Abstract 617: MEK inhibitor rescued the efficacy of PD-1 blocker in STK11/LKB1 mutated colorectal cancer model

Abstract

Abstract Introduction: The mechanism of action of primary resistance to PD-1 blockade is largely unknown, however STK11/LKB1 alterations have been reported to have a significant role in primary resistance to PD-1/PD-L1 axis inhibitors in KRAS-mutant lung adenocarcinoma. It is importsnt to identify treatments which can rescue the efficacy of PD-1 blocker in STK11/LKB1-mutant patients. We have developed a STK11 knockout (KO) model using the CT26 colorectal cancer syngeneic line which harbors a KRAS mutation and evaluated the response to checkpoint inhibitor alone and in combination with MEK inhibitors. Method: CT26-STK11KOwas developed by CRISPR/Cas9 technology and STK11/LTB1 deletion was verified by Western Blot. To test the response of the cell line to anti-PD-1 treatment (10mg/kg), we engrafted CT26-WT and CT26-STK11KO tumor lines into BALB/c mice. Tumor growth inhibition (TGI) was assessed as TGI%=(1-Ti/Vi) x100%; Ti as the mean tumor volume of the treatment group on the measurement day; Vi as the mean tumor volume of control group at the measurement day. At termination FACS analysis of different major types of immune cells was performed. Combination with MEK inhibitors, including Trametinib (1mg/kg) was also evaluated. Results: In comparison to CT26-WT tumor growth, PD-1 blocker could not inhibit CT26-STK11KO tumor progression. However, Combinational treatment of Trametinib and anti-PD-1 antibody delayed CT26-STK11KO tumor growth. In CT26-WT tumor bearing mice, anti-PD-1 monotherapy increased total CD45+ immune cells, suggesting an ongoing immune response; significantly increased the ratio between M1 and M2, which might be an indicator for enhanced type I T cell response. CD8+ T cell infiltration in CT26-STK11KO tumors was dramatically decreased associated with increased percentage of G-MDSC which may have contributed to the loss of response to anti-PD-1 treatment. MET inhibitor, Trametinib, decreased G-MDSC and restored CD8+ T cell infiltration and PD-1 blocker efficacy in CT26-STK11KO tumor. Conclusions: We successfully generated a CT26-STK11KO cell line which was valuable for evaluation of PD-1 blocker and MEK inhibitor in STK11/LTB1 deficient tumor, in which Trametinib could rescue the efficacy of PD-1 treatment in CT26-STK11KO tumor via inhibiting G-MDSC. Taken together, our data suggest that altered immune cell infiltration, particularly increased G-MDSCs, in tumor microenvironment might be the reason for poor PD-1 blocker efficacy in CT26-STK11KO tumor. Citation Format: Demi X. Liu, Jun Zhou, Chenpan Nie, Annie X. An, Henry Q.X. Li, Jingjing Wang. MEK inhibitor rescued the efficacy of PD-1 blocker in STK11/LKB1 mutated colorectal cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 617.