👤 Frederic Silvestre

Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells has shown promising results in early-phase clinical studies. However, advancing CAR-NK cell therapeutic efficacy is imperative. In this study, we investigated the impact of a fourth-generation CD19-targeted CAR (CAR.19) coexpressing IL-27 on NK-92 cells. We observed a significant improvement in NK-92 cell proliferation and cytotoxicity activity against B-cell cancer cell lines, both in vitro and in a xenograft mouse B-cell lymphoma model. Our systematic transcriptome analysis of the activated NK-92 CAR variants further supports the potential of IL-27 in fourth-generation CARs to overcome limitations of NK cell-based targeted tumor therapies by providing essential growth and activation signals. Integrating IL-27 into CAR-NK cells emerges as a promising strategy to enhance their therapeutic potential and elicit robust responses against cancer cells. These findings contribute substantially to the mounting evidence supporting the potential of fourth-generation CAR engineering in advancing NK cell-based immunotherapies. Show less

Histone modifications such as methylation of key lysine residues play an important role in embryonic development in a variety of organisms such as of Pacific oysters, zebrafish and mice. The action of demethylase ("erasers") and methyltransferase ("writers") enzymes regulates precisely the methylation status of each lysine residue. However, despite fishes being very useful model organisms in medicine, evolution and ecotoxicology, most studies have focused on mammalian and plant model organisms, and mechanisms underlying regulation of histones are unknown in fish development outside of zebrafish. Here, putative histone lysine demethylases (Kdm) and methyltransferases (Kmt) were identified in an isogenic lineage of the self-fertilizing hermaphroditic vertebrate, the mangrove rivulus fish, Kryptolebias marmoratus. Evolutionary relationships with other animal demethylases and methyltransferases were examined, and expression patterns during embryonic development and in adult tissues were characterized. Twenty-five Kdm orthologues (Jarid2, Jmjd1c, Jmjd4, Jmjd6, Jmjd7, Jmjd8, Kdm1a, Kdm1b, Kdm2a, Kdm2b, Kdm3b, Kdm4a, Kdm4b, Kdm4c, Kdm5a, Kdm5b, Kdm5c, Kdm6a, Kdm6b, Kdm7a, Kdm8, Kdm9, UTY, Phf2 and Phf8) and forty-eight Kmt orthologues (Ezh1, Ezh2, Setd2, Nsd1, Nsd2, Nsd3, Ash1l, Kmt2e, Setd5, Prdm1, Prdm2, Prdm4, Prdm5, Prdm6, Prdm8, Prdm9, Prdm10, Prdm11, Prdm12, Prdm13, Prdm14, Prdm15, Prdm16, Setd3, Setd4, Setd6, Setd1a, Setd1b, Kmt2a, Kmt2b, Kmt2c, Kmt2d, Kmt5a, Kmt5b, Ehmt1, Ehmt2, Suv39h1, Setmar, Setdb1, Setdb2, Smyd1, Smyd2, Smyd3, Smyd4, Smyd5, Setd7, Setd9, Dot1l) were discovered. Expression patterns of both Kdm and Kmt were variable during embryonic development with a peak in gastrula stage and a reduction in later embryogenesis. Expression of both Kdm and Kmt was higher in male brains compared to hermaphrodite brains whereas specific expression patterns of Kdm and Kmt were observed in the hermaphrodite ovotestes and male testes, respectively. Putative histone demethylases (Kdm) and methyltransferases (Kmt) were for the first time characterized in a teleost besides zebrafish, the mangrove rivulus. Their domain conservation and expression profiles suggest that they might play important roles during development, gametogenesis and neurogenesis, which raises questions about epigenetic regulation of these processes by histone lysine methylation in K. marmoratus. Due to its peculiar mode of reproduction and the natural occurrence of isogenic lineages, this new model species is of great interest for understanding epigenetic contributions to the regulation of development and reproduction. Show less