{
  "abstract": "Background Immune Checkpoint Inhibitors (ICI)s are a burgeoning class of anti-cancer therapeutics that work by promoting host immune activation against the tumor. While ICIs continue to be approved for a wide range of cancers and improve durable response, the majority of patients have tumors that are resistant to ICI treatment. The mechanisms that drive ICI resistance are multifactorial and not fully elucidated. 1–3 Overcoming ICI resistance represents an unmet medical need to broaden ICI efficacy to a greater number of patients. Recent reports suggest a sexually dimorphic response to ICI therapy, indicating sex hormones may influence outcome and affect ICI resistance.4 Estrogens are the predominant female sex signaling hormone and are known to influence immunity. Estrogen signaling primarily occurs through the activation of two estrogen receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Activation of ERα can lead to pro-oncogenic effects and is responsible for the development of secondary sexual characteristics.5–8 ERβ activation, however, is associated with anti-tumor effects.9 10 Methods In this study, we employ OSU-ERβ-12, a potent, carborane-based molecule that can selectively target ERβ at a 10 mg/kg once daily oral dose. In syngeneic CT26 tumor-bearing mouse models resistant to ICIs, mice were treated with anti-PD-1, OSU-ERβ-12, or combination treatment.Results We found the combination treatment with αnti-PD1 immunotherapy and OSU-ERβ-12 significantly reduced tumor volumes compared to either monotherapy or vehicle control. OSU-ERβ-12/anti-PD-1 combination therapy significantly increased splenic T cell populations, including CD8+PD1+ and CD8+Tim-3+, indicating terminal CD8+ T cell differentiation and activation.Conclusions OSU-ERβ-12 potentiates anti-PD-1 therapy in an ICI-resistant model. This could be through T cell priming, which is consistent with literature showing ERβ activation can prime T cell response. 11 Further study is required to investigate mechanisms of immune modulation by ERβ activation in ICI-resistant models.References Zhou S, Yang H. Immunotherapy resistance in non-small-cell lung cancer: From mechanism to clinical strategies. Front Immunol. 2023 Apr 6;14:1129465. doi: 10.3389/fimmu.2023.1129465. PMID: 37090727; PMCID: PMC10115980.Shan J, Han D, Shen C, Lei Q, Zhang Y. Mechanism and strategies of immunotherapy resistance in colorectal cancer. Front Immunol. 2022 Sep 27;13:1016646. doi: 10.3389/fimmu.2022.1016646. PMID: 36238278; PMCID: PMC9550896.Bai R, Chen N, Li L, Du N, Bai L, Lv Z, Tian H, Cui J. Mechanisms of cancer resistance to immunotherapy. Front Oncol. 2020 Aug 6;10:1290. doi: 10.3389/fonc.2020.01290. PMID: 32850400; PMCID: PMC7425302.Conforti F, Pala L, Bagnardi V, De Pas T, Martinetti M, Viale G, Gelber RD, Goldhirsch A. Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis. Lancet Oncol. 2018 Jun;19(6):737-746. doi: 10.1016/S1470-2045(18)30261-4. Epub 2018 May 16. PMID: 29778737Rothenberger NJ, Somasundaram A, Stabile LP. The role of the estrogen pathway in the tumor microenvironment. Int J Mol Sci. 2018 Feb 19;19(2):611. doi: 10.3390/ijms19020611. PMID: 29463044; PMCID: PMC5855833Clusan L, Ferrière F, Flouriot G, Pakdel F. A basic review on estrogen receptor signaling pathways in breast cancer. Int J Mol Sci. 2023 Apr 6;24(7):6834. doi: 10.3390/ijms24076834. PMID: 37047814; PMCID: PMC10095386.Wang T, Jin J, Qian C, et al. Estrogen/ER in anti-tumor immunity regulation to tumor cell and tumor microenvironment. Cancer Cell Int. 2021;21:295. https://doi.org/10.1186/s12935-021-02003-wOuyang