ABSTRACT
Tumor-associated macrophages (TAMs) are pivotal within the immunosuppressive tumor microenvironment (TME), and recently, have attracted intensive attention for cancer treatment. However, concurrently to promote TAMs repolarization and phagocytosis of cancer cells remains challenging. Here, a TAMs-targeted albumin nanoparticles-based delivery system (M@SINPs) was constructed for the co-delivery of photosensitizer IR820 and SHP2 inhibitor SHP099 to potentiate macrophage-mediated cancer immunotherapy. M@SINPs under laser irradiation can generate the intracellular reactive oxygen species (ROS) and facilitate M2-TAMs to an M1 phenotype. Meanwhile, inhibition of SHP2 could block the CD47-SIRPa pathway to restore M1 macrophage phagocytic activity. M@SINPs-mediated TAMs remodeling resulted in the immunostimulatory TME by repolarizing TAMs to an M1 phenotype, restoring its phagocytic function and facilitating intratumoral CTLs infiltration, which significantly inhibited tumor growth. Furthermore, M@SINPs in combination with anti-PD-1 antibody could also improve the treatment outcomes of PD-1 blockade and exert the synergistic anticancer effects. Thus, the macrophage repolarization/phagocytosis restoration combination through M@SINPs holds promise as a strategy to concurrently remodel TAMs in TME for improving the antitumor efficiency of immune checkpoint block and conventional therapy.
Subject(s)
CD47 Antigen , Immunotherapy , Nanoparticles , Phagocytosis , Tumor Microenvironment , Tumor-Associated Macrophages , Animals , Immunotherapy/methods , Mice , Nanoparticles/chemistry , Tumor-Associated Macrophages/immunology , Tumor Microenvironment/drug effects , Cell Line, Tumor , Neoplasms/therapy , Neoplasms/immunology , Humans , Reactive Oxygen Species/metabolism , Mice, Inbred C57BL , Receptors, Immunologic/metabolism , FemaleABSTRACT
Here, the authors propose a light-activated reactive oxygen species (ROS)-responsive nanoplatform that can boost immunogenic cell death (ICD) to release "eat me" signals, and improve CD47-blocking immunotherapy by tumor-targeted codelivery of photosensitizer IR820 and anti-CD47 antibody (αCD47). Human serum albumin and αCD47 are first constructed into a single nanoparticle using ROS-responsive linkers, which are further conjugated with photosensitizer IR820 via a matrix metalloproteinase-sensitive peptide as linker and then modified with poly(ethylene glycol) on the surface of the obtained nanoparticles. When exposed to the first wave of near-infrared (NIR) laser irradiation, the obtained nanoplatform (M-IR820/αCD47@NP) can generate ROS, which triggers nanoparticles dissociation and thus, facilitates the release of αCD47 and IR820. The second wave of NIR laser irradiation is subsequently used to perform phototherapy and induce ICD of tumor cells. An in vitro cellular study shows that M-IR820/αCD47@NP can stimulate dendritic cells activation while simultaneously enhancing the phagocytic activity of macrophage against tumor cells. In 4T1 tumor-bearing mice, M-IR820/αCD47@NP-mediated combination of phototherapy and CD47 blockade can effectively induce the synergistic antitumor immune responses to inhibit the growth of tumors and prevent local tumor recurrence. This work offers a promising strategy to improve the CD47-blocking immunotherapy efficacy using αCD47 nanomedicine.
Subject(s)
Nanoparticles , Neoplasms , Animals , CD47 Antigen , Cell Line, Tumor , Immunologic Factors , Immunotherapy , Mice , Photosensitizing Agents/pharmacology , Reactive Oxygen SpeciesABSTRACT
Based on the interpretive structure model of system dynamics, this paper constructs a hierarchical structure model of factors affecting the entrepreneurial learning from failure, which has been also tested through a case of entrepreneurship. The study finds that: (1) there are 15 factors influencing entrepreneurial learning from failure that play different hierarchical roles; (2) the entrepreneurs' self-efficacy, as a key influencing factor of entrepreneurial learning from failure, can be cultivated and improved by enriched the entrepreneurs' successful career experience. In addition, emotion regulation after the entrepreneurial failure is also a key influencing factor of the entrepreneurial learning from failure and the emotion management is deemed as an important part of entrepreneurship education; (3) the entrepreneurial education may affect the entrepreneurship learning from failure indirectly by affecting the entrepreneurs' self-efficacy; (4) the economic conditions, the policy support, the industry characteristics and the cultural sensemaking of failure are the macro factors that may affect the entrepreneurship learning from failure.
