Abstract Introduction Immune checkpoint blockade therapies, particularly those targeting the PD-1/PD-L1 and CTLA-4 pathways, have fundamentally transformed cancer treatment, achieving clinical responses in approximately 25% of patients. Although combinatorial strategies have improved these outcomes, a substantial proportion of patients remain refractory to treatment or develop resistance. Emerging evidence implicates tonic PD-1 signaling–a ligand-independent, constitutive pathway distinct from canonical checkpoint inhibition–as a potential contributor to therapeutic resistance. To elucidate the impact of tonic PD-1 signaling on dendritic cell (DC) function and to explore innovative therapeutic approaches aimed at restoring their immunogenic capacity. Methods We utilized lentiviral transduction to generate DC2.4 dendritic cell lines stably overexpressing PD-1. Under conditions of tonic PD-1 signaling, we evaluated cell viability and the expression of key costimulatory molecules (MHC II, CD80, CD86). Additionally, we investigated the effects of RIPR-PD-1, a bispecific molecule that disrupts tonic PD-1 signaling via CD45 tethering, and SHP009, a pharmacological inhibitor targeting SHP2 recruitment. Results PD-1 overexpression in DCs led to a significant reduction in both cell viability and the expression of costimulatory markers. Treatment with RIPR-PD-1 or SHP009 effectively reversed these inhibitory effects, restoring DC viability and promoting the upregulation of MHC II, CD80, and CD86 expression. Conclusion These findings demonstrate that tonic PD-1 signaling compromises dendritic cell functionality by attenuating their viability and costimulatory potential. Pharmacological blockade of tonic PD-1 signaling–either through RIPR-PD-1 or SHP2 inhibition–reinstates a pro-immunogenic DC phenotype. Targeting this non-canonical PD-1 pathway represents a promising strategy to potentiate antitumor immune responses and overcome resistance to existing immunotherapies. Funding Source n/a Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)
Purpose:Recent improvements in MRI gradient design and amplifiers, advanced MRI scanners are now routinely utilizing slew rates of several hundred T/m/s. However, full gradient performance cannot be exploited in high-resolution EPI due to peripheral nerve stimulation (PNS) limits. We aim to characterize and mitigate these PNS constraints using a simple sequence modification: PNS-optimized EPI gradient pulse shapes. Methods:PNS-Optimized Pulses for EPI (POPE): we selectively reduce the slew rate of gradient pulses at periods of high predicted PNS spikes, while leaving the rest of the waveform unchanged. PNS sensation was evaluated. Results:POPE allows 7%-35% faster imaging of EPI protocols resolutions of 1mm-0.3mm resolutions without exceeding predicted PNS. With such improvements, POPE allows robust 0.3 mm isotropic fMRI protocols that would have exceeded safety limits without it. Conclusion:POPE facilitates locally precise fMRI activation mapping on clinical 7T scanners at spatial resolution that were previously unattainable due to PNS limitations.
