Genomic Profiling of Patient-Derived Xenografts for Lung Cancer Identifies <i>B2M</i> Inactivation Impairing Immunorecognition

Abstract

<b>Purpose:</b> We aimed to maximize the performance of detecting genetic alterations in lung cancer using high-throughput sequencing for patient-derived xenografts (PDXs).<b>Experimental Design:</b> 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.<b>Results:</b> We identified alterations in genes involved in various functions, such as <i>B2M</i> involved in immunosurveillance. We extended the mutational analysis of <i>B2M</i> 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 <i>CALR, PDIA3</i>, and <i>TAP1</i>, 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 <i>B2M</i> 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.<b>Conclusions:</b> Here, we report recurrent inactivation of <i>B2M</i> in lung cancer. These observations, coupled with the mutations found at <i>CALR, PDIA3</i>, and <i>TAP1</i>, 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. <i>Clin Cancer Res; 23(12); 3203-13. ©2016 AACR</i>.