The Potential of Nanoparticle-Mediated Macrophage Polarization for Solid Tumor Therapy: Evidence Synthesis and Temporal Monitoring

Cancer persists as a significant public health challenge despite treatment advances.  Colorectal cancer is especially a concern because its incidence and mortality are increasing in  young individuals. Solid tumors, such as colorectal cancer, are challenging to treat with  immunotherapies due to their immunosuppressive microenvironment preventing T cell infiltration.  Tumor-associated macrophages (TAMs) play a pivotal role in supporting this immunosuppression  by adopting an anti-inflammatory and pro-tumoral phenotype within the tumor microenvironment.  Leveraging nanoparticles to repolarize TAMs towards a proinflammatory and tumoricidal  phenotype holds promise for solid tumor therapy. However, clinical translation of cancer nanomedicines has been slow. This dissertation aims to address this through quantitative review  of the intersection between the colorectal cancer nanomedicine and macrophage polarization,  and by proposing a novel method of temporally tracking macrophage polarization using  bioluminescent reporter cells.  

Using eLDA topic modeling, the dissertation identifies six major topics in the intersection  of cancer medicine and macrophage polarization, providing insights into nanoparticle design  choices and therapeutic strategies across various cancer types. A scoping review and meta analysis of colorectal cancer nanomedicine over two decades reveal evolving nanoparticle design  strategies and their impact on macrophage polarization. We also demonstrate how a  nanoparticle’s ability to increase macrophages’ ratio of M1 to M2 polarization is correlated with  their efficacy at reducing tumor growth and increasing survival. This dissertation also includes a  technology assessment of how evidence synthesis of preclinical studies informs open science  policy.   

To better temporally track macrophage polarization, the dissertation introduces a method  utilizing THP-1 reporter cells with bioluminescently labeled polarization-relevant transcription  factors. We demonstrated how these reporter cells enable time-resolved activation curves for  tumor-associated macrophages, revealing unique NFκB activation profiles dependent on cancer  type that we linked to the tumor microenvironments immunogenicity. Furthermore, monitoring  monocyte to macrophage differentiation with this method highlights the importance of selecting appropriate differentiation protocols for the intended use. These examples demonstrate the  potential use of this bioluminescent platform to monitor macrophage polarization in response to  immunomodulatory treatments, like macrophage-targeted cancer nanomedicine.