Abstract 1600: Dose-dependent effects of interferon-gamma treatment on pancreatic ductal adenocarcinoma cell states

Abstract

Abstract Interferon-gamma (IFNγ) is a canonical proinflammatory cytokine that has well-studied antitumor functions such as the upregulation of MHC Class I (MHC-I), increased Th1 development, macrophage activity, innate immune cell recruitment, and in tumor cells increased apoptosis, decreased angiogenesis and proliferation. However, IFNγ is also important in limiting tissue destruction due to inflammation, taking on an immunotolerant role and allowing cancer cells to evade immune surveillance. We previously identified an interferon response cell state across diverse cancer types, as defined by the relative expression of IFIT1, HLA-A, HLA-DRA, STAT1, and IRF1. The interferon response cell state is heterogeneously expressed in cancer cells and appears to function both by cancer cell extrinsic and intrinsic mechanisms. Several clinical trials have tested the efficacy of IFNγ as a therapeutic for immune system stimulation in patients with melanoma. However, these have failed to detect effective outcomes, and have even noted some pro-growth actions, perhaps consistent with IFNγ’s immunotolerant role in maintaining tissue homeostasis. We are interested in identifying cell populations that are vulnerable to the antitumor functions of IFNγ, as well as cell populations that may be susceptible to IFNγ’s pro-tumor actions. To test this, we treated a pancreatic ductal adenocarcinoma cell line with three doses of IFNγ in vitro every day for five days and analyzed expression of proteins associated with IFNγ signaling by flow cytometry each day. Distinct doses of IFNγ have been shown to affect varying degrees of antitumor and pro-tumor responses. For example, growth inhibition has been seen upon treatment with high dose IFNγ, while treatment with low dose IFNγ is consistent with increased metastatic capability such as increased resistance to cytotoxic lymphocytes and natural killer cells despite the upregulation of MHC-I. We thus treated cells with three doses of IFNγ: low, normal, and high. Preliminary results have shown a dose dependent effect of IFNγ including the upregulation of MHC-I and PDL1. Ongoing work includes identifying changes in cell states using single-cell RNA-sequencing to uncover how cancer cells respond to varying intensities of IFNγ exposure. Additionally, we are analyzing how release of IFNγ from cancer cells changes following treatment of IFNγ at different doses. This work will provide insight into the mechanisms by which cancer cells evade immune surveillance and how cell states can describe a tumor’s vulnerability to IFNγ’s antitumor and pro-tumor effects. Citation Format: Deborah A. Liberman, Dalia Barkley, Itai Yanai. Dose-dependent effects of interferon-gamma treatment on pancreatic ductal adenocarcinoma cell states [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1600.