This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abbreviations: ABC, ammonium bicarbonate; ACN, acetonitrile; ALSFRS-R, amyotrophic lateral sclerosis functional rating scale-revised; APC, absolute protein cluster; ASO, antisense oligonucleotide; CDH18, cadherin 18; COL6A1, collagen type VI alpha 1; CPE, carboxypeptidase E; CSF, cerebrospinal fluid; DDA, data-dependent acquisition; DPC, differential protein cluster; DTT, dithiothreitol; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; HFMSE, hammersmith functional rating scale expanded; IAA, iodoacetamide; IgG, immunoglobulin G; IPA, ingenuity pathway analysis; IQR, interquartile range; LFQ, label-free quantification; MS, mass spectrometry; N/A, not applicable; NPTX1, neuronal pentraxin-1; OCB, oligoclonal immunoglobulin G (IgG) bands; PARK7, Parkinson's disease protein 7; PCA, principle component analysis; pNfH, plasma phosphorylated neurofilament heavy chain; Q alb , CSF/ serum quotients of albumin; rpm, rounds per minute; RRID, Research Resource Identifier (see scicrunch.org); SEM, standard error of the mean; SEMA7A, semaphorin 7A; SMA, 5q-linked spinal muscular atrophy; SMN1, survival motor neuron 1 gene; SMN2, survival motor neuron 2 gene; T 0 , first nusinersen injection at baseline; T 10 , sixth nusinersen injection after 10 months; TFA, trifluoracetic acid; WPCNA, weighted protein correlation network analysis; ΔHFMSE (T 0 -T 10 ), change in Hammersmith Functional Rating Scale Expanded score between T 0 and T 10 . AbstractPromising results from recent clinical trials on the approved antisense oligonucleotide nusinersen in pediatric patients with 5q-linked spinal muscular atrophy (SMA) still have to be confirmed in adult patients but are hindered by a lack of sensitive biomarkers that indicate an early therapeutic response. Changes in the overall neurochemical composition of cerebrospinal fluid (CSF) under therapy may yield additive diagnostic and predictive information. With this prospective proof-of-concept and feasibility study, we evaluated non-targeted CSF proteomic profiles by mass spectrometry along with basic CSF parameters of 10 adult patients with SMA types 2 or 3 before and after 10 months of nusinersen therapy, in comparison with 10 age-and gender-matched controls. These data were analyzed by bioinformatics and correlated with clinical outcomes assessed by the Hammersmith Functional Rating Scale Expanded (HFMSE). CSF proteomic profiles of SMA patients differed from controls. Two groups of SMA patients were identified based on unsupervised clustering. These groups differed in age and expression of proteins related to neurodegeneration and neuroregeneration. Intraindividual CSF differences in response to nusinersen treatment varied between patients who clinically improved and those who did not. Data are available via P...

Tumor-infiltrating dendritic cells (DCs) correlate with effective anticancer immunity and improved responsiveness to anti–PD-1 checkpoint immunotherapy. However, the drivers of DC expansion and intratumoral accumulation are ill-defined. We found that interleukin-2 (IL-2) stimulated DC formation through innate and adaptive lymphoid cells in mice and humans, and this increase in DCs improved anticancer immunity. Administration of IL-2 to humans within a clinical trial and of IL-2 receptor (IL-2R)–biased IL-2 to mice resulted in pronounced expansion of type 1 DCs, including migratory and cross-presenting subsets, and type 2 DCs, although neither DC precursors nor mature DCs had functional IL-2Rs. In mechanistic studies, IL-2 signals stimulated innate lymphoid cells, natural killer cells, and T cells to synthesize the cytokines FLT3L, CSF-2, and TNF. These cytokines redundantly caused DC expansion and activation, which resulted in improved antigen processing and correlated with favorable anticancer responses in mice and patients. Thus, IL-2 immunotherapy–mediated stimulation of DCs contributes to anticancer immunity by rendering tumors more immunogenic.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.