Nanodrug-bacteria conjugates-mediated oncogenic collagen depletion enhances immune checkpoint blockade therapy against pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) cancer cells specifically produce abnormal oncogenic collagen to bind with integrin α3ß1 receptor and activate the downstream focal adhesion kinase (FAK), protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) signaling pathway. Collectively, this promotes immunosuppression and tumor proliferation and restricts the response rate of clinical cancer immunotherapies. METHODS: Here, by leveraging the hypoxia tropism and excellent motility of the probiotic Escherichia coli strain Nissle 1917 (ECN), we developed nanodrug-bacteria conjugates to penetrate the extracellular matrix (ECM) and shuttle the surface-conjugated protein cages composed of collagenases and anti-programmed death-ligand 1 (PD-L1) antibodies to PDAC tumor parenchyma. FINDINGS: We found the oncogenic collagen expression in human pancreatic cancer patients and demonstrated its interaction with integrin α3ß1. We proved that reactive oxygen species (ROS) in the microenvironment of PDAC triggered collagenase release to degrade oncogenic collagen and block integrin α3ß1-FAK signaling pathway, thus overcoming the immunosuppression and synergizing with anti-PD-L1 immunotherapy. CONCLUSIONS: Collectively, our study highlights the significance of oncogenic collagen in PDAC immunotherapy, and consequently, we developed a therapeutic strategy that can deplete oncogenic collagen to synergize with immune checkpoint blockade for enhanced PDAC treatment efficacy. FUNDING: This work was supported by the University of Wisconsin Carbone Cancer Center Research Collaborative and Pancreas Cancer Research Task Force, UWCCC Transdisciplinary Cancer Immunology-Immunotherapy Pilot Project, and the start-up package from the University of Wisconsin-Madison (to Q.H.).

Redox modulation with a perfluorocarbon nanoparticle to reverse Treg-mediated immunosuppression and enhance anti-tumor immunity.

Tumor hypoxia and high glutathione (GSH) expression promote regulatory T cell (Treg) infiltration and maintain its immunosuppressive function, which significantly reduces the response rate of cancer immunotherapy. Here, we developed an immunomodulatory nano-formulation (FEM@PFC) to reverse Treg-mediated immunosuppression by redox regulation in the tumor microenvironment (TME). Oxygen carried in perfluorocarbon (PFC) was delivered to the TME, thus relieving the hypoxic condition and inhibiting Treg infiltration. More importantly, GSH depletion by the prodrug efficiently restricted the Foxp3 expression and immunosuppressive function of Tregs, thus breaking the shackles of tumor immunosuppression. Additionally, the supplement of oxygen cooperated with the consumption of GSH to enhance the irradiation-induced immunogenic cell death and subsequent dendritic cell (DC) maturation, thereby efficiently promoting the activation of effector T cells and restricting the immunosuppression of Tregs. Collectively, the FEM@PFC nano-formulation reverses Treg-mediated immunosuppression and regulates the redox balance in the TME to boost anti-tumor immunity and prolong the survival of tumor-bearing mice, which provides a new immunoregulatory strategy from the perspective of redox modulation.

Active recruitment of anti-PD-1-conjugated platelets through tumor-selective thrombosis for enhanced anticancer immunotherapy.

Immune checkpoint inhibitors (ICIs) can reinvigorate T cells to eradicate tumor cells, showing great potential in combating various types of tumors. We propose a delivery strategy to enhance tumor-selective ICI accumulation, which leverages the responsiveness of platelets and platelet-derivatives to coagulation cascade signals. A fused protein tTF-RGD targets tumor angiogenic blood vessel endothelial cells and initiates the coagulation locoregionally at the tumor site, forming a "cellular hive" to recruit anti-PD-1 antibody (aPD-1)-conjugated platelets to the tumor site and subsequently activating platelets to release aPD-1 antibody to reactivate T cells for improved immunotherapy. Moreover, on a patient-derived xenograft breast cancer model, the platelet membrane-coated nanoparticles can also respond to the coagulation signals initiated by tTF-RGD, thus enhancing the accumulation and antitumor efficacy of the loaded chemotherapeutics. Our study illustrates a versatile platform technology to enhance the local accumulation of ICIs and chemodrugs by taking advantage of the responsiveness of platelets and platelet derivatives to thrombosis.

Chemically engineering cells for precision medicine.

