Cancer stem cell-derived extracellular vesicles preferentially target MHC-II– macrophages and PD1+ T cells in the tumor microenvironment

Immunotherapy is an approved treatment option for head and neck squamous cell carcinoma (HNSCC). However, the response rate to immune checkpoint blockade is only 13% for recurrent HNSCC, highlighting the urgent need to better understand tumor-immune interplay, with the ultimate goal of improving patient outcomes. HNSCC present high local recurrence rates and therapy resistance that can be attributed to the presence of cancer stem cells (CSC) within tumors. CSC exhibit singular properties that enable them to avoid immune detection and eradication. The immune cell types that directly engage with CSC to allow immune escape and cancer recurrence are still unknown. Here, we genetically engineered CSC-derived extracellular vesicles (EVs) to perform sortase-mediated in vivo proximity labeling. We identified specific immune cell subsets recruited into the CSC niche. We demonstrated that unmanipulated CSC-EVs preferentially target MHC-II– macrophages and PD1+ T cells, and that such EV-mediated intercellular communication between CSC and these immune cells contributed to the observed spatial interactions and niche sharing. These results suggest that combination therapies targeting CSC, tumor macrophages and PD1 may synergize and lower local recurrence rates in HNSCC patients.