Abstract: Objective To investigate the effect of LRP1B on the proliferation, migration, invasion and immune microenvironment of Lewis cells.Methods The expression of LRP1B gene in lung cancer and other cancers was analyzed using TCGA database. We constructed the LRP1B knock-out Lewis cells by CRISPR/Cas9 technique, and set as a KO group. Meanwhile, wild Lewis cells were used as a control (NC) group. Their expression of LRP1B was detected by Western blot. The cell viability was measured by CCK-8 assay. The cell migration and invasion abilities were evaluated by would healing assay and Transwell assay. The cell suspensions from either the KO group or the NC group were injected into the right armpit of C57BL/6 mice and set as KO mice or NC mice, respectively. The tumor growth in both KO and NC mice was observed. The infiltration of bone marrow-derived suppressor cells (MDSCs) and CD8⁺ T cells in tumor-bearing mice was detected by flow cytometry. The levels of programmed death receptor -1 (PD-1) and its ligand (PD-L1) were detected by immunohistochemistry.Results The expression of LRP1B gene in lung adenocarcinoma and lung squamous cell carcinoma was significantly higher than that in adjacent tissues (P＜0.05). Compared with the NC group, LRP1B gene knockout resulted in remarkably increased abilities of proliferation, migration and invasion of the cells in the KO group (P＜0.05). Furthermore, compared with the NC mice, the KO mice showed significant increases in the volumes of tumors (P＜0.05), increases in the percentage of MDSCs, decreases in the percentage of CD8⁺ T cells and increases in PD-L1 and PD-1 levels (P<0.05).Conclusions Knockout of LRP1B gene may promote the proliferation, migration and invasion of Lewis cells, and stimulate the expression of PD-L1 and PD-1.