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

In the nanomedicine field, there is a need to widen the availability of nanovectors to compensate for the increasingly reported side effects of poly­(ethene glycol). Nanovectors enabling cross-linking can further optimize drug delivery. Cross-linkable polyoxazolines are therefore relevant candidates to address these two points. Here we present the synthesis of coumarin-functionalized poly­(2-alkyl-2-oxazoline) block copolymers, namely, poly­(2-methyl-2-oxazoline)-block-poly­(2-phenyl-2-oxazoline) and poly­(2-methyl-2-oxazoline)-block-poly­(2-butyl-2-oxazoline). The hydrophilic ratio and molecular weights were varied in order to obtain a range of possible behaviors. Their self-assembly after nanoprecipitation or film rehydration was examined. The resulting nano-objects were fully characterized by transmission electron microscopy (TEM), cryo-TEM, multiple-angle dynamic and static light scattering. In most cases, the formation of polymer micelles was observed, as well as, in some cases, aggregates, which made characterization more difficult. Cross-linking was performed under UV illumination in the presence of a coumarin-bearing cross-linker based on polymethacrylate derivatives. Addition of the photo-cross-linker and cross-linking resulted in better-defined objects with improved stability in most cases.

<div>Abstract<p>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 functional approaches to dissect the relation between CD8⁺ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor–specific CD8⁺ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading, <i>in situ</i>, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison with their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor–specific CD8⁺ T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated patients with head and neck cancer. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors.</p></div>