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Description
Evolving knowledge about the tumor microenvironment (TME) is driving innovation in designing novel therapies against hard-to-treat breast cancer. Addressing the immune elements within the tumor microenvironment (TME) has emerged as a highly encouraging strategy for treating cancer. Although current immunotherapies have made advancements in reinstating the body's ability to fight tumors, the search for effective cancer treatments to combat tumor evasion remains a formidable challenge. In line with this objective, there is a pressing need to better understand the complex tumor-immune dynamics and crosstalk within the TME. To evaluate the cancer-immune interaction, this study aimed at investigating the crosstalk between naïve macrophages and cytotoxic T cells in driving tumor progression using an organotypic 3D ex vivo tumor on-a-chip model. The presented microfluidic platform consists of two distinct regions namely: The tumor region and the stroma region separated by trapezoidal microposts to ensure interconnectivity between regions thereby incorporating high spatial organization. In the established triculture platform, the complex Tumor Immune Microenvironment was successfully recapitulated by incorporating naïve macrophage and T cells within an appropriate 3D matrix. Through invasion and morphometric analyses, definitive outcomes were obtained that underscore the significant contribution of macrophages in facilitating tumor progression. Furthermore, the inclusion of T cells led to a notable decrease in the migratory speed of cancer cells and macrophages, underscoring the reciprocal communication between these two immune cell populations in the regulation of tumor advancement. Overall, this study highlights the complexity of TME and underscores the critical role of immune cells in regulating cancer progression.
ContributorsManoharan, Twinkle Jina Minette (Author) / Nikkhah, Mehdi (Thesis advisor) / Acharya, Abhinav P (Committee member) / Wang, Shaopeng (Committee member) / Arizona State University (Publisher)
Created2023
Description
Drug delivery has made a significant contribution to cancer immunotherapy and can have a tremendous impact on modulating immunometabolism, thereby affecting cancer outcomes. Notably, the science of delivery of cancer vaccines and immunotherapeutics, modulating immune cell functions has inspired development of several successful companies and clinical products. For example, cancer vaccines require activation of dendritic cells (DCs) and tumour associated Mɸs (TAMs) through modulation of their energy metabolism (e.g., glycolysis, glutaminolysis, Krebs cycle). Similar to activated immune cells, cancer cells also upregulate glucose and glutamine transporters for proliferation and survival. Cancer cells having accelerated energy metabolism, which has been exploited as a target for various therapeutic studies. In the first strategy, an immunometabolism strategy based on sustained release of succinate from biomaterials, which incorporate succinate in the backbone of the polymer was developed. This study demonstrates that succinate-based polymeric microparticles act as alarmins by modulating the immunometabolism of DCs and Mɸs to generate robust pro-inflammatory responses for melanoma treatment in immunocompetent young as well as aging mice. In the second strategy, a biomaterial-based strategy was developed to deliver metabolites one-step downstream of the node where the glycolytic pathway is inhibited, to specifically rescue DCs from glycolysis inhibition. The study successfully demonstrated for the first time that the glycolysis of DCs can be rescued both in vitro and in vivo using a biomaterial strategy of delivering metabolites downstream of the inhibitory node. Overall, it is believed that advanced drug delivery strategies will play an important role in marrying the fields of immunometabolism and immunotherapy to generate translatable anti-cancer treatments.
ContributorsInamdar, Sahil (Author) / Acharya, Abhinav P (Thesis advisor) / Rege, Kaushal (Committee member) / Green, Matthew (Committee member) / Curtis, Marion (Committee member) / Seetharam, Mahesh (Committee member) / Arizona State University (Publisher)
Created2022