Cell-based therapy holds great potential to address unmet medical needs and revolutionize the healthcare industry, as demonstrated by several therapeutics such as CAR-T cell therapy and stem cell transplantation that have achieved great success clinically. Nevertheless, natural cells are often restricted by their unsatisfactory in vivo trafficking and lack of therapeutic payloads. Chemical engineering offers a cost-effective, easy-to-implement engineering tool that allows for strengthening the inherent favorable features of cells and confers them new functionalities. Moreover, in accordance with the trend of precision medicine, leveraging chemical engineering tools to tailor cells to accommodate patients individual needs has become important for the development of cell-based treatment modalities. This review presents a comprehensive summary of the currently available chemically engineered tools, introduces their application in advanced diagnosis and precision therapy, and discusses the current challenges and future opportunities.

Enhancing Gasdermin-induced tumor pyroptosis through preventing ESCRT-dependent cell membrane repair augments antitumor immune response.

Pore-forming Gasdermin protein-induced pyroptosis in tumor cells promotes anti-tumor immune response through the release of pro-inflammatory cytokines and immunogenic substances after cell rupture. However, endosomal sorting complexes required for transport (ESCRT) III-mediated cell membrane repair significantly diminishes the tumor cell pyroptosis by repairing and subsequently removing gasdermin pores. Here, we show that blocking calcium influx-triggered ESCRT III-dependent membrane repair through a biodegradable nanoparticle-mediated sustained release of calcium chelator (EI-NP) strongly enhances the intracellularly delivered GSDMD-induced tumor pyroptosis via a bacteria-based delivery system (VNP-GD). An injectable hydrogel and a lyophilized hydrogel-based cell patch are developed for peritumoral administration for treating primary and metastatic tumors, and implantation for treating inoperable tumors respectively. The hydrogels, functioning as the local therapeutic reservoirs, can sustainedly release VNP-GD to effectively trigger tumor pyroptosis and EI-NP to prevent the ESCRT III-induced plasma membrane repair to boost the pyroptosis effects, working synergistically to augment the anti-tumor immune response.

Depletion of tumor associated macrophages enhances local and systemic platelet-mediated anti-PD-1 delivery for post-surgery tumor recurrence treatment.

Immunosuppressive cells residing in the tumor microenvironment, especially tumor associated macrophages (TAMs), hinder the infiltration and activation of T cells, limiting the anti-cancer outcomes of immune checkpoint blockade. Here, we report a biocompatible alginate-based hydrogel loaded with Pexidartinib (PLX)-encapsulated nanoparticles that gradually release PLX at the tumor site to block colony-stimulating factor 1 receptors (CSF1R) for depleting TAMs. The controlled TAM depletion creates a favorable milieu for facilitating local and systemic delivery of anti-programmed cell death protein 1 (aPD-1) antibody-conjugated platelets to inhibit post-surgery tumor recurrence. The tumor immunosuppressive microenvironment is also reprogrammed by TAM elimination, further promoting the infiltration of T cells into tumor tissues. Moreover, the inflammatory environment after surgery could trigger the activation of platelets to facilitate the release of aPD-1 accompanied with platelet-derived microparticles binding to PD-1 receptors for re-activating T cells. All these results collectively indicate that the immunotherapeutic efficacy against tumor recurrence of both local and systemic administration of aPD-1 antibody-conjugated platelets could be strengthened by local depletion of TAMs through the hydrogel reservoir.

Narrating life in the military: Links between veterans' narrative processing of service experiences and their posttraumatic stress symptoms and well-being.

Military veterans frequently experience traumatic, highly stressful events; thus, it is especially important for them to find positive ways of making meaning from these experiences. The present study used the methods of narrative personality psychology to investigate the associations between veterans' narrative processing of highly stressful and significant events from their military service and postdischarge functioning, including posttraumatic stress symptoms (PTSS). United States military veterans (N = 154; M age = 64.28 years, 86.4% men, 57.8% deployed) completed an online survey in which they wrote narratives about one "highly stressful" and one "key scene" military service memory and completed questionnaires to assess PTSS, symptoms of depression and anxiety, functional impairment, and well-being. Narratives were coded for personal growth from the experience, themes of agency and interpersonal communion, affective tone, and coherence. In the highly stressful narratives, small-to-moderate negative associations emerged between both growth and agency and PTSS, depression and anxiety, and functional impairment; growth was also modestly positively associated with well-being. In contrast, affective tone and communion were each only associated modestly with one outcome, and coherence with none, and narrative processing of the key scene narrative was not linked with any mental health outcomes. These findings suggest that (1) the theory and methods of narrative identity research are relevant for studying trauma narratives, and (2) veterans who narrate themselves as growing from and exerting control over their most stressful service experiences may achieve better mental health and day-to-day functioning.