GENOMIC PROFILING OF PATIENT-DERIVED XENOGRAFTS FOR LUNG CANCER IDENTIFIES B2M INACTIVATION IMPAIRING IMMUNORECOGNITION.

PURPOSE: We aimed to maximize the performance of detecting genetic alterations in lung cancer (LC) using high-throughput sequencing for patient-derived xenografts (PDXs).

EXPERIMENTAL DESIGN: We undertook an integrated RNA and whole-exome sequencing of 14 PDXs. We focused on the genetic and functional analysis of B2-microglobulin (B2M), a component of the HLA class-I complex.

RESULTS: We identified alterations in genes involved in various functions, such as B2M involved in immunosurveillance. We extended the mutational analysis of B2M to about 230 LCs. Five per cent of the LCs carried somatic mutations, most of which impaired the correct formation of the HLA-I complex. We also report that genes such as CALR, PDIA3 and TAP1, which are involved in the maturation of the HLA-I complex, are altered in LC. By gene expression microarrays, we observed that restitution of B2M in LC cells up-regulated targets of IFNalpha/IFNgamma. Furthermore, one third of the LCs 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 LC patients treated with anti-PD1-/anti-PD-L1.

CONCLUSIONS: Here, we report recurrent inactivation of B2M in LC. These observations, coupled with the mutations found at CALR, PDIA3 and TAP1, and the down-regulation of the HLA-I complex, indicate that an abnormal immunosurveillance axis contributes to LC development. Finally, our observations suggest that an impaired HLA-I complex affects the response to anti-PD-1/anti-PD-L1 therapies.