UC San Diego
Type-I interferon regulates resistance to carboplatin in the human ovarian cancer cell line CAOV3
- Author(s): Venkatesh, Hrishi
- Advisor(s): Bui, Dr. Jack D
- et al.
Interferons are a group of signaling proteins produced by host cells in response to infection by a variety of pathogens, as well as during cancer. Type-I interferons are produced by immune and non-immune cells when pathogenic or self-nucleic acid is recognized by cytosolic sensors such as STING. In the context of chemoresistance in cancer, type-I interferons have been predominantly shown to play anti-tumor roles through direct tumor killing and enhancement of anti-tumor immunity. However, recent work by Andy Minn’s group hints at a potential pro-tumor role for interferons. In this thesis, we take advantage of the parental and resistant clones of the human ovarian cancer cell line generated by Dr. Oliver Harismendy and Dr. Stephen Howell’s group. We were able to reproduce Dr. Harismendy and Dr. Howell’s findings showing that the resistant clones had increased percent survival in response to carboplatin, and that the resistant clones had a type-I interferon gene signature. Treatment of the resistant clones with the pharmacological JAK inhibitor Ruxolitinib resulted in a pronounced loss of resistance to carboplatin, particularly in clone 18 that had the strongest type-I interferon gene signature. A type-I interferon neutralizing antibody was also able to reduce resistance in clone 18. Conversely, pre-treatment of the parental clone with either human interferon-b or the human STING agonist G10 induced resistance to carboplatin. We were thus able to demonstrate that type-I interferon signaling is necessary and sufficient to induce resistance to carboplatin in the human ovarian cancer cell line CAOV3.