Tumor Stem Cells Arising From A Non-Stem Origin Maintain A Differentiated Phenotype And Modulate T Cell Activity.

Tumor stem cells (TSCs) contribute to cancer mortality via therapeutic resistance, tumor recurrence, and metastatic mechanisms. However, the origins of the stem capacity to TSCs remains in question, but all TSCs descend from the original tumor cell-of-origin where the first oncogenic event occurred. Tumors arising from different cells-of-origin are histologically identical, but it is unknown whether TSCs that arose from different origins are molecularly and functionally distinct. Using mouse models driving identical Apc mutations from Lrig1-expressing and Mist1-expressing cells, we characterized TSCs of tumors driven from stem and non-stem cells-of-origin using single cell RNA sequencing (scRNA-seq), organoids, and multiplexed imaging. We revealed reduced stem capacity but increased class II antigen presentation ability for non-stem cell (Mist1) driven TSCs compared with stem cell (Lrig1) driven TSCs, which resulted in a favorable immune microenvironment skewed towards active cytotoxic response in Mist1-driven tumors. These results suggest that the cell-of-origin of tumorigenesis provides a specific context by which TSCs are generated, dictating their interactions with the tumor microenvironment. Citation Format: Cherie’ R. Scurrah, Bob Chen, Nick Markham, Alan Simmons, Austin Southard-Smith, Mary Macedonia, Eunyoung Choi, Qi Liu, Kay Washington, Bob Coffey, Jeremy Goettel, Ken Lau. Tumor stem cells arising from a non-stem origin maintain a differentiated phenotype and modulate T cell activity [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-051.