Targeting focal adhesion kinase boosts immune response in KRAS/LKB1 co-mutated lung adenocarcinoma via remodeling the tumor microenvironment
Background: KRAS mutation is one of the most common oncogenic drivers in NSCLC, however, the response to immunotherapy is heterogeneous owing to the distinct co-occurring genomic alterations. KRAS/LKB1 co-mutated lung adenocarcinoma displays poor response to PD-1 blockade whereas the mechanism remains undetermined. Methods: We explored the specific characteristics of tumor microenvironment (TME) in KL tumors using syngeneic KRASG12DLKB1-/-(KL) and KRASG12DTP53-/- (KP) lung cancer mouse models. The impact of focal adhesion kinase (FAK) inhibitor on KL lung tumors was investigated in vitro and in vivo through evaluation of both KL cell lines and KL lung cancer mouse models. Results: We identified KL tumors as “immune-cold” tumors with excessive extracellular matrix (ECM) collagen deposition that formed a physical barrier to block the infiltration of CD8+T cells. Mechanistically, abundant activated cancer-associated fibroblasts (CAFs) resulted from FAK activation contributed to the formation of the unique TME of KL tumors. FAK inhibition with a small molecular inhibitor could remodel the TME by inhibiting CAFs activation, decreasing collagen deposition and further facilitating the infiltration of anti-tumor immune cells, including CD8+ T cells, DC cells and M1-like macrophages into tumors, hence, converting “immune-cold” KL tumors into “immune-hot” tumors. The combined FAK inhibitor and PD-1 blockade therapy synergistically retarded primary and metastatic tumor growth of KL tumors.Conclusions: Our study identified FAK as a promising intervention target for KL tumors and provided basis for the combination of FAK inhibitor with PD-1 blockade in the management of KL lung cancers. Overall design: To investigate the characteristics of TME in KP and KL tumors, in vivo tumor formation assay was performed. A total of 2 × 106 KP or KL cells were suspended in 200 µL PBS and then injected subcutaneously into 6 week old male C57BL/6 mice in the right flank. The tumor volumes were measured by caliper and calculated with a formula of p/6 × long diameter × short diameter × short diameter. Mice were sacrificed when tumor volume reached 700-800mm3. ce were sacrificed when tumor volume reached 700-800mm3. Tumors from KP or KL cell-bearing mice were excised for further analysis.