Perturbational sequencing of patient tumors reveals midkine as an innate immune checkpoint in neuroendocrine tumors

We developed PERCEPT, an approach that uses ex vivo perturbational single-cell RNA sequencing to compare the response of immunomodulatory treatments with unstimulated controls directly in patient samples. Using PERCEPT, we tested cytokines and innate immune agonists in melanoma and Merkel cell carcinoma (MCC) and identified the dsRNA mimetic, RIG-I agonist, Stem Loop RNA (SLR) 14 as a powerful inducer of anti-viral states and enhancer of T cell activation. Our results demonstrate the utility of high-dimensional controlled perturbation of patient samples to identify mechanisms of innate immune response and resistance.