Abstract 80P
Background
LILRB2 is an immune checkpoint of leukocyte immunoglobulin-like receptor B family. The blockade of LILRB2 can reprogram the immunosuppressive phenotype of myeloid cells to enhance the efficacy of immune checkpoint inhibitor (ICB) in preclinical studies, which are undergoing early clinical testing in NSCLC. The single-cell-level resolution of LILRB2 and its impact on the PD-1/PD-L1 immunotherapy have not been fully explored.
Methods
The predictive value of LILRB2 mRNA expression for ICB was first evaluated in two independent phase III randomized controlled trials (RCTs), including ORIENT-11 [sintilimab plus chemotherapy, n = 113; chemotherapy, n = 58] and OAK (atezolizumab, n = 344; chemotherapy, n = 355). BayesPrism algorithm were used to deconvolute monocyte subsets from GSE123904, GSE127465 and GSE207422.
Results
Higher LILRB2 expression was significantly associated with significantly prolonged progression free survival with ICB (ORIENT-11: HR=0.57 p=0.027;OAK: HR=0.77, p=0.023). However, no trend was observed in chemotherapy arm in each study. These findings maintained in patients with PD-L1 expression≥1%. From the three single-cell RNA-seq datasets, we identified a monocyte subset with high LILRB2 expression, referred as LILRB2+monocyte. Deconvolution of LILRB2+ monocyte in the two RCTs demonstrated its predictiveness for ICB. Further, in a single-cell dataset, the transcriptional signatures of LILRB2+ monocytes were enriched in MPR patients treated with neoadjuvant PD-1 blockade. Functionally, LILRB2+ monocytes were positively correlated with immune-related interferon-ɑ (IFN-ɑ) and interferon-γ (IFN-γ) signaling. LILRB2+ monocytes were predicted to interact with GZMB+ and GZMK+ cytotoxic T lymphocyte, which thereby promotes anti-tumor immunity by enhancing CD8+ T cell effector functions.
Conclusions
LILRB2+ defines a monocyte subset that is positively associated with greater benefits from ICB, in contrast to most previously-revealed monocyte subsets with an immunosuppressive phenotype. The evaluation of LILRB2+ monocytes may help identify patients who could benefit from future co-inhibition of PD-1/PD-L1 and LILRB2 signaling.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.