A SREBF2-dependent genetic program drives a novel immunotolerant dendritic cell population that supports cancer progression

Abstract The development of immune responses to cancers are crucially dependent upon effective antigen cross-presentation by local dendritic cell (DC) populations. Indeed, DC-mediated T cell stimulation is essential for generating responses to anti-PD-1 immunotherapy. Tumors have been shown to hijack DC function in a process broadly known as tolerization. Despite the significant implications of this process on the modulation of anti-tumor immunity, the underlying mechanisms of this process remain unclear. We have identified a unique population of DCs in transgenic models of both melanoma and non-small cell lung cancer that arise within the tumor microenvironment and migrate to the draining lymph node (LN) tissues during the course of disease progression. RNAseq and flow cytometry studies revealed this DC population to exhibit a unique CD63 surface marker, enabling us to determine this subset to drive regulatory T cell (Treg) and TH2 expansion while suppressing conventional DC-mediated activation of CD8+ T cell responses, even at rare numbers. Additional transcriptional and metabolic studies showed these CD63+ DCs to be a subset of the previously identified 'mature DCs enriched in immunoregulatory molecules' (mregDC) population and to exhibit both enhanced activity of the mevalonate biosynthetic pathway as well as increased lipid stores and dependence on fatty acid oxidation. Inhibitor studies confirmed that mevalonate biosynthesis drives CD63+ mregDC-mediated immune tolerance while scATACseq studies have identified open regulatory elements in CD63+ mregDCs associated with key rate-limiting genes associated with the mevalonate pathway. Additional lineage analysis revealed the CD63+ mregDC population to evolve primarily from type 2 conventional DCs in vivo. Both DC-specific genetic deletion of the SREBF2 master transcription factor as well as SREBP2 pharmacologic inhibition suppresses melanoma progression while enhancing tumor CD8+ T cell infiltration. Adoptive transfer of CD63+ mregDCs enhances melanoma metastases and promotes the accumulation of Tregs in draining LN tissues. scRNAseq studies as well as spatial transcriptomic analysis has confirmed this same DC population in the sentinel LN tissues of melanoma patients. We propose that this novel DC subset represents a key target for augmenting anti-tumor immune responses and suppressing metastatic progression. Ongoing work is focused on dissecting the regulatory pathways dictating the transcriptional program of CD63+ mregDCs and developing a CD11c-CD63 bispecific depletion antibody for further pre-clinical testing. Citation Format: Michael P. Plebanek, Yue Xue, Y-Van Nguyen, Nicholas C. DeVito, Xueying Wang, Georgia Beasley, Nagendra Yarla, Bala Thievanthiran, Brent A. Hanks. A SREBF2-dependent genetic program drives a novel immunotolerant dendritic cell population that supports cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2892.