Immune Resistance Emerges from Tumor-Initiating Stem Cells

Tumors are initiated and maintained by a stem cell-like population. However, our bodies have a powerful immune surveillance system to clear out cancerous cells as they emerge. Whether tumor-initiating stem cells (tSCs) are programmed to resist anti-tumor immunity and/or how they overcome the barrier of immune surveillance remains poorly understood. To address these questions, we designed a murine skin tumor model that can be effectively challenged by adoptive cell transfer (ACT)-based immunotherapy. By lineage tracing the tumor cells that survive targeted T cell treatment, we discovered that a subset of TGFβ-responding tSCs are refractory and responsible for tumor relapse. Single cell RNA-sequencing revealed that during malignant transformation, these tSCs selectively acquire CD80. Thought to be an immune cell ligand, stem cell CD80 (scCD80) engagement with CTLA4 on activated cytotoxic T cells attenuates their attack. Moreover, without CD80 or in the face of CTLA4 blocking antibodies, tSCs become vulnerable to ACT immunotherapy. Our findings place the tumor-initiating stem cell at the crux of how immune checkpoint pathways are activated, and add a new mechanism to the fray. Mouse skin squamous cell carcinoma cells including tumor initiating cells before and after adoptive cell transfer (ACT)-based immunotherapy were FACS-purified and analyzed by single cell RNA-seq.