Journal Article

Cystine–glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity

Rosfjord, Edward C., Eng, Christina H., Toral-Barza, Lourdes, Yang, Xiaoran S., Deng, Shibing, Mileski, Mary, Wang, Fang, Leahy, Danielle M., Myers, Jeremy S., Arensman, Michael D., Abraham, Robert T.

2019

Overview

T cell-invigorating cancer immunotherapies have near-curative potential. However, their clinical benefit is currently limited, as only a fraction of patients respond, suggesting that these regimens may benefit from combination with tumor-targeting treatments. As oncogenic progression is accompanied by alterations in metabolic pathways, tumors often become heavily reliant on antioxidant machinery and may be susceptible to increases in oxidative stress. The cystine–glutamate antiporter xCT is frequently overexpressed in cancer and fuels the production of the antioxidant glutathione; thus, tumors prone to redox stress may be selectively vulnerable to xCT disruption. However, systemic inhibition of xCT may compromise antitumor immunity, as xCT is implicated in supporting antigeninduced T cell proliferation. Therefore, we utilized immune-competent murine tumor models to investigate whether cancer cell expression of xCT was required for tumor growth in vivo and if deletion of host xCT impacted antitumor immune responses. Deletion of xCT in tumor cells led to defective cystine uptake, accumulation of reactive oxygen species, and impaired tumor growth, supporting a cancer cell-autonomous role for xCT. In contrast, we observed that, although T cell proliferation in culture was exquisitely dependent on xCT expression, xCT was dispensable for T cell proliferation in vivo and for the generation of primary and memory immune responses to tumors. These findings prompted the combination of tumor cell xCT deletion with the immunotherapeutic agent anti–CTLA-4, which dramatically increased the frequency and durability of antitumor responses. Together, these results identify a metabolic vulnerability specific to tumors and demonstrate that xCT disruption can expand the efficacy of anticancer immunotherapies.

• Publisher: National Academy of Sciences
• Subject: Amino Acid Transport System y+ - deficiency / Amino Acid Transport System y+ - immunology / Animal models / Animals / Anticancer properties / Antigen-Presenting Cells - immunology / Antigen-Presenting Cells - pathology / Antigens / Antioxidants / Antitumor activity / Biological Sciences / Cancer / Cancer immunotherapy / Cell culture / Cell growth / Cell Line / Cell Proliferation / Clonal deletion / CTLA-4 protein / Cystine / Disruption / Gene Deletion / Glutathione / Glutathione - genetics / Glutathione - immunology / Immunity / Immunologic Memory / Immunological memory / Immunotherapy / Lymphocytes / Lymphocytes T / Medical Sciences / Memory cells / Metabolic pathways / Metabolism / Mice / Mice, Knockout / Neoplasms, Experimental - genetics / Neoplasms, Experimental - immunology / Neoplasms, Experimental - pathology / Neoplasms, Experimental - therapy / Oxidative stress / PNAS Plus / Reactive oxygen species / T-Lymphocytes - immunology / T-Lymphocytes - pathology / Tumor cells / Tumors