Genomic Profiling of Patient-Derived Xenografts for Lung Cancer Identifies B2M Inactivation Impairing Immunorecognition

Abstract

We aimed to maximize the performance of detecting genetic alterations in lung cancer using high-throughput sequencing for patient-derived xenografts (PDXs). We undertook an integrated RNA and whole-exome sequencing of 14 PDXs. We focused on the genetic and functional analysis of β2-microglobulin (B2M), a component of the HLA class-I complex. We identified alterations in genes involved in various functions, such as involved in immunosurveillance. We extended the mutational analysis of to about 230 lung cancers. Five percent of the lung cancers carried somatic mutations, most of which impaired the correct formation of the HLA-I complex. We also report that genes such as , and, which are involved in the maturation of the HLA-I complex, are altered in lung cancer. By gene expression microarrays, we observed that restitution of in lung cancer cells upregulated targets of IFNα/IFNγ. Furthermore, one third of the lung cancers lacked the HLA-I complex, which was associated with lower cytotoxic CD8 lymphocyte infiltration. The levels of B2M and HLA-I proteins correlated with those of PD-L1. Finally, a deficiency in HLA-I complex and CD8 infiltration tended to correlate with reduced survival of patients with lung cancer treated with anti-PD-1/anti-PD-L1. Here, we report recurrent inactivation of in lung cancer. These observations, coupled with the mutations found at, and , and the downregulation of the HLA-I complex, indicate that an abnormal immunosurveillance axis contributes to lung cancer development. Finally, our observations suggest that an impaired HLA-I complex affects the response to anti-PD-1/anti-PD-L1 therapies..

A natural killer cell gene signature predicts melanoma patient survival

“…Finally, we note that transcript abundance for the B2M gene encoding beta-2 microglobulin has one of the most negative hazard coefficients, likely reflecting its role in MHC class I antigen presentation of neo-antigens to CD8 T cells and consistent with recent reports of the importance of this process for immune control of tumors [54]. Further, a truncation mutant of B2M can confer resistance to PD-1 blockade in melanoma [55], and mutations in B2M have been shown to disrupt immune surveillance in lung cancer [56]. The large negative hazard coefficient associated with HAPLN3, encoding a hyaluronan and proteoglycan link protein, suggests that this gene may warrant further investigation in the context of immune recognition and targeting.…”

Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

“…Moreover, since genetic defects in antigen processing machinery genes have been found in ~5% of lung cancers and have been linked to reduced survival upon treatment with immune checkpoint inhibitors (25,43), the contribution of this pathway to primary resistance in lung cancer should also be considered.…”

Prognostic Factors for Checkpoint Inhibitor Based Immunotherapy: An Update With New Evidences

“…Afterward, multiple clinical reports and subsequent experiments have confirmed that B2M alterations in tumor cells (i.e., mutations, deletions, and down-regulation) can largely induce acquired CPI resistance ( Gettinger et al, 2017 ; Janjigian et al, 2017 ; Grasso et al, 2018 ). Importantly, high frequency of initial B2M mutations were found in patient-derived xenografts for lung cancer, suggesting patients with this gene mutation may experience primary resistance to CPIs ( Pereira et al, 2017 ). With CRISPR screening, multiple genes were also identified to be essential for cancer immunotherapy, including APLNR , which can interact with JAK1 ( Patel et al, 2017 ).…”