Bsbm-16 hla class-i antigen presentation machinery and ifn-γ pathway alterations in lung cancer brain metastases

Abstract BACKGROUND Immune checkpoint inhibitors (ICI) can have activity in lung cancer brain metastases (LBM). However, the duration of responses is limited and most patients with LBM do not benefit from these therapies. Alterations in HLA class-I antigen presentation machinery via beta-2 microglobulin (B2M) downregulation and disruption of IFN-γ sensing were identified as mechanisms of immune evasion and ICI resistance in solid tumors. However, the expression and clinical significance of these pathways in LBM are poorly understood. METHODS Using multiplex quantitative immunofluorescence we measured the localized expression of B2M protein; and the IFN-γ pathway markers phospho-STAT1 (pSTAT1), and Interferon Regulatory Factor 1 (IRF-1) in 67 immunotherapy naïve LBM and 45 primary lung tumors (PLT), including 15 patients with paired samples represented in a tissue microarray. The markers were selectively measured in cytokeratin + tumor cells and in cytokeratin- stromal cells. Associations between the markers, PD-L1, TILs and clinicopathologic variables were compared between LBM and PLT. RESULTS LBM showed lower levels of B2M in both tumor and stroma compartments compared to PLT. In contrast, high tumor and stromal levels of pSTAT1 were observed in LBM and comparable levels of IRF-1 were found between both tumor sites. Consistently across LBM and PLT samples, pSTAT1 and IRF1 were strongly correlated, and a positive but weaker association was observed with B2M and TILs. Only in PLT high tumor-cell PD-L1 expression was associated with high levels of IRF-1. No statistically significant association was observed between the markers and clinicopathologic variables. Tumor B2M downregulation in PLT was associated with worse survival. CONCLUSION LBM show distinct immunomodulatory properties relative to PLT, characterized by reduced HLA class-I antigen presentation machinery, elevated IFN-γ signaling and reduced local adaptive immune responses. These results support differences in immune evasion mechanisms in LBM compared with the PLT, which may have biological and clinical implications.