is commonly amplified and high expression in cancer cells correlates with poor immune checkpoint blockade response.

Immunotherapies, in particular immune checkpoint blockade (ICB), have improved the clinical outcome of cancer patients, although many fail to mount a durable response. Several resistance mechanisms have been identified, but our understanding of the requirements for a robust ICB response is incomplete. We have engineered an MHC I/antigen: TCR-matched panel of human NSCLC cancer and T cells to identify tumor cell-intrinsic T cell resistance mechanisms. The top differentially expressed gene in resistant tumor cells was . This serine protease inhibitor of the effector T cell-derived molecule granzyme B prevents caspase-mediated tumor apoptosis. Concordantly, we show that genetic ablation of reverts T cell resistance of NSCLC cell lines, whereas its overexpression reduces T cell sensitivity. expression in NSCLC strongly correlates with a mesenchymal phenotype. We also find that is commonly amplified in cancer, particularly melanoma in which it is indicative of poor prognosis. Single-cell RNA sequencing of ICB-treated melanomas revealed that expression is elevated not only in cells from post- versus pre-treatment cancers, but also in ICB-refractory cancers. In NSCLC we commonly observed rare SERPINB9-positive cancer cells, possibly accounting for reservoirs of ICB-resistant cells. While underscoring as a potential target to combat immunotherapy resistance, these results suggest its potential to serve as a prognostic and predictive biomarker.