IFI16 inhibits DNA repair that potentiates type-I interferon-induced antitumor effects in triple negative breast cancer

Na-Lee Ka; Ga Young Lim; Sewon Hwang; Seung-Su Kim; Mi-Ock Lee

doi:10.1016/j.celrep.2021.110138

IFI16 inhibits DNA repair that potentiates type-I interferon-induced antitumor effects in triple negative breast cancer

Cell Rep. 2021 Dec 21;37(12):110138. doi: 10.1016/j.celrep.2021.110138.

Authors

Na-Lee Ka¹, Ga Young Lim², Sewon Hwang², Seung-Su Kim², Mi-Ock Lee³

Affiliations

¹ College of Pharmacy, Seoul National University, Seoul 08826, South Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, South Korea.
² College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
³ College of Pharmacy, Seoul National University, Seoul 08826, South Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, South Korea; Bio-MAX institute, Seoul National University, Seoul 08826, South Korea. Electronic address: molee@snu.ac.kr.

PMID: 34936865
DOI: 10.1016/j.celrep.2021.110138

Abstract

Tumor DNA-damage response (DDR) has an important role in driving type-I interferon (IFN)-mediated host antitumor immunity, but it is not clear how tumor DNA damage is interconnected with the immune response. Here, we report the role of IFN-γ-inducible protein 16 (IFI16) in DNA repair, which amplifies the stimulator of IFN genes (STING)-type-I IFN signaling, particularly in triple-negative breast cancer (TNBC). IFI16 is rapidly induced and accumulated to the histone-evicted DNA at double-stranded breakage (DSB) sites, where it inhibits recruitment of DDR factors. Subsequently, IFI16 increases the release of DNA fragments to the cytoplasm and induces STING-mediated type-I IFN production. Synergistic cytotoxic and immunomodulatory effects of doxorubicin and type-I IFNs are decreased upon IFI16 depletion in vivo. Furthermore, IFI16 expression correlates with improved clinical outcome in patients with TNBC treated with chemotherapy. Together, our findings suggest that type-I IFNs and IFI16 could offer potential therapeutic strategies for TNBC.

Keywords: DNA damage; DNA repair; IFI16; STING; antitumor immunity; cytosolic DNA; triple-negative breast cancer; type-I IFN.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
DNA / metabolism*
DNA Damage
DNA Repair / drug effects
Doxorubicin / pharmacology
Drug Synergism
Female
Histones / metabolism*
Humans
Immunity
Interferon Type I / pharmacology
Membrane Proteins / metabolism*
Mice
Mice, Inbred BALB C
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Nuclear Proteins / pharmacology
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Phosphoproteins / pharmacology
Signal Transduction
Tissue Array Analysis
Triple Negative Breast Neoplasms / drug therapy
Triple Negative Breast Neoplasms / genetics*
Triple Negative Breast Neoplasms / immunology
Triple Negative Breast Neoplasms / metabolism*

Substances

Antineoplastic Agents
Histones
Interferon Type I
Membrane Proteins
Nuclear Proteins
Phosphoproteins
STING1 protein, human
IFI16 protein, human
Doxorubicin
DNA