L, Chang W, Fang B, et al. Estrogen-induced SDF-1α production promotes the progression of ER-negative breast cancer via the accumulation of MDSCs in the tumor microenvironment. Sci Rep. 2016;6:39541. https://doi.org/10.1038/srep39541Sun L, Gao Z, Luo L, Tan H, Zhang G. Estrogen affects cell growth and IGF-1 receptor expression in renal cell carcinoma. Onco Targets Ther. 2018 Sep 17;11:5873-5878. doi:10.2147/OTT.S172149. PMID: 30271170; PMCID: PMC6149902.Rudolph A, Toth C, Hoffmeister M, Roth W, Herpel E, Jansen L, Marx A, Brenner H, Chang-Claude J. Expression of oestrogen receptor β and prognosis of colorectal cancer. Br. J. Cancer. 2012;107:831–839. doi: 10.1038/bjc.2012.323Yuan B, Clark CA, Wu B, Yang J, Drerup JM, Li T, Jin VX, Hu Y, Curiel TJ, Li R. Estrogen receptor beta signaling in CD8+ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch. J Immunother Cancer. 2021 Jan;9(1):e001932. doi: 10.1136/jitc-2020-001932. Erratum in: J Immunother Cancer. 2021 Oct;9(10):e001932corr1. doi:10.1136/jitc-2020-001932corr1. PMID: 33462142; PMCID: PMC7816924.",
  "authors": [
    {
      "affiliations": [
        "The University of Ohio, Grove City, OH, USA"
      ],
      "name": "Gregory M Young"
    },
    {
      "affiliations": [
        "The Ohio State University College of Pharmacy, Columbus, OH, USA"
      ],
      "name": "Justin Thomas"
    },
    {
      "affiliations": [
        "Drug Discovery Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA"
      ],
      "name": "Tyler A Wilson"
    },
    {
      "affiliations": [
        "The Ohio State University College of Pharmacy, Columbus, OH, USA"
      ],
      "name": "Gillian Mulcahy"
    },
    {
      "affiliations": [
        "The Ohio State University College of Pharmacy, Columbus, OH, USA"
      ],
      "name": "Mayu Fukuda"
    },
    {
      "affiliations": [
        "The Ohio State University College of Pharmacy, Columbus, OH, USA",
        "The Ohio State University Drug Development Institute, Columbus, OH, USA"
      ],
      "name": "Hanna S Radomska"
    },
    {
      "affiliations": [
        "The Ohio State University College of Pharmacy, Columbus, OH, USA"
      ],
      "name": "Samuel K Kulp"
    },
    {
      "affiliations": [
        "Drug Discovery Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA",
        "The Ohio State University Drug Development Institute, Columbus, OH, USA"
      ],
      "name": "Chad Bennett"
    },
    {
      "affiliations": [
        "The Ohio State University Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Columbus, OH, USA",
        "The Ohio State University Pelotonia Institute for Immuno-Oncology, Columbus, OH, USA",
        "The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA"
      ],
      "name": "Thomas A Mace"
    },
    {
      "affiliations": [
        "The Ohio State University Pelotonia Institute for Immuno-Oncology, Columbus, OH, USA",
        "The Ohio State University, Columbus, OH, USA"
      ],
      "name": "Mitch A Phelps"
    },
    {
      "affiliations": [
        "The Ohio State University College of Pharmacy, Columbus, OH, USA",
        "The Ohio State University Drug Development Institute, Columbus, OH, USA",
        "The Ohio State University Pelotonia Institute for Immuno-Oncology, Columbus, OH, USA",
        "The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA"
      ],
      "name": "Christopher C Coss"
    }
  ],
  "title": "414 Estrogen receptor beta agonist OSU-ERβ-12 enhances αnti-PD1 efficacy in an immunotherapy resistant mouse model",
  "uid": "a844c89a-8a02-5a60-8e85-178f14a756b3"
}