LXR-inverse agonism stimulates immune-mediated tumor destruction by enhancing CD8 T-cell activity in triple negative breast cancer
| Autor: | Richard J. Di Paolo, Suomia Abuirqeba, Colin A. Flaveny, Jinsong Zhang, Aurore-Cecile Valfort, Arindam Chatterjee, Katherine J. Carpenter, Laurie P. Shornick, Nick Steinauer, Shabnam Majidi, Monideepa Sengupta |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer microenvironment medicine.medical_treatment lcsh:Medicine Antineoplastic Agents Triple Negative Breast Neoplasms CD8-Positive T-Lymphocytes Article 03 medical and health sciences Mice 0302 clinical medicine Immune system Immunoediting Cell Line Tumor medicine Tumor Microenvironment Cytotoxic T cell Animals Humans lcsh:Science Liver X receptor Triple-negative breast cancer Tumor microenvironment Multidisciplinary Chemistry lcsh:R Lipid metabolism Immunotherapy Xenograft Model Antitumor Assays 3. Good health Mice Inbred C57BL 030104 developmental biology Nuclear receptor 030220 oncology & carcinogenesis Cancer research lcsh:Q Female T-Lymphocytes Cytotoxic |
| Zdroj: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-18 (2019) |
| ISSN: | 2045-2322 |
| Popis: | Triple-negative breast cancer (TNBC) is a highly aggressive subtype that is untreatable with hormonal or HER2-targeted therapies and is also typically unresponsive to checkpoint-blockade immunotherapy. Within the tumor microenvironment dysregulated immune cell metabolism has emerged as a key mechanism of tumor immune-evasion. We have discovered that the Liver-X-Receptors (LXRα and LXRβ), nuclear receptors known to regulate lipid metabolism and tumor-immune interaction, are highly activated in TNBC tumor associated myeloid cells. We therefore theorized that inhibiting LXR would induce immune-mediated TNBC-tumor clearance. Here we show that pharmacological inhibition of LXR activity induces tumor destruction primarily through stimulation of CD8+ T-cell cytotoxic activity and mitochondrial metabolism. Our results imply that LXR inverse agonists may be a promising new class of TNBC immunotherapies. |
| Databáze: | OpenAIRE |
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