InVivoMAb recombinant Flt-3L-Ig (hum/hum)

Microwave ablation (MWA) has shown favorable safety and efficacy in patients with non-small cell lung cancer (NSCLC). However, local recurrence remains a major concern that compromises long-term survival. Dysfunction of dendritic cells (DCs) constitutes a key immunosuppressive factor that limits effective T cell-mediated antitumor responses. To overcome this limitation, we evaluated the therapeutic potential of combining MWA with DC-based immunotherapy.

Type 1 conventional dendritic cells (cDC1s) are infrequent immune cells with an essential role in orchestrating immune responses to malignancies or infections. Despite their significance in regulating adaptive immunity, the absence of efficient manufacturing techniques to produce sufficient cDC1s hinders their therapeutic application. Here, we show that interleukin 4 (IL-4) markedly increases the yield of cDC1 cells derived from Flt3 ligand cultures of mouse and human progenitors, while concurrently inhibiting plasmacytoid DCs development. IL-4 predominantly acts on DC progenitors, and its activity requires cell-intrinsic IL4-RA or STAT6 signaling. Both in vitro and in vivo, IL-4-stimulated cDC1s efficiently prime cytotoxic CD8+ T cells. Transcriptomic analyses reveal that IL-4 promotes cDC1 proliferation, providing a mechanistic basis for the enhanced output. Together, these findings uncover an unexpected role for IL-4 in driving the development and scalable production of bona fide cDC1s, facilitating mechanistic studies and supporting their future therapeutic application in human disease.

The antigenic landscape of autoimmune diabetes reflects a failure to preserve self-tolerance, yet how novel neoantigens emerge in humans remains incompletely understood. Here we designed an immunopeptidomics-based approach to probe HLA-II-bound, islet-derived neoepitopes in patients with type 1 diabetes. We uncovered a Cys→Ser transformation, conserved between mice and humans, that reshapes autoreactivity to insulin at the single-residue level. This transformation, which we call C19S, arises from oxidative remodeling of insulin in stressed pancreatic islets and also occurs in cytokine-activated antigen-presenting cells, contributing to a feed-forward loop of neoepitope formation and presentation. Despite involving just one amino acid, C19S is recognized by HLA-DQ8-restricted, register-specific CD4+ T cells that expand at diabetes onset. These neoepitope-specific CD4+ T cells lack regulatory potential but acquire a poised central memory phenotype that persists throughout disease progression. These findings reveal a distinct, microenvironment-driven route of neoantigen formation that fuels sustained autoreactivity in diabetes.

Diffuse midline glioma (DMG) is a devastating pediatric brain tumor. The oncolytic adenovirus Delta-24-RGD has shown promising efficacy and safety in DMG patients but is not yet curative. Thus, we hypothesized that activating dendritic cells (DCs) through the CD40 costimulatory receptor could increase antigen presentation and enhance the anti-tumor effect of the virus, resulting in long-term responses. This study shows that the intratumoral co-administration of Delta-24-RGD and a CD40 agonistic antibody is well tolerated and induces long-term anti-tumor immunity, including complete responses (up to 40%) in DMG preclinical models. Mechanistic studies revealed that this therapy increased tumor-proliferating T lymphocytes and proinflammatory myeloid cells, including mature DCs with superior tumor antigen uptake capacity. Moreover, the lack of cross-presenting DCs and the prevention of DC recruitment into the tumor abolish the Delta-24-RGD+anti-CD40 anti-DMG effect. This approach shows potential for combining virotherapy with activating antigen-presenting cells in these challenging tumors.