LILRB2+ monocytes reshape the immune activation landscape in immunotherapy with non-small cell lung cancer: Evidence from real-world cohorts and single-cell analyses.

The role of monocytes in tumor progression is controversial, especially in immune response. LILRB2 expression can reprogram the immunosuppressive phenotype of monocytes to enhance the efficacy of immune checkpoint inhibitors (ICIs). However, the single-cell-level resolution of LILRB2 and its impact on the PD-1/PD-L1 immunotherapy are not fully explored. We used transcriptomic and clinical data from OAK, POPLAR and ORIENT-11 trials to determine the predictive value of LILRB2 expression in patients with NSCLC treated with ICIs. Deconvolution of pre-treatment non-small cell lung cancer (NSCLC) transcriptomes using single-cell sequencing identified LILRB2+ and S100A8+ monocyte subsets. Following ICIs treatment, lower LILRB2 expression levels were linked to poor PFS (P = 0.020), while high LILRB2+ monocyte abundance was associated with prolonged OS (P = 0.004) and PFS (P = 0.0003) in the OAK ICI cohort. And the LILRB2+/S100A8+ monocyte ratio (L/S ratio) showed significantly better OS (P = 0.0013) and PFS (P = 0.01) than those with a low L/S ratio. LILRB2+ monocytes promoted the activation of CD8+ T cells, further enhanced the anti-tumor efficacy of PD-1 blockade. And S100A8+ monocytes were enriched in NMPR patients, while LILRB2+ monocytes had higher MHC-I expression and higher density of CD8+ T cells, and were significantly increased in MPR patients. These findings demonstrated that LILRB2+ monocyte reversed the immunosuppressive phenotype, and is positively associated with greater benefits from ICIs.