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Cutting edge advances in electrical visual cortical prosthetics have evoked perception of shapes, motion, and letters in the blind. Here, we present an alternative optical approach using pulsed infrared neural stimulation. To interface with dense arrays of cortical columns with submillimeter spatial precision, both linear array and 100-fiber bundle array optical fiber interfaces were devised. We deliver infrared stimulation through these arrays in anesthetized cat visual cortex and monitor effects by optical imaging in contralateral visual cortex. Infrared neural stimulation modulation of response to ongoing visual oriented gratings produce enhanced responses in orientation-matched domains and suppressed responses in non-matched domains, consistent with a known higher order integration mediated by callosal inputs. Controls include dynamically applied speeds, directions and patterns of multipoint stimulation. This provides groundwork for a distinct type of prosthetic targeted to maps of visual cortical columns., (© 2024. The Author(s).)

TGFβ signaling is associated with non-response to immune checkpoint blockade in patients with advanced cancers, particularly in the immune-excluded phenotype. While previous work demonstrates that converting tumors from excluded to inflamed phenotypes requires attenuation of PD-L1 and TGFβ signaling, the underlying cellular mechanisms remain unclear. Here, we show that TGFβ and PD-L1 restrain intratumoral stem cell-like CD8 T cell (T SCL ) expansion and replacement of progenitor-exhausted and dysfunctional CD8 T cells with non-exhausted T effector cells in the EMT6 tumor model in female mice. Upon combined TGFβ/PD-L1 blockade IFNγ hi CD8 T effector cells show enhanced motility and accumulate in the tumor. Ensuing IFNγ signaling transforms myeloid, stromal, and tumor niches to yield an immune-supportive ecosystem. Blocking IFNγ abolishes the anti-PD-L1/anti-TGFβ therapy efficacy. Our data suggest that TGFβ works with PD-L1 to prevent T SCL expansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state., (© 2023. Springer Nature Limited.)

Response to immunotherapies can be variable and unpredictable. Pathology-based phenotyping of tumors into 'hot' and 'cold' is static, relying solely on T-cell infiltration in single-time single-site biopsies, resulting in suboptimal treatment response prediction. Dynamic vascular events (tumor angiogenesis, leukocyte trafficking) within tumor immune microenvironment (TiME) also influence anti-tumor immunity and treatment response. Here, we report dynamic cellular-level TiME phenotyping in vivo that combines inflammation profiles with vascular features through non-invasive reflectance confocal microscopic imaging. In skin cancer patients, we demonstrate three main TiME phenotypes that correlate with gene and protein expression, and response to toll-like receptor agonist immune-therapy. Notably, phenotypes with high inflammation associate with immunostimulatory signatures and those with high vasculature with angiogenic and endothelial anergy signatures. Moreover, phenotypes with high inflammation and low vasculature demonstrate the best treatment response. This non-invasive in vivo phenotyping approach integrating dynamic vasculature with inflammation serves as a reliable predictor of response to topical immune-therapy in patients., (© 2022. The Author(s).)