3D microvascular model recapitulates the diffuse large B-cell lymphoma tumor microenvironment in vitro

Abstract

Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer that affects ~22,000 people in the United States yearly. Understanding the complex cellular interactions of the tumor microenvironment is critical to the success and development of DLBCL treatment strategies. In vitro platforms that successfully model the complex tumor microenvironment without introducing the variability of in vivo systems are vital for understanding these interactions. To date, no such in vitro model exists that can accurately recapitulate the interactions that occur between immune cells, cancer cells, and endothelial cells in the tumor microenvironment of DLBCL. To that end, we developed a lymphoma-on-chip model consisting of a hydrogel based tumor model traversed by a vascularized, perfusable, round microchannel that successfully recapitulates key complexities and interactions of the in vivo tumor microenvironment in vitro. We have shown that the perfusion capabilities of this technique allow us to study targeted treatment strategies, as well as to model the diffusion of infused reagents spatiotemporally. Furthermore, this model employs a novel fabrication technique that utilizes common laboratory materials, and allows for the microfabrication of multiplex microvascular environments without the need for advanced microfabrication facilities. Through our facile microfabrication process, we are able to achieve micro vessels within a tumor model that are highly reliable and precise over the length of the vessel. Overall, we have developed a tool that enables researchers from many diverse disciplines to study previously inaccessible aspects of the DLBCL tumor microenvironment, with profound implications for drug delivery and design.

Tumor CD73/A2aR adenosine immunosuppressive axis and tumor‐infiltrating lymphocytes in diffuse large B‐cell lymphoma: correlations with clinicopathological characteristics and clinical outcome

“…Interestingly, CD73 expression on tumor cells was observed to have significant correlations with clinical outcome as well as several clinicopathologic parameters, including IPI score, LDH levels and Ki67 expression. The main reasons for this discrepancy could be as follows: The TME is comprised of complex cellular and noncellular components, including lymphocytes, endothelial cells and tumor microvessels, which exist within and around the tumor mass in DLBCL. Actually, a part of CD73 is also expressed on endothelial cells and tumor microvessels, which is involved in mediating lymphocyte adhesion to the endothelium, atherogenesis, vascular leakage, and cardiac allograft vasculopathy, that are functions independent of the immunosuppressive function of CD73.…”

Engineering of Hydrogel Materials with Perfusable Microchannels for Building Vascularized Tissues

“…Mouse B‐cell lymphoma and immune cells were directly embedded inside the hydrogel, enabling the recapitulation of interactions that occur between immune cells, cancer cells, and ECs. The vascularized channel can also be extended to connect a healthy lymph node model and a lymphoma model …”

Microphysiological Systems as Enabling Tools for Modeling Complexity in the Tumor Microenvironment and Accelerating Cancer Drug Development

“…Endothelial cells can be maintained in the channels under physiological shear stress, and drugs can be perfused through this vascular network to tumor cells in adjoining tumor chambers. Combining this system with a 3D hydrogel on a chip technology, the in vivo TME can be mimicked with increased accuracy. Spatial drug distribution and tumor cell growth within the tumor chambers were different depending on the local vasculature patterns of different in vivo tumors .…”

“…Combining this system with a 3D hydrogel on a chip technology, the in vivo TME can be mimicked with increased accuracy. Spatial drug distribution and tumor cell growth within the tumor chambers were different depending on the local vasculature patterns of different in vivo tumors . These studies demonstrate the potential for employing microfluidic‐based TME‐mimetic models as a pharmaceutical testing platform for the variation of vascular structures.…”