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Measles live attenuated vaccine (MV) induces strong humoral and cellular systemic memory responses allowing the successful control of measles since decades. MV has also been adapted into a promising vaccine platform with several vaccine candidates in clinical development. To understand and document the tissue-scaled memory response induced by MV, we explored the specific induction and persistence of resident memory T cells (Trm) in the lungs and the liver, two critical targeted tissues for vaccine development against several diseases. Trm are a subset of non-circulating highly specialized T cells. They are found at multiple barrier and mucosal sites, conveniently positioned to rapidly react against pathogens. The induction of Trm in different tissues is therefore critical for vaccine development. We demonstrated in mice the rapid generation of MV-specific and vectorized antigen-specific Trm in the liver and the lungs after a single dose, whatever the route of immunization. The intranasal route induced more Trm in the lungs than other routes, confirming the potential of intranasal vaccine administration of replicative viral vectors to generate a strong pulmonary immune response. MV-specific Trm cells were functionally active, with CD8 + Trm secreting granzyme B upon in vitro restimulation and CD4 + Trm cells secreting IFN-γ and TNF-α. We confirmed in human lymphocytes this tissue tropism by showing an overexpression of homing receptors directing them to epithelial and inflamed tissues. Vaccination strategies able to induce Trm cells at key sites represent a promising field to improve current vaccines, prioritize vaccine platforms and design future vaccines with enhanced protective efficacy.

Attenuated measles virus (MV) exerts its oncolytic activity in malignant pleural mesothelioma (MPM) cells that lack type-I interferon (IFN-I) production or responsiveness. However, other cells in the tumor microenvironment (TME), such as myeloid cells, possess functional antiviral pathways. In this study, we aimed to characterize the interplay between MV and the myeloid cells in human MPM. We cocultured MPM cell lines with monocytes or macrophages and infected them with MV. We analyzed the transcriptome of each cell type and studied their secretion and phenotypes by high-dimensional flow cytometry. We also measured transgene expression using an MV encoding GFP (MV-GFP). We show that MPM cells drive the differentiation of monocytes into M2-like macrophages. These macrophages inhibit GFP expression in tumor cells harboring a defect in IFN-I production and a functional signaling downstream of the IFN-I receptor, while having minimal effects on GFP expression in tumor cells with defect of responsiveness to IFN-I. Interestingly, inhibition of the IFN-I signaling by ruxolitinib restores GFP expression in tumor cells. Upon MV infection, cocultured macrophages express antiviral pro-inflammatory genes and induce the expression of IFN-stimulated genes in tumor cells. MV also increases the expression of HLA and costimulatory molecules on macrophages and their phagocytic activity. Finally, MV induces the secretion of inflammatory cytokines, especially IFN-I, and PD-L1 expression in tumor cells and macrophages. These results show that macrophages reduce viral proteins expression in some MPM cell lines through their IFN-I production and generate a pro-inflammatory interplay that may stimulate the patient's anti-tumor immune response., Competing Interests: FT and JFF are authors of patents on MV. FT owns equity in Oncovita, an oncolytic virotherapy company., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Attenuated measles virus (MV) is currently being evaluated in clinical trials as an oncolytic therapeutic agent. Originally used for its lytic activity against tumor cells, it is now admitted that the effectiveness of MV also lies in its ability to initiate antitumor immune responses through the activation of dendritic cells (DCs). In this study, we investigated the capacity of oncolytic MV to convert human blood myeloid CD1c + DCs and plasmacytoid DCs (pDCs) into cytotoxic effectors. We found that MV induces the expression of the cytotoxic protein TNF-related apoptosis-inducing ligand (TRAIL) on the surface of DCs. We demonstrate that the secretion of interferon-α (IFN-α) by DCs in response to MV is responsible for this TRAIL expression. Several types of PRRs (pattern recognition receptors) have been implicated in MV genome recognition, including RLRs (RIG-I-like receptors) and TLRs (Toll-like receptors). We showed that CD1c + DCs secrete modest amounts of IFN-α and express TRAIL in an RLR-dependent manner upon exposure to MV. In pDCs, MV is recognized by RLRs and also by TLR7, leading to the secretion of high amounts of IFN-α and TRAIL expression. Finally, we showed that MV-stimulated DCs induce TRAIL-mediated cell death of Jurkat cells, confirming their acquisition of cytotoxic functions. Our results demonstrate that MV can activate cytotoxic myeloid CD1c + DCs and pDCs, which may participate to the antitumor immune response.

RNA viruses exhibit small-sized genomes encoding few proteins, but still establish complex networks of protein-protein and RNA-protein interactions within a cell to achieve efficient replication and spreading. Deciphering these interactions is essential to reach a comprehensive understanding of the viral infection process. To study RNA-protein complexes directly in infected cells, we developed a new approach based on recombinant viruses expressing tagged viral proteins that were purified together with their specific RNA partners. High-throughput sequencing was then used to identify these RNA molecules. As a proof of principle, this method was applied to measles virus nucleoprotein (MV-N). It revealed that in addition to full-length genomes, MV-N specifically interacted with a unique population of 5' copy-back defective interfering RNA genomes that we characterized. Such RNA molecules were able to induce strong activation of interferon-stimulated response element promoter preferentially via the cytoplasmic pattern recognition receptor RIG-I protein, demonstrating their biological functionality. Thus, this method provides a new platform to explore biologically active RNA-protein networks that viruses establish within infected cells.