Spatiotemporal Mapping of Immune Cell Behavior in Glioblastoma

Ziel

Immune cells, particularly cytotoxic T lymphocytes, are highly motile capable of infiltrating and eliminating tumors—a feature driving the recent revolution of immunotherapies. Yet a common barrier is the failure of T cells to infiltrate tumors, with local peritumoral and perivascular arrest as a key hurdle. Efforts to overcome this, such as decades of targeting of major tumor-supportive cytokines have yielded limited breakthroughs. A likely reason is methodological bias: most studies profile bulk tissues at single endpoints, detecting only sustained, widespread signals while overlooking the transient, localized interactions that may drive T-cell arrest.
I propose to develop spatially and temporally resolved transcriptomic technology to map immune cell interactions and behavior over time, and apply it to study immune dysfunction in glioblastoma (GBM), a lethal brain tumor. I recently developed Zman-seq, the first in vivo single-cell method to capture immune cell state transitions over time and their driving signals. Zman-seq revealed that immune reprogramming occurs rapidly within just a day after infiltration. To resolve the early local interactions driving this, we will combine spatial data with Zman-seq, and measure T-cell motility as a functional readout. First, to pinpoint the early niches, I will combine Zman-seq timestamps with spatial transcriptomics and describe how immune cells occupy cellular niches over time. Next, to study T-cell behavior within these niches, I will directly visualize T-cell motility via intravital microscopy and register in vivo tracks to ex vivo spatial transcriptomics, creating a new approach—VideoTranscriptomics. Applied in a GBM model, this will reveal the sequence of niches immune cells traverse, and pinpoint early, targetable checkpoints that drive T-cell arrest and immunotherapy resistance.

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