Title: Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression
Author: Samir Devalaraja, Tsun Ki Jerrick To, Ian W. Folkert, Ramakrishnan Natesan, Md Zahidul Alam, Minghong Li, Yuma Tada, Konstantin Budagyan, Mai T. Dang, Li Zhai, Graham P. Lobel, Gabrielle E. Ciotti, T.S. Karin Eisinger-Mathason, Irfan A. Asangani, Kristy Weber, M. Celeste Simon, Malay Haldar
Abstract: The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy.Within solid tumors, why monocytes preferentially differentiate into immunosuppressivetumor-associated macrophages (TAMs) rather than immunostimulatory dendritic cells(DCs) remains unclear. Using multiple murine sarcoma models, we find that the TMEinduces tumor cells to produce retinoic acid (RA), which polarizes intratumoral monocytedifferentiation toward TAMs and away from DCs via suppression of DC-promoting transcriptionfactor Irf4. Genetic inhibition of RA production in tumor cells or pharmacologic inhibitionof RA signaling within TME increases stimulatory monocyte-derived cells, enhancesT cell-dependent anti-tumor immunity, and synergizes with immune checkpoint blockade.Furthermore, an RA-responsive gene signature in human monocytes correlates with animmunosuppressive TME in multiple human tumors. RA has been considered as an anti-canceragent, whereas our work demonstrates its tumorigenic capability via myeloid-mediatedimmune suppression and provides proof of concept for targeting this pathway for tumorimmunotherapy.