ICOS‐ImmunoPET Monitors T Cell Activation After Combination Immune Checkpoint Blockade in a Mouse Model of Melanoma Brain Metastasis

ABSTRACT

Immune checkpoint inhibitors (ICIs) have transformed outcomes for melanoma brain metastases (MBM), yet early response assessment remains challenging because currently available tools such as magnetic resonance imaging (MRI) lack molecular specificity and are confounded by pseudoprogression. Antibody‐based positron emission tomography (immunoPET) is a highly sensitive and specific molecular imaging technique that enables noninvasive, whole‐body visualization of immune dynamics in vivo. The inducible T cell costimulatory receptor (ICOS) is a promising biomarker of therapy‐induced T cell activation. Here, a previously validated tracer, [ ⁸⁹ Zr]DFO‐ICOS mAb, is used to track activated T cells in a murine MBM model treated with combined anti‐PD‐1/anti‐CTLA‐4 therapy, and immunoPET signal is shown to correspond with therapeutic response and intratumoral T cell activation. To establish clinical relevance of ICOS‐immunoPET, single‐cell RNA sequencing data from 6 human MBM specimens are reanalyzed, revealing significantly higher ICOS expression accompanied by coordinated activation signatures in ICI‐treated tumors. These findings support ICOS‐immunoPET as a promising strategy for earlier, noninvasive, functionally informative assessment of immunotherapy response, with potential to improve patient stratification in brain metastases.