Oncolytic adenoviruses expressing checkpoint inhibitors for cancer therapy

Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic viruses(OVs)can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts.Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy.According to the diverse immune cell landscapes among different types of tumors,we rationally and precisely generated three recombinant oncolytic adenoviruses(OAds):OAd-SIRPα-Fc,OAd-Siglec10-Fc and OAd-TIGIT-Fc.These viruses were designed to locally deliver SIRPα-Fc,Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47,CD24 or CD155,respectively,in the TME to achieve enhanced antitumor effects.Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors,while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+T-cell-dominated tumors.Importantly,the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory.In addition,the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME.In summary,rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.

Therapeutic effects of a novel BAFF blocker on arthritis

B-cell targeted therapy is effective for autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis(RA),although there are setbacks in RA clinical trials.In this study,we designed a novel B-cell activating factor(BAFF)antagonist:BAFF-Trap,a recombinant glycoprotein with BAFF-binding domains of two BAFF receptors(TACI and Br3)linked to Fc domain of human IgG1.Unlike TACI-Fc,BAFF-Trap bound BAFF but not APRIL(a proliferation-inducing ligand),and significantly suppressed the development of collagen-induced arthritis and adjuvant-induced arthritis.Furthermore,BAFF-Trap inhibited proinflammatory cytokine expression,ameliorated joint damage and suppressed B-and T-cell activation.BAFF-Trap reduced dendritic cells in joints,and increased regulatory T cell,regulatory B-cell,and M2 macrophage.The function of BAFF-Trap was related to inhibition of canonical and noncanonical NF-κB activation.Thus,BAFF-Trap may be a valuable agent for the effective treatment of RA.

Mechanical stretching boosts expansion and regeneration of intestinal organoids through fueling stem cell self-renewal

Intestinal organoids,derived from intestinal stem cell self-organization,recapitulate the tissue structures and behav-iors of the intestinal epithelium,which hold great potential for the study of developmental biology,disease modeling,and regenerative medicine.The intestinal epithelium is exposed to dynamic mechanical forces which exert profound effects on gut development.However,the conventional intestinal organoid culture system neglects the key role of mechanical microenvironments but relies solely on biological factors.Here,we show that adding cyclic stretch to intestinal organoid cultures remarkably up-regulates the signature gene expression and proliferation of intestinal stem cells.Furthermore,mechanical stretching stimulates the expansion of SOX9+progenitors by activating the Wnt/β-Catenin signaling.These data demonstrate that the incorporation of mechanical stretch boosts the stemness of intestinal stem cells,thus benefiting organoid growth.Our findings have provided a way to optimize an organoid generation system through understanding cross-talk between biological and mechanical factors,paving the way for the application of mechanical forces in organoid-based models.