Abstract A68: Targeting metabolic vulnerabilities of MDSCs to enhance the antitumor activity of PD-1 blockade

Abstract

Abstract Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that differentiate from bone marrow precursors and expand in cancer-bearing hosts. MDSCs significantly contribute to tumor-induced immune suppression and represent a promising target for cancer immune therapies. Biguanides, such as the diabetes therapeutics metformin and phenformin, have demonstrated antitumor activity both in vitro and in vivo. However, their potential effects on the tumor microenvironment are largely unknown. Here we report that phenformin, a mitochondrial complex I inhibitor, selectively inhibits granulocytic myeloid-derived suppressor cells (G-MDSCs) in spleens of tumor bearing mice and ex vivo. Metabolomics analysis reveal that, compared to CD11b+Ly6G- cells, CD11b+Ly6G+ MDSCs have lower levels of glutathione and NADPH/NADP+ ratio, suggesting these cells have higher level of endogenous ROS. Interestingly, phenformin further induces production of ROS in G-MDSC, whereas co-treatment of the antioxidant N-acetylcysteine dampens ROS levels in these cells and rescues the effect of phenformin on reducing the numbers of G-MDSCs. Importantly, co-treatment of phenformin enhances the effect of anti-PD-1 antibody therapy on inhibiting tumor growth in the BRAF V600E/PTEN null melanoma mouse model. Combination of phenformin and anti PD-1 cooperatively induces CD8+ T cell infiltration and decreases levels of proteins that are critical for immune suppressive activities of MDSCs. Our findings demonstrate a selective, inhibitory effect of phenformin on G-MDSCs-driven immune suppression and support that phenformin improves the anti-tumor activity of PD-1 blockade immunotherapy in melanoma. Citation Format: Sun Hye Kim, Man Li, Sebastian Trousil, bin zheng. Targeting metabolic vulnerabilities of MDSCs to enhance the antitumor activity of PD-1 blockade [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A68.