Lung Megakaryocytes are Immune Modulatory Cells that Present Antigen to CD4+ T cells.

Although platelets are the cellular mediators of thrombosis, they are also immune cells. Platelets interact both directly and indirectly with immune cells, impacting their activation and differentiation, as well as all phases of the immune response. Megakaryocytes (Mks) are the cell source of circulating platelets, and until recently Mks were typically only considered bone marrow–resident (BM-resident) cells. However, platelet-producing Mks also reside in the lung, and lung Mks express greater levels of immune molecules compared with BM Mks. We therefore sought to define the immune functions of lung Mks. Using single-cell RNA sequencing of BM and lung myeloid-enriched cells, we found that lung Mks, which we term MkL, had gene expression patterns that are similar to antigen-presenting cells. This was confirmed using imaging and conventional flow cytometry. The immune phenotype of Mks was plastic and driven by the tissue immune environment, as evidenced by BM Mks having an MkL-like phenotype under the influence of pathogen receptor challenge and lung-associated immune molecules, such as IL-33. Our in vitro and in vivo assays demonstrated that MkL internalized and processed both antigenic proteins and bacterial pathogens. Furthermore, MkL induced CD4+ T cell activation in an MHC II–dependent manner both in vitro and in vivo. These data indicated that MkL had key immune regulatory roles dictated in part by the tissue environment.pre-print236 K

BETA PRIME: Phase I study of AdAPT-001 as monotherapy and combined with a checkpoint inhibitor in superficially accessible, treatment-refractory solid tumors.

AdAPT-001 is an investigational therapy consisting of a replicative type 5 adenovirus armed with a TGF-β receptor-immunoglobulin Fc fusion trap, designed to neutralize isoforms 1 and 3 of the profibrotic and immunosuppressive cytokine, TGF-β. In preclinical studies with an immunocompetent mouse model, AdAPT-001 eradicated directly treated \u27cold\u27 tumors as well as distant untreated tumors, and, from its induction of systemic CD8+ T cell-mediated antitumor immunity, protected the mice from rechallenge with tumor cells. AdAPT-001 also sensitized resistant tumors to checkpoint blockade. This manuscript describes the rationale and design of the first-in-human phase I, dose-escalation and dose-expansion study of AdAPT-001 alone and in combination with a checkpoint inhibitor in adults with treatment-refractory superficially accessible solid tumors. Trial registration: ClinicalTrials.gov NCT04673942. Keywords: AdAPT-001; BETA PRIME; TGF-β trap; abscopal effect; oncolytic adenovirus; solid tumors; study protocol