Abstract
The induction of ectopic lymph node structures (ELNs) holds great promise to augment immunotherapy against multiple cancers including metastatic melanoma, in which ELN formation has been associated with a unique immune-related gene expression signature composed of distinct chemokines. To investigate the therapeutic potential of ELNs induction, preclinical models of ELNs are needed for interrogation of these chemokines. Computational models provide a non-invasive, cost-effective method to investigate leukocyte trafficking in the tumor microenvironment, but parameterizing such models is difficult due to differing assay conditions and contexts among the literature. To better achieve this, we systematically performed microchemotaxis assays on purified immune subsets including human pan-T cells, CD4+ T cells, CD8+ T cells, B cells, and NK cells, with 49 recombinant chemokines using a singular technique, and standardized conditions resulting in a dataset representing 238 assays. We then outline a groundwork computational model that can simulate cellular migration in the tumor microenvironment in response to a chemoattractant gradient created from stromal, lymphoid, or antigen presenting cell interactions. The resulting model can then be parameterized with standardized data, such as the dataset presented here, and demonstrates how a computational approach can help elucidate developing ELNs and their impact on tumor progression.
Highlights
The initial presence of lymphocytes in the tumor microenvironment is presumptive to the success of any immunotherapy
Recent observations suggest that the presence of tumor-localized, ectopic lymph node structures (ELNs) is associated with better prognosis across a broad spectrum of tumor types including metastatic melanoma[23], breast cancer[24], colorectal carcinoma[25], and non-small cell lung cancer[26,27]
We have used a conventional transwell migration assay to first catalogue the chemotactic index (CI) of 48 recombinant murine chemokines on resting pan T cells, CD4+ T cells, CD8+ T cells, B cells, and NK cells immunomagnetically isolated from normal C57BL/6 spleen, including the 12 chemokines associated with ELNs formation in humans
Summary
The initial presence of lymphocytes in the tumor microenvironment is presumptive to the success of any immunotherapy. Structural features of ELNs, such as the de novo generation of lymphatic vessels, can greatly enhance the infiltration of TIL deeper into the tumor parenchyma[29] Such dissemination away from the vasculature is highly associated with better clinical outcome[30]. Looking forward, the ability to induce or construct ELNs with anti-tumor activity holds great promise to help recruit TIL to the tumor microenvironment and enhance their anti-tumor activity, in solid tumors devoid of these structures To help develop such a strategy requires the creation of sound preclinical models in which to study ELNs formation. We are interested in employing these chemokines as leads to construct or induce ELNs in the solid tumor microenvironment with the intent to potentially enhance immunotherapies, in those devoid of such structures To achieve this goal will first require a series of fundamental biologic studies and modeling. The model makes use of reticular fibroblast cells (RFC) as a stromal source of chemokine production[28], antigen presenting cells as an activating source for RFC and chemokine production, and generalized T cell and B cell populations responding to chemokine gradients[32,33]
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