-5472.CAN-08-2650. PubMed DOI

Coles SJ, Wang EC, Man S, Hills RK, Burnett AK, Tonks A, et al. CD200 expression suppresses natural killer cell function and directly inhibits patient anti-tumor response in acute myeloid leukemia. Leukemia. 2011;25:792–9. doi: 10.1038/leu.2011.1. PubMed DOI PMC

Benjamin R, Khwaja A, Singh N, McIntosh J, Meager A, Wadhwa M, et al. Continuous delivery of human type I interferons (alpha/beta) has significant activity against acute myeloid leukemia cells in vitro and in a xenograft model. Blood. 2007;109:1244–7. doi: 10.1182/blood-2006-02-002915. PubMed DOI

Zhu C, Zou C, Guan G, Guo Q, Yan Z, Liu T, et al. Development and validation of an interferon signature predicting prognosis and treatment response for glioblastoma. Oncoimmunology. 2019;8:e1621677. doi: 10.1080/2162402X.2019.1621677. PubMed DOI PMC

Snijders AM, Langley S, Mao JH, Bhatnagar S, Bjornstad KA, Rosen CJ, et al. An interferon signature identified by RNA-sequencing of mammary tissues varies across the estrous cycle and is predictive of metastasis-free survival. Oncotarget. 2014;5:4011–25. doi: 10.18632/oncotarget.2148. PubMed DOI PMC

Galluzzi L, Kroemer G. Immuno-epigenetic escape of cancer stem cells. Nat Immunol. 2022;23:1300–2. doi: 10.1038/s41590-022-01293-0. PubMed DOI

Musella M, Guarracino A, Manduca N, Galassi C, Ruggiero E, Potenza A, et al. Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B. Nat Immunol. 2022;23:1379–92. doi: 10.1038/s41590-022-01290-3. PubMed DOI PMC

Smits EL, Anguille S, Berneman ZN. Interferon alpha may be back on track to treat acute myeloid leukemia. Oncoimmunology. 2013;2:e23619. doi: 10.4161/onci.23619. PubMed DOI PMC

Dagorne A, Douet-Guilbert N, Quintin-Roue I, Guillerm G, Couturier MA, Berthou C, et al. Pegylated interferon alpha2a induces complete remission of acute myeloid leukemia in a postessential thrombocythemia myelofibrosis permitting allogenic stem cell transplantation. Ann Hematol. 2013;92:407–9. doi: 10.1007/s00277-012-1560-9. PubMed DOI