Tumor antigen–specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1 hi CD39 + CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade.

Harvesting the posterior portion of the TMG up to the middle of the posterior thigh may lead to partial flap necrosis. Extending subcutaneous fat removal under the inferior skin incision may increase the risk of donor site complications. Adding a second vascular pedicle from the PAP flap may improve posterior TMG tip perfusion at the expense of a longer operation.

Although understanding of T cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T cell responsiveness to PD 1/PD L1 blockade. Here, we used single cell transcriptomic, phenotypic, and function al approaches to dissect the relation between cos + T cell exhaus tion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor specific cos + T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading, in situ, to a functionally exhausted population. Exhausted T cells were none

The impact of additive manufacturing in our lives has been increasing constantly. One of the frontiers in this change is the medical devices. 3D printing technologies not only enable the personalization of implantable devices with respect to patient-specific anatomy, pathology and biomechanical properties but they also provide new opportunities in related areas such as surgical education, minimally invasive diagnosis, medical research and disease models. In this review, we cover the recent clinical applications of 3D printing with a particular focus on implantable devices. The current technical bottlenecks in 3D printing in view of the needs in clinical applications are explained and recent advances to overcome these challenges are presented. 3D printing with cells (bioprinting); an exciting subfield of 3D printing, is covered in the context of tissue engineering and regenerative medicine and current developments in bioinks are discussed. Also emerging applications of bioprinting beyond health, such as biorobotics and soft robotics, are introduced. As the technical challenges related to printing rate, precision and cost are steadily being solved, it can be envisioned that 3D printers will become common on-site instruments in medical practice with the possibility of custom-made, on-demand implants and, eventually, tissue engineered organs with active parts developed with biorobotics techniques.

Three-dimensional (3D) printing is booming in the medical field. This technology increases the possibilities of personalized treatment for patients, while lowering manufacturing costs. To facilitate mandibular reconstruction with fibula free flap, some companies propose cutting guides obtained by CT-guided moulding. However, these guides are prohibitively expensive (€2,000 to €6,000). Based on a partnership with the CNRS, engineering students and a biomedical company, the authors have developed cutting guides and 3D-printed mandible templates, deliverable in 7days and at a lower cost. The novelty of this project is the speed of product development at a significantly lower price. In this technical note, the authors describe the logistic chain of production of mandible templates and cutting guides, as well as the results obtained. The goal is to allow access to this technology to all patients in the near future.

Implantation of biomedical devices is often followed by bacterial infections that may seriously affect implant functionalities and lead to their failure. In the context of bacterial resistance to antibiotics, which is a growing problem worldwide, new strategies that are able to overcome these problems are needed. In this work, we introduce a new formulation of hyaluronic acid (HA)-based antimicrobial material: HA hydrogels loaded with polyarginine (PAR), a polycationic antibiotic substitute. The loading is possible through electrostatic interactions between negatively charged HA and positively charged PAR. Such hydrogels absorb high quantities of PAR, which are then gradually released from the hydrogel. This original system provides a long-lasting antibacterial effect on an in vitro model of repetitive infection, thus demonstrating a strong potential to fight multiple rounds of infections that are resistant to antibiotic treatment. In addition, HA-PAR hydrogels could be deposited onto/into medical devices such as wound dressings and mesh prostheses used in clinical applications. Finally, we performed first in vivo tests of hydrogel-coated mesh materials to verify their biocompatibility in a rat model, which show no difference between control HA hydrogel and PAR-loaded hydrogel in terms of inflammation.

The advances in 3D printed silicone (PDMS: Polydimethylsiloxane) implants provide an outlook for personalized implants with highly accurate anatomical conformity. However, a potential adverse effects such as granuloma formation due to immune reactions still exists. One potential way of overcoming this problem is the control of implant/host interface using immunomodulatory coatings.In this study, a new cytokine cocktail composed of interleukin 10 and prostaglandin-E2 was designed to decrease the adverse immune reaction and promote tissue integration by fixing macrophage into M2 pro-healing phenotype for a long term. In vitro, the cytokine cocktail was able to keep the secretion of pro-inflammatory cytokines (TNF-α and IL-6) at a low level and induced the secretion of IL-10 and the upregulation of stabilin-1 (endocytotic scavenger receptor expressed by M2 macrophage). This cocktail was then loaded in a gelatin based hydrogel to develop an immunomodulatory material that can be used as a coating of a medical device. The efficacy of this coating was demonstrated in an in vivo rat model during reconstruction of a tracheal defect by 3D printed silicone implants. The coating was stable on silicone implants over 2 weeks and the controlled release of cocktail components was achieved for at least 14 days. In vivo, only 33% of the animals with bare silicone implant survived whereas 100% survived with the implant equipped with the immunomodulatory hydrogel. The presence of the hydrogel and the cytokine cocktail diminished the thickness of the inflammatory tissue, the intensity of both acute and chronic inflammation, overall fibroblastic reaction, oedema presence and fibrinoid formation (assessed by histology) and lead to a 100% survival rate. At systemic level, the presence of immunomodulatory hydrogel decreased significantly pro-inflammatory cytokines like TNF-α, IFN-γ, CXCL1 and MCP-1 levels at day 7 and IL-1α, IL-1β, CXCL1 and MCP-1 levels at day 21. The ability of this new immunomodulatory hydrogel to control the level of inflammation once applied on a 3D printed silicone implant has been demonstrated. Such thin coatings can be applied to any implants or scaffolds used in tissue engineering to diminish the initial immune response, improve integration and functionality of these materials and finally decrease potential complications related to their presence.

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