Beziaud et al. focused on the role of cancer stem cell (CSC) plasticity in immune evasion following ICB. In mouse breast tumor models, T cell-produced IFNγ increased conversion of non-CSCs to CSCs, which increased chemo- and radiotherapy resistance and the formation of metastases. RNAseq identified BCAT1 as a downstream mediator of IFNγ-induced CSC plasticity that positively correlated with IFNγ levels in ICB-treated patients with breast cancer. BCAT1 inhibition in mice with gabapentin improved ICB therapy and blocked metastases, suggesting targeting stem cell plasticity could be achieved without compromising IFNγ’s antitumor effects.
Contributed by Katherine Turner
ABSTRACT: Despite the remarkable success of immune checkpoint blockade (ICB) therapy, most cancer patients still do not respond. We now find that immunotherapy can induce stem-like properties in tumors. Using mouse models of breast cancer, we observe that cancer stem cells (CSCs) show not only enhanced resistance to T cell cytotoxicity, but that interferon gamma (IFNγ) produced by activated T cells directly converts non-CSCs to CSCs. IFNγ enhances several CSC phenotypes, such as resistance to chemo- and radiotherapy and metastasis formation. We identified the branched-chain amino acid aminotransaminase 1 (BCAT1) as a downstream mediator of IFNγ-induced CSC plasticity. Targeting BCAT1 in vivo improved cancer vaccination and ICB therapy by preventing IFNγ-induced metastasis formation. Breast cancer patients treated with ICB exhibited a similar increase in CSC markers expression indicating comparable responses to immune activation in humans. Collectively, we discover an unexpected, pro-tumoral role for IFNγ that may contribute to cancer immunotherapy failure.
Author Info: (1) Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC (Swiss Institute for Experimental Cancer Research), 1015 Lausanne, Switzerland; Agora Translational Cancer Research Cente
Author Info: (1) Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC (Swiss Institute for Experimental Cancer Research), 1015 Lausanne, Switzerland; Agora Translational Cancer Research Center, 1005 Lausanne, Switzerland. (2) Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC (Swiss Institute for Experimental Cancer Research), 1015 Lausanne, Switzerland; Agora Translational Cancer Research Center, 1005 Lausanne, Switzerland. (3) Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC (Swiss Institute for Experimental Cancer Research), 1015 Lausanne, Switzerland; Agora Translational Cancer Research Center, 1005 Lausanne, Switzerland. (4) Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC (Swiss Institute for Experimental Cancer Research), 1015 Lausanne, Switzerland; Agora Translational Cancer Research Center, 1005 Lausanne, Switzerland. (5) Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC (Swiss Institute for Experimental Cancer Research), 1015 Lausanne, Switzerland. (6) Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC (Swiss Institute for Experimental Cancer Research), 1015 Lausanne, Switzerland; Agora Translational Cancer Research Center, 1005 Lausanne, Switzerland. Electronic address: joerg.huelsken@epfl.ch.
