Inflammasomes are multiprotein platforms that activate caspase-1, which leads to the processing and secretion of the proinflammatory cytokines IL-1β and IL-18. Previous studies demonstrated that bacterial RNAs activate the nucleotide-binding domain, leucine-rich-repeatcontaining family, pyrin domain-containing 3 (NLRP3) inflammasome in both human and murine macrophages. Interestingly, only mRNA, but neither tRNA nor rRNAs, derived from bacteria could activate the murine Nlrp3 inflammasome. Here, we report that all three types of bacterially derived RNA (mRNA, tRNA, and rRNAs) were capable of activating the NLRP3 inflammasome in human macrophages. Bacterial RNA's 5′-end triphosphate moieties, secondary structure, and double-stranded structure were dispensable; small fragments of bacterial RNA were sufficient to activate the inflammasome. In addition, we also found that 20-guanosine ssRNA can activate the NLRP3 inflammasome in human macrophages but not in murine macrophages. Therefore, human and murine macrophages may have evolved to recognize bacterial cytosolic RNA differently during bacterial infections.bacterial RNA | single-stranded RNA | NLRP3 inflammasome | innate immunity | primary macrophages

The transcription factor NFATC3 binds to IRF7 and to type 1 IFN promoters, regulating IRF7-mediated IFN expression in pDCs.

Current HER2-targeted therapies have markedly improved the outcome of cancer patients with HER2 overexpressing tumors. However, these patients may eventually relapse or develop treatment resistance. In addition, HER2-low patients that are not eligible for treatment constitute a significant portion of the breast cancer patients. To address these unmet needs, we have developed a novel HER2-targeting T cell engager, SAR443216. This is a trispecific antibody with binding sites for HER2, CD3 and CD28, and containing a mutated IgG4-Fc which lacks effector functions. CD28 binding contributes to T cell activation, including activation of IL-2 and NFκB pathways, as well as induction of anti-apoptotic protein, Bcl-xL. In the presence of HER2-positive cancer cells, SAR443216 is able to activate primary human CD4 and CD8 T cells, resulting in T cell proliferation and secretion of cytokines and granzyme B. Moreover, it has potent in vitro T cell-dependent cellular cytotoxicity (TDCC) against a panel of HER2-expressing cancer cell lines, including those that are HER2-low. The potency of in vitro TDCC is largely correlated with HER2 surface expression in the target cells. Finally, in a HER2-low breast cancer xenograft model, SAR443216 also exhibited significant anti-tumor activity in immuno-deficient NSG mice reconstituted with primary human T cells. Thus, SAR443216 represents a promising new drug for cancer patients with HER2-expressing tumors, including those who are currently ineligible for stand-of-care therapy. Citation Format: Wenwen Sha, Sri Vadde, Zhili Song, Edward Seung, Zhen Xing, Liqing Chen, Virna Cortez-Retamozo, Sukhvinder Sidhu, Dinesh Bangari, Lan Wu, Ronnie Wei, Zhi-yong Yang, Gary Nabel, Vasiliki Pelekanou, Michele Sanicola-Nadel, Serena Masciari, Dmitri Wiederschain, Lily Pao. SAR443216, a novel trispecific T cell engager with potent T cell-dependent cytotoxicity for HER2-low tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1825.