Project description:RIG-I is a pattern recognition receptor involved in innate immunity, but its role in adaptive immunity remains unclear. Here, we demonstrate that RIG-I is upregulated in tumor infiltrating CD8+ T cells, where it functions as an intracellular checkpoint to negatively regulate CD8+ T cell function and limit antitumor immunity. Mechanically, up-regulation of RIG-I in CD8+ T cells is induced by retinoic acid (RA), a metabolite of vitamin A in TME, and direct inhibits the AKT/glycolysis signaling pathway. In addition, deletion of RIG-I enhances the efficacy of adoptively transferred T cells against solid tumors and inhibition of RIG-I enhances the response to PD-1 blockade. Our findings identify RIG-I as an intracellular checkpoint and a potential target for alleviating inhibitory constraints on T cells in cancer immunotherapy, either alone or in combination with immune checkpoint blockade.
Project description:MAVS-mediated cytosolic RNA sensing plays a central role in tumor immunogenicity. However, the effects of host MAVS signaling on antitumor immunity remains uncertain. Here, we demonstrate that host MAVS pathway drives accelerated tumor growth and impairs antitumor immunity, while MAVS knockout in dendritic cells (DCs) promotes tumor-reactive CD8+ T cell responses. Specifically, the CD8+ T cell priming capacity is enhanced by lack of functional MAVS in a type I interferon-independent, but IL-12-dependent, manner. Mechanistically, loss of RIG-I/MAVS cascade activates non-canonical NF-κB pathway and in turn induces IL-12 production by DCs, resulting in CD8+ T cell: DC crosstalk licensed by IFN-γ and IL-12. Moreover, ablation of host MAVS sensitizes tumors to immunotherapy and attenuates radiation resistance, thereby facilitating the maintenance of effector CD8+ T cells. These findings identify that host MAVS pathway acts as an immune checkpoint of DC-driven antitumor immunity, indicating the development of DC-based immunotherapies through MAVS signaling antagonism.
Project description:<p>The heterogeneous and immunosuppressive tumor microenvironment (TME) remains one of the major factors to the poor immunotherapeutic response in hepatocellular carcinoma (HCC). Tumor-associated macrophages (TAMs) are central orchestrators of this suppressive niche, yet the metabolic programs regulating their pro-tumorigenic functions remain incompletely understood. Here, we identify branched-chain amino acid transaminase 1 (BCAT1) as a metabolic checkpoint in TAMs that constrains tumor progression. Deficiency of BCAT1 in TAMs induces metabolic reprogramming, elevating intracellular crotonate levels and promoting histone crotonylation, which epigenetically activates lipid metabolism programs. This shift promotes TAM polarization toward a lipid-associated, immunosuppressive phenotype that accelerates HCC progression primarily by suppressing CD8+ T cell-mediated antitumor immunity</p>
Project description:The immunoreceptor retinoic acid-induced gene-I (RIG-I) is a promising target molecule for stimulating antitumor innate immunity. In this study, we evaluated the possible mechanisms of RIG-I signaling to make tumors immunogenic in the Renca cancer model. RIG-I is expressed in nucleated cells, including tumor cells, and its activation induces potent CD8 and natural killer (NK) cell responses. We used bulk RNA sequencing to uncovermolecular targets and mechanisms of action behind anti-tumor activity.
Project description:Ageing can compromise antitumor immunity, but the underlying mechanism by which ageing causes CD8+ T cell dysfunction and thus limits their antitumor activity remains poorly understood. We found that ageing greatly impaired the generation of CD8+ tissue-resident memory T (TRM) cell subset in non-lymphoid tissues (NLTs). And here we presented that in vitro differentiation of TRM cells was inhibited in the aged CD8+ T cell group compared to the young CD8+ T cell group.
Project description:Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate cell cycle progression from the G1 to S phase. Recent findings have demonstrated that CDK4/6 inhibition (CDK4/6i) enhances antitumor immunity, as evidenced by increased tumor infiltration of CD8+ T cells, though the underlying mechanism remains unclear. Our current study reveals that CDK4/6i enhances intratumoral CD8+ T cell infiltration in breast tumors through the functional reprogramming of tumor-associated macrophages (TAMs), facilitating indirect interactions between tumor cells and CD8+ T cells. Mechanistically, CDK4/6i enhances the proliferation and activation of M1 macrophages and promote the polarization of M2 to M1 macrophages via the macrophage migration inhibitory factor (MIF)-CD44/CD74 axis between tumor cells and macrophages. CDK4/6i-trained M1 TAMs increase and activate CD8+ T cells through MHC-I antigen presentation machinery. Inhibition of MIF in tumor cells or loss of MIF reverses the immunostimulatory effects of CDK4/6i on macrophages and subsequent CD8+ T cell antitumor immunity. Therefore, CDK4/6i-trained M1 TAM supernatant therapy surmounts the immunosuppressive tumor microenvironment and invokes a tumor response to low-dose PD-1 immune checkpoint blockade therapy in breast cancers.
