A-911的发现：一种强效、口服生物利用度良好的5-HT7拮抗剂，可促进DC1介导的T细胞交叉致敏和抗肿瘤免疫

Immunotherapy has revolutionized cancer therapy by activating the host immune system to attack the cancer. While immune checkpoint inhibitors that predominantly target T-cells have induced durable clinical responses across multiple tumor types, a large majority of patients do not respond, and resistance/relapse is frequently observed, highlighting the needs for new therapeutic approaches. The innate immune system also holds promise to trigger an anti-tumor immune response. Amongst the cell type of the innate immune system, Dendritic Cells (DCs) stand out as critical sentinels for the immune system as well as the bridge between the innate and adaptive immune responses. Indeed, conventional type 1 DCs (cDC1s) have emerged as critical mediators of anti-tumor immunity due to their ability to cross-prime CD8 T-cells. However, within the tumor microenvironment (TME) cDC1s are often dysfunctional but the mechanisms tumors utilize to disrupt their functions are poorly understood. Recently, serotonin (5-HT), the widely known neurotransmitter, and its downstream metabolites have emerged as immune modulators of anti-tumor immunity, but the involvement of cDC1s is unknown. To address this, we leveraged human and mouse tumor bioinformatics, which uncovered high levels of the 5-HT7 (also called HTR7) serotonin receptor in the DC compartment, specifically in cDC1s in several tumor types. Consistent with this, individually deleting all 5-HT receptors in mouse bone marrow derived DC1s (BMDC1s) indicated loss of 5-HT7 dramatically enhanced BMDC1 function and cross priming. We then leveraged our proprietary chemical library to identify compounds likely to antagonize 5-HT7, and subsequent medicinal chemistry efforts led to the discovery of A-911, a potent 5-HT7 antagonist. Phenocopying 5-HT7 deletion, A-911 enhanced BMDC1 IL-12 production, CD8 T-cell cross-priming, and antigen specific T-cell killing. A-911 has suitable properties for oral administration, exhibits low brain exposure relative to plasma and tumor, and is well tolerated in mice. Daily oral dosing inhibited tumor growth in B16-OVA and Pan02 immunocompetent tumor models and induced combination activity with anti-PD-1 or anti-CTLA-4 antibodies, respectively. A-911 also induced DC1 activation in the TME and downstream T-cell activation and cytolytic activity. These findings elucidate a mechanism by which 5-HT signaling through 5-HT7 within the TME can constrain anti-tumor immunity and identify 5-HT7 as a potential cDC1 therapeutic target for cancer immunotherapy. AbbVie Disclosure Statement: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.