Long noncoding RNAs (lncRNAs) are key regulators of gene expression both in physiologic and pathologic conditions. Although the role of lncRNAs in tumorigenesis is now emerging, their function in cancer-mediated immunosuppression remains unexplored. We have identified the interferon-γ (IFNγ)-stimulated noncoding RNA 1 (INCA1) as a novel lncRNA expressed from the PD-L1 locus and showed that INCA1 is a key regulator of PD-L1 expression. Silencing INCA1 decreased PD-L1 expression both at basal level and in response to IFNγ stimulation in multiple tumor types. INCA1 knockdown sensitized tumor cells to cytotoxic T cell-mediated killing. Moreover, tumors with silenced INCA1 showed increased CAR T trafficking and activity in vivo. These findings provide novel insights into the biology of PD-L1 regulation and tumor immune evasion. INCA1 is thus a new target for cancer immunotherapy.

Citation Format: Marco Mineo, Shawn M. Lyons, Ruben Ferrer-Luna, Hirotaka Ito, Niklas von Spreckelsen, Quazim A. Alayo, Jasneet K. Khalsa, Khalid Shah, Keith L. Ligon, Rameen Beroukhim, Pavel Ivanov, Paul J. Anderson, Hiroshi Nakashima, Sean E. Lawler, E. Antonio Chiocca. The long noncoding RNA INCA1 is a novel regulator of PD-L1 expression in tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B46.