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- W3137203732 abstract "LKB1 deficiency is reported to lead to primary resistance to immune checkpoint inhibitors (ICIs) in lung adenocarcinoma. But specific molecular mechanism behind it is still incompletely understood and probably is the breakthrough to reshape microenvironment and restore anti-tumor immunity. Tumor-Infiltrating Immune Cell Isolation and FACS Analysis were used to investigate the impact of LKB1 alteration on the immune profiles of tumor microenvironment. Then we investigated the mechanisms underlying primary resistance to ICIs through a series of invitro-studies (mRNA sequencing, mass spectrometry, Western blotting, co-immunoprecipitation, etc.). Finally, we validated our findings in syngeneic mouse models in a treatment setting. We found that LKB1 alteration (including loss and mutation) could significantly affect the whole tumor immune landscape and caused the “immune-desert” microenvironment, which was significantly associated with the expression of intercellular adhesion molecule-1 (ICAM1). ICAM1 influenced cytotoxicity of CTLs , and its expression on cancer cells was positively linked to CD8+ T cells infiltration into lung cancer tissue, indicating that ICAM1 was the core effector downstream LKB1. Mechanistic studies indicated that LKB1 hindered the interaction between cyclin-dependent kinase 4 (CDK4) and retinoblastoma protein (Rb), inhibiting the phosphorylation of Rb, which thereby lead to active transcription of ICAM1. Ultimately, we found that CDK4/6 inhibitors (Palbociclib) and PD-1 antibody combination strategy could yield therapeutic benefits with slower tumor growth and longer survival in our mouse model (figure 1), associated with a T cell and NK cell inflamed and activated immune microenvironment, through an ICAM1-dependent way (figure 2).View Large Image Figure ViewerDownload Hi-res image Download (PPT) LKB1/STK11 deficiency could lead to a primary resistance to ICIs through the induction of “immune-desert” microenvironment in an pRB-ICAM1 dependent way. And an effective combination strategy of using CDK4/6 inhibitors and PD-1 antibody could reverse the resistant state, which may guide future clinical practice in lung adenocarcinoma." @default.
- W3137203732 created "2021-03-29" @default.
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- W3137203732 date "2021-03-01" @default.
- W3137203732 modified "2023-09-27" @default.
- W3137203732 title "P16.04 CDK4/6 Inhibitors Reverse Resistance to Anti-PD-1 Therapy in Lung Adenocarcinoma with LKB1 Deficiency Through pRB-ICAM1 Dependent Signaling" @default.
- W3137203732 doi "https://doi.org/10.1016/j.jtho.2021.01.550" @default.
- W3137203732 hasPublicationYear "2021" @default.
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