Gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma
Background Limited data exist on the role of alterations in HLA Class I antigen processing and presentation machinery in mediating response to immune checkpoint blockade (ICB). Methods This retrospective cohort study analyzed transcriptional profiles from pre-treatment tumor samples of 51 chemotherapy-refractory advanced non-small cell lung cancer (NSCLC) patients and two independent melanoma cohorts treated with ICB. An antigen processing machinery (APM) score was generated utilizing eight genes associated with APM ( B2M, CALR, NLRC5, PSMB9, PSME1, PSME3, RFX5, and HSP90AB1 ). Associations were made for therapeutic response, progression-free survival (PFS) and overall survival (OS). Results In NSCLC, the APM score was significantly higher in responders compared with non-responders (p=0.0001). An APM score above the median value for the cohort was associated with improved PFS (HR 0.34 (0.18 to 0.64), p=0.001) and OS (HR 0.44 (0.23 to 0.83), p=0.006). The APM score was correlated with an inflammation score based on the established T-cell-inflamed resistance gene expression profile (Pearson’s r=0.58, p<0.0001). However, the APM score better predicted response to ICB relative to the inflammation score with area under a receiving operating characteristics curve of 0.84 and 0.70 for PFS and OS, respectively. In a cohort of 14 high-risk resectable stage III/IV melanoma patients treated with neoadjuvant anti-PD1 ICB, a higher APM score was associated with improved disease-free survival (HR: 0.08 (0.01 to 0.50), p=0.0065). In an additional independent melanoma cohort of 27 metastatic patients treated with ICB, a higher APM score was associated with improved OS (HR 0.29 (0.09 to 0.89), p=0.044). Conclusion Our data demonstrate that defects in antigen presentation may be an important feature in predicting outcomes to ICB in both lung cancer and melanoma.