Abstract IA18: Metabolic impact on cancer immunity

We have studied the crosstalk among immune cell subsets, including myeloid cells, and tumor (stem) cells in the tumor microenvironment, and its impact on tumor progression, tumor immunity, and therapy. Our research efforts demonstrate that the tumor microenvironment comprises immune cells that have been reprogrammed by active tumor-mediated processes to defeat tumor immunity and promote tumor progression in a highly effective manner. These studies, including the first demonstration of PD-L1 expression, regulation, and blockade in the human cancer microenvironment, have helped define the nature of immune responses in the cancer microenvironment, form the concept of immunosuppressive networks in the cancer microenvironment, and provide significant insights into designing current immune therapies to treat cancer patients. In this talk, I focus on cancer metabolic impact on regulatory T cells and effector T cells. (a) Regulatory T cells and oxidative stress in the cancer microenvironment: Using ovarian cancer as an example, we found that tumor Treg cells undergo apoptosis and such apoptotic Treg cells abolish spontaneous and PD-L1 blockade-mediated antitumor T-cell immunity. Biochemical and functional analyses identify that adenosine, but not typical suppressive factors such as PD-L1, CTLA4, TGF-β, IL-35, and IL-10, contributes to apoptotic Treg cell-mediated immunosuppression. Mechanistically, apoptotic Treg cells release and convert a large amount of ATP to adenosine via CD39 and CD73, and mediate immunosuppression via the adenosine and A2A pathway. Treg cell apoptosis is attributed to their weak NRF2-associated antioxidant system and high vulnerability to free oxygen species in the tumor microenvironment. Thus, the data support a model wherein tumor Treg cells sustain and amplify their suppressor capacity by inadvertent death via oxidative stress. The work highlights the oxidative pathway as a metabolic checkpoint controlling Treg cell behavior and affecting cancer checkpoint therapeutic efficacy. (b) Effector T cells and glutamate-cystine metabolism in the cancer microenvironment: In patients with ovarian cancer and melanoma, and in multiple tumor-bearing mouse models, we find that immunotherapy-activated CD8+ T cells sensitize tumor cell ferroptosis. Mechanistically, IFNg released from CD8+ T cells downregulates expression of SLC3A2 and SLC7A11, two subunits of glutamate-cystine antiporter system xc-, restrains tumor cell cystine uptake, and as a consequence, promotes tumor cell lipid peroxidation and ferroptosis. In preclinical models, depletion of cyst(e)ine by cyst(e)inase in combination with checkpoint blockade synergistically enhances T cell-mediated antitumor immunity and induces tumor cell ferroptosis. Expression of glutamate-cystine antiporter system xc- is negatively associated with CD8+ T-cell signature, IFNg expression, and cancer patient outcome. Transcriptome analyses before and during nivolumab therapy reveal that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNg and CD8. Thus, T cell-promoted tumor ferroptosis is a novel antitumor mechanism. Targeting tumor ferroptosis pathway constitutes a therapeutic approach in combination with checkpoint blockade. Citation Format: Weiping Zou. Metabolic impact on cancer immunity [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA18.