Dysregulation of the Hippo Pathway in Cancer Associated Fibroblasts is Associated with anti-PD-L1 atezolizumab Resistance

The use of immunotherapy in solid tumors has significantly improved the outcomes and quality of life for cancer patients. However, a substantial fraction of patients remain unresponsive, highlighting the urgent need to identify novel mechanisms of resistance to enhance immune-centric, chemo-free treatment regimens. In this study, we investigate associations with immunotherapy resistance by integrating RNAseq data from 2800 bladder cancer patients enrolled in the IMvigor trials, focusing on resistance to the anti-PD-L1 therapy atezolizumab, along with single-cell data from 200 patient samples and healthy donors. To expand the analysis to a massive collection of over 100M cells from hundreds of diverse single cell studies, we present Firmament, a newly developed method to efficiently identify cell populations that show enrichment for expression of gene signatures. Through these analyses, we identify the Hippo pathway as critically associated with immunotherapy resistance in bladder cancer and other solid tumors. Our findings indicate that Hippo dysregulation in stromal cells, rather than cancer cells, drives the high YAP/TAZ signal in these tumors. We specifically identify dysregulated Hippo signaling in cancer-associated fibroblasts compared to healthy donor fibroblasts. These insights will be important for developing novel therapeutic combinations to improve outcomes for patients with solid tumors treated with immune checkpoint inhibitors.