Abstract B28: Development and validation of a novel organotypic in vitro model of the tumor-lymph-immune interface for predicting immunotherapy resistance

Tumor-associated lymphatics and their connection to the tumor-draining lymph node (TdLN) play important roles in cancer metastasis as well as in modulating the tumor immune microenvironment. They bathe the TdLN in cytokines, exosomes, antigens, and suppressive factors from the tumor microenvironment (TME) to alter the antitumor immune response. Such interactions are complex and difficult to study in vivo, yet currently they cannot be readily explored in vitro either. To address this need, we developed a novel in vitro model system of the tumor-lympho-immune (TLI) circuit. These in vitro ”avatars,” dubbed TLI-Ivatars, can sustain ex vivo cocultures of tumors and their TdLNs in a parallelized format, within perfused 3D matrices and communicating channels in a flexible manner. The TLI-Ivatar platform has been shown to sustain long-term cultures (> 3 weeks) of a number of tumor cell lines, which form complex architectures reminiscent of actual tumors, as well as of ex vivo tumor tissue. It also supports the function and viability of immune cells (such as T lymphocytes and dendritic cells) and stromal cells (such as lymphatic endothelial cells and fibroblasts). To validate the modeling of the crosstalk between the tumor and TdLN, we demonstrate that TLI-Ivatar can faithfully recapitulate major in vivo immunotherapy responses with the B16 melanoma model, including (i) dampened cytotoxic T-cell function in tumor-conditioned tdLNs, (ii) enhanced tumor invasion to TdLN of lymphangiogenic (and more metastatic) tumors (compared to the TdLN of non-lymphangiogenic tumors), and (iii) immunotherapy potentiation by factors known to enhance immunotherapy efficacy in vivo, such as lymphangiogenic growth factors and matrix-binding immunomodulatory cytokines. Together, these data highlight the potential of TLI-Ivatar for long-term study of the complex tumor-host cell interplay in TME to gain mechanistic insight and pave the way for patient-specific screening of cancer immunotherapy. Citation Format: Ruolan Zhou, Rachel Weathered, Trevin Kurtanich, Renata Mezyk-Kopec, Aslan Mansurov, Jeffrey Hubbell, Melody A. Swartz. Development and validation of a novel organotypic in vitro model of the tumor-lymph-immune interface for predicting immunotherapy resistance [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B28.