Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer

Myeloid-derived suppressor cells(MDSCs)are a heterogenic population of immature myeloid cells with immunosuppressive effects,which undergo massive expansion during tumor progression.These cells not only support immune escape directly but also promote tumor invasion via various non-immunological activities.Besides,this group of cells are proved to impair the efficiency of current antitumor strategies such as chemotherapy,radiotherapy,and immunotherapy.Therefore,MDSCs are considered as potential therapeutic targets for cancer therapy.Treatment strategies targeting MDSCs have shown promising outcomes in both preclinical studies and clinical trials when administrated alone,or in combination with other anticancer therapies.In this review,we shed new light on recent advances in the biological characteristics and immunosuppressive functions of MDSCs.We also hope to propose an overview of current MDSCs-targeting therapies so as to provide new ideas for cancer treatment.

A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis

Pleural and peritoneal metastasis accompanied by malignant pleural effusion(MPE)or malignant ascites(MA)is frequent in patients with advanced solid tumors that originate from the lung,breast,gastrointestinal tract and ovary.Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities.However,malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction.Here,we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA,which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment.Interestingly,we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells.Based on this feature,a novel PD-L1-targeting chimeric switch receptor(PD-L1.BB CSR)was designed,which can bind to PD-L1,switching the inhibitory signal into an additional 4-1BB signal.When co-expressed with a 2nd-generation CAR,PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment,causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models.Further investigations revealed elevated expressions of T-cell activation,proliferation,and cytotoxicity-related genes,and we confirmed that PD-L1 scFv and 4-1BB intracellular domain,the two important components of PD-L1.BB CSR,were both necessary for the functional improvements of CAR-T cells.Overall,our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells.Based on this study,a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis(NCT04684459).