Shiyu Li

Abstract Background Our previous work showed that the anti-TGF-β/PD-L1 bispecific antibody YM101 effectively overcame anti-PD-L1 resistance in immune-excluded tumor models. However, in immune-desert models, the efficacy of YM101 was limited. Bivalent manganese (Mn 2+ ) is identified as a natural stimulator of interferon genes (STING) agonist, which might enhance cancer antigen presentation and improve the therapeutic effect of YM101. Methods The effect of Mn 2+ on STING pathway was validated by western blotting and enzyme-linked immunosorbent assay. Dendritic cell (DC) maturation was measured by flow cytometry. The synergistic effect between Mn 2+ and YM101 in vitro was determined by one-way mixed lymphocyte reaction, CFSE dilution assay, and cytokine detection. The in vivo antitumor effect of Mn 2+ plus YM101 therapy was assessed in CT26, EMT-6, H22, and B16 tumor models. Flow cytometry, RNA-seq, and immunofluorescent staining were adopted to investigate the alterations in the tumor microenvironment. Results Mn 2+ could activate STING pathway and promote the maturation of human and murine DC. The results of one-way mixed lymphocyte reaction showed that Mn 2+ synergized YM101 in T cell activation. Moreover, in multiple syngeneic murine tumor models, Mn 2+ plus YM101 therapy exhibited a durable antitumor effect and prolonged the survival of tumor-bearing mice. Relative to YM101 monotherapy and Mn 2+ plus anti-PD-L1 therapy, Mn 2+ plus YM101 treatment had a more powerful antitumor effect and a broader antitumor spectrum. Mechanistically, Mn 2+ plus YM101 strategy simultaneously regulated multiple components in the antitumor immunity and drove the shift from immune-excluded or immune-desert to immune-inflamed tumors. The investigation in the TME indicated Mn 2+ plus YM101 strategy activated innate and adaptive immunity, enhanced cancer antigen presentation, and upregulated the density and function of tumor-infiltrating lymphocytes. This normalized TME and reinvigorated antitumor immunity contributed to the superior antitumor effect of the combination therapy. Conclusion Combining Mn 2+ with YM101 has a synergistic antitumor effect, effectively controlling tumor growth and prolonging the survival of tumor-bearing mice. This novel cocktail strategy has the potential to be a universal regimen for inflamed and non-inflamed tumors.

Liquid biopsy is a revolutionary strategy in cancer diagnosis and prognosis prediction, which is used to analyze cancer cells or cancer-derived products through biofluids such as blood, urine and so on. Exosomes play a crucial role in mediating cell communication. A growing number of studies have reported that exosomes are involved in tumorigenesis, tumor growth, metastasis and drug resistance by delivering cargos including nucleic acids and protein. Thus, exosomes, as a new type of liquid biopsy, have the potential to be diagnostic or prognostic biomarkers. Herein, we elaborate on the current methods and introduce novel techniques for exosome isolation and characterization. Moreover, we elucidate the advantages of exosomes compared to other biological components in liquid biopsy and summarize the different exosomal biomarkers in cancer diagnosis and prognosis prediction.

Cancer stem cells (CSCs) are a small group of cancer cells, which contribute to tumorigenesis and cancer progression. Cancer cells undergoing epithelial-to-mesenchymal transition (EMT) acquire the chemoresistant ability, which is regarded as an important feature of CSCs. Thus, there emerges an opinion that the generation of CSCs is considered to be driven by EMT. In this complex process, microRNAs (miRNAs) are found to play a key role. In order to overcome the drug resistance, inhibiting EMT as well as CSCs phenotype seem feasible. Thereinto, regulating the EMT- or CSCs-associated miRNAs is a crucial approach. Herein, we conduct this review to elaborate on the complicated interplay between EMT and CSCs in cancer chemoresistance, which is modulated by miRNAs. In addition, we elucidate the therapeutic strategy to overcome drug resistance through targeting EMT and CSCs.

Abstract The durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC), mainly depending on an immunosuppressive microenvironment with limited number of CD8 + T cells, especially stem-like CD8 + T cells, in tumor tissues. Here we develop engineered microparticles (MPs) derived from alpha-fetoprotein (AFP)-overexpressing macrophages to load resiquimod (R848@M2pep-MPs AFP ) for enhanced anti-PD-1 therapy in HCC. R848@M2pep-MPs AFP target and reprogram immunosuppressive M2-like tumor-associated macrophages (TAMs) into M1-like phenotype. Meanwhile, R848@M2pep-MPs AFP -reprogrammed TAMs act as antigen-presenting cells, not only presenting AFP antigen to activate CD8 + T cell-mediated antitumor immunity, but also providing an intra-tumoral niche to maintain and differentiate stem-like CD8 + T cells. Combination immunotherapy with anti-PD-1 antibody generates strong antitumor immune memory and induces abundant stem-like CD8 + T cell proliferation and differentiation to terminally exhausted CD8 + T cells for long-term immune surveillance in orthotopic and autochthonous HCC preclinical models in male mice. We also show that the R848-loaded engineered MPs derived from macrophages overexpressing a model antigen ovalbumin (OVA) can improve anti-PD-1 therapy in melanoma B16-OVA tumor-bearing mice. Our work presents a facile and generic strategy for personalized cancer immunotherapy to boost anti-PD-1 therapy.