(H-285) Scoping Review of Pre-clinical and Translational Studies on Macrophage Polarization in Nanoparticle-based Colorectal Cancer Immunotherapy

Introduction:: Colorectal cancer (CRC) remains a prevalent disease with a high incidence rate. The American Cancer Society (ACS) reports that 4.4% of men and 4.1% of women will develop CRC in their lifetime. The immune system plays a critical role in the progression and treatment of cancer, making it an inherently immunological disease. While many immunotherapies target T-cells, their efficacy heavily relies on T-cell infiltration into the tumor, which is affected by the immunosuppressive nature of the tumor microenvironment. Tumor-associated macrophages (TAMs) are a crucial contributor to the immunosuppressive environment. Macrophages are a type of innate immune cell that can polarize along an inflammatory spectrum in response to environmental signals. TAMs polarize to an M2 (anti-inflammatory) phenotype in response to signaling from the tumor, which is associated with poor prognosis for patients. Consequently, many therapy studies aim to reprogram TAMs to a more beneficial M1 phenotype.

Nanoparticles are increasingly being utilized as a strategy to target tumors and the macrophages within the tumor microenvironment. By encapsulating therapeutics in nanoparticles, pharmacokinetics can be altered. The tunable nanoparticle characteristics offer a vast number of potential therapeutic strategies. However, despite numerous preclinical studies in the field, there are only a few FDA approved formulations, indicating a translational gap. Therefore, a better analysis of the body of preclinical literature is needed. In this study, we employed a scoping review to identify the current state of the field, knowledge gaps, and relationships between nanoparticle characteristics, anti-cancer efficacy, and macrophage polarization modulation in nanotherapeutic-based colorectal cancer immunotherapy.


Materials and Methods:: A scoping review was conducted to investigate the modulation of macrophage polarization by nanotherapeutic-based colorectal cancer immunotherapy. The search process is outlined in Figure 1. A comprehensive database search was conducted for articles mentioning cancer, macrophages, and nanotherapeutics. We utilized Sysrev, an open-source tool designed for systematic evidence reviews, to facilitate the screening phases and data extraction. We began with a title and abstract screening. Two reviewers screened the title and abstract of approximately 7,700 articles for relevance to the study’s criteria. A third reviewer resolved any discrepancies between the first two reviewers. Around 3,460 articles were automatically excluded based on Sysrev’s prediction score, which uses machine learning trained on hand-labeled articles in the project to assign prediction scores. Articles with an inclusion prediction score below 39% were excluded. The remaining articles were hand-screened. Full-text screening was conducted to ensure the articles had the necessary data and incorporated a colorectal cancer model, resulting in 94 studies for data extraction. Extracted data were stored in a relational database using SQL, and initial visualizations of the data were created using Excel.


Results, Conclusions, and Discussions:: Analyzing the dataset allows us to make inferences about the cancer nanotherapeutic field. Identifying the overall purpose of the study helped us analyze why the study was conducted and what the goal was (Figure 2). Most of the studies were attempting to leverage the innate immune system to help increase the nanoparticle anti-cancer efficacy either by repolarizing the TAMs, targeting the macrophages within the tumor, or utilizing circulating monocytes as a drug delivery vehicle into the tumor. Simply depleting TAMs was one of the least used strategies, with researchers seeming to prefer utilizing the macrophages rather than suppress them.

Looking into the cancer models: CT-26, HCT116, 4T1, and B16-F10 were the four most used cancer cell types (Figure 3). Three out of the four here are mouse-derived cell lines. This preference might be to make the transition to in vivo studies easier since the tumors would not be xenografts. Furthermore, this trend continued with the analysis of macrophage types used (Figure 4). RAW264.7 is an immortalized mouse macrophage line, and many of the primary cells used in the studies were from mice. This does mean that many of these studies are based on data found using mouse cell biology and physiology rather than human, perhaps contributing to the translational gap seen in nanoparticle formulations.

The nanoparticle information demonstrated how varied nanoparticle design can be (Figure 5). Polymeric nanoparticles were the most studied, perhaps due to the large number of potential polymers, from PLGA to natural polymers like Chitosan. PEGylation was very commonly seen in the nanoparticle formulations, perhaps surprisingly, as recent data demonstrated that patients can produce anti-PEG antibodies. The cluster of nanoparticle sizes around 100 nm matches the size needed to utilize the enhanced permeability and retention effect, where abnormal blood vessels feeding a tumor have gaps that allow for nanoparticles to permeate the tumor.

Next steps with our dataset are to identify relationships between nanoparticle characteristics and their ability to modulate macrophage polarization along with their anti-cancer efficacy. Furthermore, we want to see if there is a link between pro-inflammatory macrophage polarization and reduced tumor sizes.

Acknowledgements (Optional): :

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