Hall, S. M. | bioRxiv Science

bioRxiv2023

Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression

Therapeutic benefit to immune checkpoint blockade (ICB) is currently limited to the subset of cancers thought to possess a sufficient tumor mutational burden (TMB) to allow for the spontaneous recognition of neoantigens (NeoAg) by autologous T cells. We explored whether the response of an aggressive low TMB squamous cell tumor to ICB could be improved through combination immunotherapy using functionally defined NeoAg as targets for endogenous CD4+ and CD8+ T cells. We found that, whereas vaccination with CD4+ or CD8+ NeoAg alone did not offer prophylactic or therapeutic immunity, vaccines containing NeoAg recognized by both subsets overcame ICB resistance and led to the eradication of large established tumors that contained a subset of PD-L1+ tumor-initiating cancer stem cells (tCSC), provided the relevant epitopes were physically linked. Therapeutic CD4+/CD8+ T cell NeoAg vaccination produced a modified tumor microenvironment (TME) with increased numbers of NeoAg-specific CD8+ T cells existing in progenitor and intermediate exhausted states enabled by combination ICB-mediated intermolecular epitope spreading. The concepts explored herein should be exploited for the development of more potent personalized cancer vaccines that can expand the range of tumors treatable with ICB.

immunology↗

bioRxiv2020

Investigating motor preparatory processes and conscious volition using machine learning

BackgroundConscious volition is a broad term and is difficult to reduce to a single empirical paradigm. It encompasses many areas of cognition, including decision-making and empirical studies can be done on these components. This work follows on the seminal work of Libet et al. (1983) which focused on brain activity preceding motor activity and conscious awareness of the intention to move. Previous results have subsequently faced criticism, particularly methods used to average out EEG data over all the trials and the readiness potential not being present on an individual trial basis. This following study aims to address these criticisms. ObjectivesTo use machine learning to investigate brain activity preceding left/right hand movements with relation to conscious intent and motor action. MethodologyThe data collection involved the recreation of the Libet experiment, with electroencephalography (EEG) data being collected. An addition made in this study was the choice between "left" and "right" while observing the Libet clock to subjectively mark the moment of conscious awareness. Twenty-one participants were included (four females, all right-handed). A deep (machine) learning model known as a convolutional neural network (CNN) was used for the EEG data analysis. ResultsSubjectively reported conscious intent preceded the action by 108 ms. The CNN model was able to predict the decision "left" or "right" as early as 4.45 seconds before the action with a test accuracy of 98%. ConclusionThis study has shown motor preparatory processes start up to 4.45 seconds before conscious awareness of a decision to move.

neuroscience↗