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Immune Resistance Emerges from Tumor-Initiating Stem Cells

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE108679 | GEO | 2019/05/07

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

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Immune Resistance Emerges from Tumor-Initiating Stem Cells

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