Immune targeted shortwave infrared emitting nanoprobes for the prognostication of cancer
Creators: name: Siebert, Jake Norton
Publisher: name: No Publisher Supplied
Year: 2024

description: Advances in the detection and treatment of breast cancer over the previousdecades has led to remarkable improvements in patient outcomes, thanks in largepart to early detection modalities and targeted treatments. However, breast cancersthat lack the three common receptors for targeted treatment, termed triple-negativebreast cancer (TNBC), remain difficult to treat and have higher rates of metastaticrelapse. Recently, immune checkpoint inhibitors (ICIs) have gained traction as atherapeutic option for TNBC due to their ability to reinvigorate the native immuneresponse to the tumor. Variable response rates to ICIs and poor stratification ofpatients prior to therapy has stymied progress in this approach and spurred interestin the development of novel technologies to better prognosticate disease progressionand therapy response in TNBC patients.To fulfill this clinical need, researchers have been investigating biomarkersand detection methods to identify the metastases and therapy non-responders earlierfor enhanced precision medicine. Targeting key promoters of metastatic nicheformation is one pathway to earlier detection of metastases, which can supportimproved clinical decision making. Immunosuppressive populations, such as theiiimyeloid derived suppressor cell (MDSC), have recently been identified as markersof metastatic disease due to their role in preparing the pre-metastatic niche (PMN)for tumor colonization. Accumulating evidence demonstrates that theseimmunosuppressive populations, previously overlooked, may be also be a significantsource of immunotherapy evasion within the primary tumor and thus serve asvaluable biomarkers for prediction of therapy response. Although tumor infiltratinglymphocyte index and PD-L1 expression were established as potential prognosticindicators for immunotherapy response, their accuracy in patient stratification isseverely limited. It has become clear that when evaluating tumors for immunotherapyresponsiveness there is a need for a more robust evaluation of the tumor immuneenvironment, including evaluation of immunosuppressive populations in addition tothe cytotoxic lymphocytes. Designing a tool for the evaluation of the tumor associatedimmune population can provide a complementary approach to assessing theprognostic outlook of patients in regard to metastasis formation and immunotherapyresponse.This dissertation is focused on the development of molecularly targetedoptical nanoprobes for the tracking of immune dynamics in TNBC, and how thiscorrelates with disease progression and immunotherapy responsiveness. We userare earth metal-doped nanoprobes that, when excited by near infrared light (NIR, λ= 980 nm), emit in the shortwave infrared (SWIR, λ = 1000-1700 nm). These SWIRemitting nanoprobes permit improved optical imaging at greater tissue depths, withreduced tissue scattering and autofluorescence compared to traditional opticalimaging. We engineer these nanoprobes for the molecular targeting of MDSCs withinthe tumor microenvironment and lung pre-metastatic niche. We demonstrate that thenon-invasive imaging of MDSCs within the lungs was able to identify the pre-ivmetastatic niche in a model with high metastatic propensity, compared to a modelwith low rates of metastasis. Further, we use MDSC targeted probes to track changesin immune dynamics associated with response to combination therapy with an ICIand doxorubicin in the tumor microenvironment. We present observations suggestingthat dual imaging of MDSCs and cytotoxic T cell targeted nanoprobes could providea better metric for stratifying response to immunotherapy. The findings of this thesisreinforce the value of SWIR imaging to identify biomarkers for cancer prognosis, suchas immune cell dynamics, laying the groundwork for the development of a tool thatcan stratify patients in terms of metastatic risk and immunotherapy responsiveness.