The upregulation of immune checkpoint programmed death protein-1 (PD-1) expressed on CD8+ activated T cells, and interaction of PD-1 with its ligand, PD-L1, strongly contributes to an immunosuppressive tumor microenvironment (TME). Blockade of PD-L1 with therapeutic antibodies have shown long-term survival in many cancer patients and several clinical trials are ongoing. However, 75% of patients do not respond to PD-L1 blockade, in part due to inaccurate identification of PD-L1 expression in tumors incurring high costs of immunotherapy and toxicities in patients. Therefore, a compelling need exists for high resolution noninvasive detection techniques that will accurately detect PD-L1 and simultaneously identify other immunomarkers that show engagement of the immune TME. In this work we address this unmet clinical need with an innovative immunoPET-Raman multimodal imaging platform using novel immunoactive gold nanostructures (IGNs). IGNs are biocompatible ~55 nm gold nanostars labeled with antibodies, Raman-active molecules, and Cu64 radiotracers. ImmunoPET-Raman enabled by multifunctional IGNs combines the depth-resolved whole body imaging of PET with high spatiotemporal resolution and multiplexing of surface-enhanced Raman imaging. Here we simultaneously track PD-L1 and CD8 (cluster of differentiation 8), which is expressed in effector T cells, with IGNs mediated ImmunoPET-Raman imaging to allow rapid assessment of PD-L1 status and longitudinal analysis of CD8+ engagement in the tumor microenvironment in vivo. Longitudinal imaging demonstrated maximum accumulation of IGNs in tumor occur 12h post intraperitoneal delivery and showed strong correlation between PET and Raman. Histology, transmission electron microscopy, and inductively coupled plasma mass spectrometry (ICPMS) of tissues was performed to evaluate IGNs bioavailability, toxicity, and nd clearance from tissues. Our in vivo study was combined ex vivo Raman spatial maps of whole tumor lesions that provided both a qualitative and quantitative assessment of biomarker status with near cellular-level resolution. High resolution SERS maps also provided an overview of MGNs distribution in tumors which correlated well with the vascular density. This study demonstrates ImmunoPET-Raman mediated by IGNs provides an accurate measure of multiple biomarkers both in vivo and ex vivo which will ultimately enable a clinically-translatable platform for patient-tailored immunotherapies and combination treatment.

Patient-tailored immunotherapies enabled by multimodal ImmunoPET-Raman imaging

256th National Meeting (2018)

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