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Multimodal Multiplexed Immunoimaging with Nanostars to Detect Multiple Immunomarkers and Monitor Response to Immunotherapies


Ou YCYu-Chuan , Wen XXiaona , Johnson CAChristopher A , Shae DDaniel , Ayala ODOscar D , Webb JAJoseph A , Lin ECEugene C , DeLapp RCRossane C , Boyd KLKelli L , Richmond AAnn , Mahadevan-Jansen AAnita , Rafat MMarjan , Wilson JTJohn T , Balko JMJustin M , Tantawy MNMohammed N , Vilgelm AEAnna E , Bardhan RRizia . ACS nano. 2020 1 2; 14(1). 651-663


The overexpression of immunomarker programmed cell death protein 1 (PD-1) and engagement of PD-1 to its ligand, PD-L1, are involved in the functional impairment of cluster of differentiation 8 (CD8) T cells, contributing to cancer progression. However, heterogeneities in PD-L1 expression and variabilities in biopsy-based assays render current approaches inaccurate in predicting PD-L1 status. Therefore, PD-L1 screening alone is not predictive of patient response to treatment, which motivates us to simultaneously detect multiple immunomarkers engaged in immune modulation. Here, we have developed multimodal probes, immunoactive gold nanostars (IGNs), that accurately detect PD-L1 tumor cells and CD8 T cells simultaneously , surpassing the limitations of current immunoimaging techniques. IGNs integrate the whole-body imaging of positron emission tomography with high sensitivity and multiplexing of Raman spectroscopy, enabling the dynamic tracking of both immunomarkers. IGNs also monitor response to immunotherapies in mice treated with combinatorial PD-L1 and CD137 agonists and distinguish responders from those nonresponsive to treatment. Our results showed a multifunctional nanoscale probe with capabilities that cannot be achieved with either modality alone, allowing multiplexed immunologic tumor profiling critical for predicting early response to immunotherapies.