PDF(Pubmed)
Abstract：
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 SERPINB9. 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 SERPINB9 reverts T cell resistance of NSCLC cell lines, whereas its overexpression reduces T cell sensitivity. SERPINB9 expression in NSCLC strongly correlates with a mesenchymal phenotype. We also find that SERPINB9 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 SERPINB9 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 SERPINB9 as a potential target to combat immunotherapy resistance, these results suggest its potential to serve as a prognostic and predictive biomarker.
摘要：
免疫疗法,特别是免疫检查点阻断（ICB），改善了癌症患者的临床预后，尽管许多人未能做出持久的回应。已经确定了几种抗性机制，但是我们对稳健ICB响应要求的理解是不完整的。我们已经改造了人类NSCLC癌症和T细胞的MHCI/抗原：TCR匹配组，以鉴定肿瘤细胞固有的T细胞抗性机制。耐药肿瘤细胞中差异表达最高的基因是SERPINB9。效应T细胞衍生分子颗粒酶B的这种丝氨酸蛋白酶抑制剂可防止caspase介导的肿瘤凋亡。和谐地，我们显示SERPINB9的遗传消融可恢复NSCLC细胞系的T细胞抗性，而它的过表达降低了T细胞的敏感性。NSCLC中的SERPINB9表达与间质表型密切相关。我们还发现SERPINB9通常在癌症中扩增，特别是黑色素瘤，它表明预后不良。ICB处理的黑素瘤的单细胞RNA测序显示，SERPINB9表达不仅在治疗后和治疗前的细胞中升高，而且在ICB难治性癌症中也是如此。在NSCLC中，我们通常观察到罕见的SERPINB9阳性癌细胞，可能是ICB抗性细胞的水库。虽然强调SERPINB9是对抗免疫疗法耐药性的潜在靶标，这些结果提示其作为预后和预测生物标志物的潜力.
