Chromosome 9p24.1 Deletions As A Determinant Of Tumor Immune Surveillance And Immune Checkpoint Blockade Therapy In Non-Small Cell Lung Cancer

Anti-PD-1/PD-L1 immune checkpoint blockade therapy requires the presence of PD-L1/PD-L2 and MHC class I antigens on the tumor cell surface. We previously found JAK1 truncating mutations in endometrial cancer cells that impairs JAK1/JAK2-STAT1-IRF1-mediated signaling pathway, which regulates MHC class I antigen presentation. To determine the potential role and genetic defects in the IFN-γ-IRF1 pathway in non-small cell lung cancer (NSCLC), we analyzed the Cancer Genome Atlas (TCGA) data. Expression of IRF1 correlated with cytolytic activity markers GZMA and PRF1. Loss-of-function (LOF) genetic alterations in the IFN-γ-IRF1 pathway genes were found in 64 cases (6.3%) among 1016 patients. These genetic defects occurred prevalently in the JAK2 gene (33 cases) and often through deletions (29 cases) of chromosome 9p24.1. JAK2 gene deletions were frequently associated with deletions of CD274 and PDCD1LG2 genes that encode PD-L1 and PD-L2, respectively, whereas CD274 and PDCD1LG2 deletions were always accompanied by JAK2 deletions. Chromosome 9p is frequently deleted in NSCLC. This has been attributed to CDKN2A/CDKN2B and PTPRD tumor suppressor genes located at the chromosome 9p21.3-9p24.1. Interestingly, JAK2, CD274, and PDCD1LG2 genes are co-localized at chromosome 9p24.1 near the CDKN2A/CDKN2B and PTPRD genes. JAK2, CD274, and PDCD1LG2 deletion often but not always coincided with CDKN2A/CDKN2B and PTPRD deletions. IFN-γ induced IRF1 expression and cell surface HLA-ABC levels in A549 cells that contain wildtype JAK2 but not in H1573 cells that had a truncating JAK2. Deletion of JAK2 or inhibition of JAK2 kinase activity in A549 cells resulted in loss of IFN-γ-regulated IRF1 and cell surface HLA-ABC, whereas expression of exogenous JAK2 in H1573 cells restored IFN-γ responses. These findings reveal a previously unrecognized significance of chromosome 9p deletion in NSCLC and point to chromosome 9p24.1 as a determinant of immune checkpoint therapy. Citation Format: Tao Shen, Jie Wu. Chromosome 9p24.1 deletions as a determinant of tumor immune surveillance and immune checkpoint blockade therapy in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 585. doi:10.1158/1538-7445.AM2017-585