ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity.

Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues1,2. Although ILC2s are found in cancers of these tissues3, their roles in cancer immunity and immunotherapy are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumour immunity. Interleukin-33 (IL33) activates tumour ILC2s (TILC2s) and CD8+ T cells in orthotopic pancreatic tumours but not heterotopic skin tumours in mice to restrict pancreas-specific tumour growth. Resting and activated TILC2s express the inhibitory checkpoint receptor PD-1. Antibody-mediated PD-1 blockade relieves ILC2 cell-intrinsic PD-1 inhibition to expand TILC2s, augment anti-tumour immunity, and enhance tumour control, identifying activated TILC2s as targets of anti-PD-1 immunotherapy. Finally, both PD-1+ TILC2s and PD-1+ T cells are present in most human PDACs. Our results identify ILC2s as anti-cancer immune cells for PDAC immunotherapy. More broadly, ILC2s emerge as tissue-specific enhancers of cancer immunity that amplify the efficacy of anti-PD-1 immunotherapy. As ILC2s and T cells co-exist in human cancers and share stimulatory and inhibitory pathways, immunotherapeutic strategies to collectively target anti-cancer ILC2s and T cells may be broadly applicable.

Mesenchymal stem cells facilitate axon sorting, myelination, and functional recovery in paralyzed mice deficient in Schwann cell-derived laminin.

Peripheral nerve function depends on a regulated process of axon and Schwann cell development. Schwann cells interact with peripheral neurons to sort and ensheath individual axons. Ablation of laminin γ1 in the peripheral nervous system (PNS) arrests Schwann cell development prior to radial sorting of axons. Peripheral nerves of laminin-deficient animals are disorganized and hypomyelinated. In this study, sciatic nerves of laminin-deficient mice were treated with syngenic murine adipose-derived stem cells (ADSCs). ADSCs expressed laminin in vitro and in vivo following transplant into mutant sciatic nerves. ADSC-treatment of mutant nerves caused endogenous Schwann cells to differentiate past the point of developmental arrest to sort and myelinate axons. This was shown by (1) functional, (2) ultrastructural, and (3) immunohistochemical analysis. Treatment of laminin-deficient nerves with either soluble laminin or the immortalized laminin-expressing cell line 3T3/L1 did not overcome endogenous Schwann cell developmental arrest. In summary, these results indicate that (1) laminin-deficient Schwann cells can be rescued, (2) a cell-based approach is beneficial in comparison with soluble protein treatment, and (3) mesenchymal stem cells modify sciatic nerve function via trophic effects rather than transdifferentiation in this system.

Ixabepilone-induced mitochondria and sensory axon loss in breast cancer patients.

BACKGROUND: We sought to define the clinical and ultrastructure effects of ixabepilone (Ix), a microtubule-stabilizing chemotherapy agent on cutaneous sensory nerves and to investigate a potential mitochondrial toxicity mechanism. METHODS: Ten breast cancer patients receiving Ix underwent total neuropathy score clinical (TNSc) assessment, distal leg skin biopsies at cycle (Cy) 3 (80-90 mg/m(2)), Cy5 (160-190 mg/m(2)), and Cy7 (>200 mg/m(2)) and were compared to 5 controls. Skin blocks were processed for EM and ultrastructural morphometry of Remak axons done. RESULTS: At baseline, Ix-treated subjects had higher TNSc values (4.5 ± 0.8 vs. 0.0 ± 0.0), greater percentage of empty (denervated) Schwann cells (29% vs. 12%), altered axonal diameter (422.9 ± 17 vs. 354.9 ± 14.8 nm, P = 0.01), and axon profiles without mitochondria tended to increase compared to control subjects (71% vs. 70%). With increasing cumulative Ix exposure, an increase in TNSc values (Cy3: 5.4 ± 1.2, Cy7: 10 ± 4, P < 0.001), empty Schwann cells (39% by Cy7), and dilated axons (in nm, Cy3: 506.3 ± 22.1, Cy5: 534.8 ± 33, Cy7: 527.8 ± 24.4; P < 0.001) was observed. In addition, axon profiles without mitochondria (Cy3:74%, Cy7:78%) and mitochondria with abnormal morphology (grade 3 or 4) increased from 24% to 79%. Schwann cells with atypical mitochondria and perineuronal macrophage infiltration in dermis were noted. INTERPRETATION: This study provides functional and structural evidence that Ix exposure induces a dose-dependent toxicity on small sensory fibers with an increase in TNSc scores and progressive axonal loss. Mitochondria appear to bear the cumulative toxic effect and chemotherapy-induced toxicity can be monitored through serial skin biopsy-based analysis.