Cell–cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models

Mesenchymal stem cells(MSCs),which are pluripotent cells with immunomodulatory properties,have been considered good candidates for the therapy of several immune disorders,such as inflammatory bowel diseases,concanavalin A-induced liver injury,and graft-versus-host disease.The embryo is a natural allograft to the maternal immune system.A successful pregnancy depends on the timely extinction of the inflammatory response induced by embryo implantation,followed by the switch to a tolerant immune microenvironment in both the uterus and the system.Excessive infiltration of immune cells and serious inflammatory responses are triggers for embryo rejection,which results in miscarriage.Here,we demonstrated that adoptive transfer of MSCs could prevent fetal loss in a lipopolysaccharide(LPS)-induced abortion model and immune response-mediated spontaneous abortion model.The immunosuppressive MSCs alleviated excessive inflammation by inhibiting CD4+T cell proliferation and promoting the decidual macrophage switch to M2 in a tumor necrosis factor-stimulated gene-6(TSG-6)-dependent manner.Cell-tocell contact with proinflammatory macrophages increased the TSG-6 production by the MSCs,thereby enhancing the suppressive regulation of T cells and macrophages.Moreover,proinflammatory macrophages in contact with the MSCs upregulated the expression of CD200 on the stem cells and facilitated the reprogramming of macrophages towards an anti-inflammatory skew through the interaction of CD200 with CD200R on proinflammatory macrophages.Therefore,the results demonstrate that a TSG-6-mediated paracrine effect,reinforced by cell-to-cell contact between MSCs and proinflammatory macrophages,is involved in the mechanism of MSC-mediated abortion relief through the induction of immune tolerance.Our study also indicates the potential application of MSCs in clinical recurrent miscarriages.

Recent advancements in the B7/CD28 immune checkpoint families:new biology and clinical therapeutic strategies

The B7/CD28 families of immune checkpoints play vital roles in negatively or positively regulating immune cells in homeostasis and various diseases.Recent basic and clinical studies have revealed novel biology of the B7/CD28 families and new therapeutics for cancer therapy.In this review,we discuss the newly discovered KIR3DL3/TMIGD2/HHLA2 pathways,PD-1/PD-L1 and B7-H3 as metabolic regulators,the glycobiology of PD-1/PD-L1,B7x(B7-H4)and B7-H3,and the recently characterized PD-L1/B7-1 cis-interaction.We also cover the tumor-intrinsic and-extrinsic resistance mechanisms to current anti-PD-1/PD-L1 and anti-CTLA-4 immunotherapies in clinical settings.Finally,we review new immunotherapies targeting B7-H3,B7x,PD-1/PD-L1,and CTLA-4 in current clinical trials.

Crosstalk between the B7/CD28 and EGFR pathways:Mechanisms and therapeutic opportunities

Somatic activating mutations in the epidermal growth factor receptor(EGFR)are one of the most common oncogenic drivers in cancers such as non-small-cell lung cancer(NSCLC),metastatic colorectal cancer,glioblastoma,head and neck cancer,pancreatic cancer,and breast cancer.Molecular-targeted agents against EGFR signaling pathways have shown robust clinical efficacy,but patients inevitably experience acquired resistance.Although immune checkpoint inhibitors(ICIs)targeting PD-1/PD-L1 have exhibited durable anti-tumor responses in a subset of patients across multiple cancer types,their efficacy is limited in cancers harboring activating gene alterations of EGFR.Increasing studies have demonstrated that upregulation of new B7/CD28 family members such as B7-H3,B7x and HHLA2,is associated with EGFR signaling and may contribute to resistance to EGFR-targeted therapies by creating an immunosuppressive tumor microenvironment(TME).In this review,we discuss the regulatory effect of EGFR signaling on the PD-1/PD-L1 pathway and new B7/CD28 family member pathways.Understanding these interactions may inform combination therapeutic strategies and potentially overcome the current challenge of resistance to EGFR-targeted therapies.We also summarize clinical data of anti-PD-1/PD-L1 therapies in EGFR-mutated cancers,as well as ongoing clinical trials of combination of EGFR-targeted therapies and anti-PD-1/PD-L1 immunotherapies.

2018 Nobel Prize in medicine awarded to cancer immunotherapy:Immune checkpoint blockade e A personal account

James P Allison and Tasuku Honjo were awarded the 2018 Nobel Prize in Physiology or Medicine for the development of a revolution in cancer therapy1:immune checkpoint blockade.This is a truly well-deserved honor for both Allison and Honjo.The immune system has multiple levels of brakes,known as immune checkpoints,to negatively downregulate activation and function of T cells and other immune cells.Immune checkpoints are important mechanisms for preventing the immune system from attacking the host’s own cells.