Abstract
Cancer immunoediting is a dynamic process of crosstalk between tumor cells and the immune system. Herein, we explore the fast zebrafish xenograft model to investigate the innate immune contribution to this process. Using multiple breast and colorectal cancer cell lines and zAvatars, we find that some are cleared (regressors) while others engraft (progressors) in zebrafish xenografts. We focus on two human colorectal cancer cells derived from the same patient that show contrasting engraftment/clearance profiles. Using polyclonal xenografts to mimic intra-tumor heterogeneity, we demonstrate that SW620_progressors can block clearance of SW480_regressors. SW480_regressors recruit macrophages and neutrophils more efficiently than SW620_progressors; SW620_progressors however, modulate macrophages towards a pro-tumoral phenotype. Genetic and chemical suppression of myeloid cells indicates that macrophages and neutrophils play a crucial role in clearance. Single-cell-transcriptome analysis shows a fast subclonal selection, with clearance of regressor subclones associated with IFN/Notch signaling and escaper-expanded subclones with enrichment of IL10 pathway. Overall, our work opens the possibility of using zebrafish xenografts as living biomarkers of the tumor microenvironment.
Highlights
Cancer immunoediting is a dynamic process of crosstalk between tumor cells and the immune system
We focus on a pair of human colorectal cancer (CRC) cells derived from the same patient at different stages of tumor progression: SW480 was derived from the primary tumor, and SW620 from a lymph node metastasis isolated 6 months later
In the present study, we take advantage of the fast zebrafish larvae xenograft model to study the crosstalk between human cancer cells and the innate immune system
Summary
Cancer immunoediting is a dynamic process of crosstalk between tumor cells and the immune system. Therapy may fail because tumor cells do not express sufficient neo-antigens (not immunogenic enough)[5] Another major obstacle may be the presence of a suppressive (cold) TME composed of stroma and a variety of immune cells, such as regulatory T cells (Treg), myeloidderived suppressor cells (MDSC), alternative activated pro-tumoral macrophages (“M2-like”), and neutrophils (“N2-like”), that may block anti-tumor immune responses[5,6]. Zebrafish have a highly conserved vertebrate innate immune system, including complement, Toll-like receptors, neutrophils, and macrophages capable of phagocytic activity Another advantage is that the full maturation of adaptive immunity only occurs at 2–3 weeks post-fertilization[13,14]. Transparency allows for unprecedented real-time imaging of cell–cell interactions and genetic tractability enables the engineering of reporter lines and mutants[14]
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