Docosahexaenoic acid reverses PD-L1-mediated immune suppression by accelerating its ubiquitin-proteasome degradation.

PD-L1 interacts with its receptor PD-1 on T cells to negatively regulate T cell function, leading to cancer cell immune escape from the immune surveillance. Therefore, targeting PD-L1 is considered to be an attractive approach for cancer immunotherapy. In this study, we demonstrated for the first time that ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) reduced the expression of PD-L1 in cancer cells both in vitro and in vivo. Promotion of PD-L1 ubiquitin-proteasome degradation by DHA resulted in a decrease of PD-L1 expression, leading to reduction of PD-L1 and PD-1 interaction, and reversing PD-L1-mediated immune suppression, which in turn contributed to the inhibitory effect on tumor growth. Furtherly, DHA significantly reduced fatty acid synthase (FASN) expression in cancer cells, which inhibited the palmitoyltransferases DHHC5, promoting the CSN5-dependent PD-L1 degradation. Our present finding uncovered a novel mechanism involved in the anti-cancer activity of DHA, and implicated that DHA holds promising potential to be developed as a novel immune-enhancer for cancer treatment and prevention.

Author Correction: H2A.Z facilitates licensing and activation of early replication origins.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

H2A.Z facilitates licensing and activation of early replication origins.

DNA replication is a tightly regulated process that ensures the precise duplication of the genome during the cell cycle1. In eukaryotes, the licensing and activation of replication origins are regulated by both DNA sequence and chromatin features2. However, the chromatin-based regulatory mechanisms remain largely uncharacterized. Here we show that, in HeLa cells, nucleosomes containing the histone variant H2A.Z are enriched with histone H4 that is dimethylated on its lysine 20 residue (H4K20me2) and with bound origin-recognition complex (ORC). In vitro studies show that H2A.Z-containing nucleosomes bind directly to the histone lysine methyltransferase enzyme SUV420H1, promoting H4K20me2 deposition, which is in turn required for ORC1 binding. Genome-wide studies show that signals from H4K20me2, ORC1 and nascent DNA strands co-localize with H2A.Z, and that depletion of H2A.Z results in decreased H4K20me2, ORC1 and nascent-strand signals throughout the genome. H2A.Z-regulated replication origins have a higher firing efficiency and early replication timing compared with other origins. Our results suggest that the histone variant H2A.Z epigenetically regulates the licensing and activation of early replication origins and maintains replication timing through the SUV420H1-H4K20me2-ORC1 axis.

RelB intrinsically regulates the development and function of medullary thymic epithelial cells.

Medullary thymic epithelial cells (mTECs) act as one of the major stromal components in the thymus for selection and maturation of both conventional T cells and non-conventional T cells. Extensive efforts have been spent to understand how mTEC development and function are regulated. Although RelB has been well accepted to be a critical transcriptional factor for mTEC development, the underlying mechanisms still remain largely unclear. In this study, by generating thymic epithelial cell specific RelB deficient mice, we found that epithelial intrinsic RelB is required for mTEC homeostatic proliferation. Mechanistically, RelB regulates the expression of genes involved in cell cycle. Functionally, lack of intrinsic RelB in thymic epithelial cells results in dramatically reduced population of mTECs and impaired development of thymic invariant natural killer T (iNKT) cells and intraepithelial lymphocyte precursors (IELPs). This study thus reveals an epithelial intrinsic role of RelB on mTEC development and function.

Epithelial LTßR signaling controls the population size of the progenitors of medullary thymic epithelial cells in neonatal mice.

The establishment of T cell central tolerance critically relies on the development and maintenance of the medullary thymic epithelial cells (mTECs). Disrupted signaling of lymphotoxin beta receptor (LTßR) results in dramatically reduced mTEC population. However, whether LTßR directly or indirectly control mTECs remains undetermined; how LTßR controls this process also remain unclear. In this study, by utilizing K14-Cre × Ltbrfl/fl conditional knockout (cKO) mice, we show that epithelial intrinsic LTßR was essential for the mTEC development postnatally. Mechanistically, LTßR did not directly impact the proliferation or survival of mTECs; the maturation of mTECs from MHC-IIlo to MHC-IIhi stage was also unaltered in the absence of LTßR; interestingly, the number of mTEC progenitors (Cld3,4hiSSEA-1+) was found significantly reduced in LTßR cKO mice at the neonatal stage, but not at E18.5. Consequently, epithelial deficiency of LTßR resulted in significant defect of thymic negative selection as demonstrated using OT-I and RIP-OVA transgenic mouse system. In summary, our study clarifies the epithelial intrinsic role of LTßR on mTEC development and function; more importantly, it reveals a previously unrecognized function of LTßR on the control of the size of mTEC progenitor population.

LTßR controls thymic portal endothelial cells for haematopoietic progenitor cell homing and T-cell regeneration.

Continuous thymic homing of haematopoietic progenitor cells (HPCs) via the blood is critical for normal T-cell development. However, the nature and the differentiation programme of specialized thymic endothelial cells (ECs) controlling this process remain poorly understood. Here using conditional gene-deficient mice, we find that lymphotoxin beta receptor (LTßR) directly controls thymic ECs to guide HPC homing. Interestingly, T-cell deficiency or conditional ablation of T-cell-engaged LTßR signalling results in a defect in thymic HPC homing, suggesting the feedback regulation of thymic progenitor homing by thymic products. Furthermore, we identify and characterize a special thymic portal EC population with features that guide HPC homing. LTßR is essential for the differentiation and homeostasis of these thymic portal ECs. Finally, we show that LTßR is required for T-cell regeneration on irradiation-induced thymic injury. Together, these results uncover a cellular and molecular pathway that governs thymic EC differentiation for HPC homing.