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AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells
Huiyu Li1,2, Zhida Liu3, Longchao Liu3
1Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-8593, USA.
Abstract:
Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+PD-1+CD8 T cells, restoring therapeutic response to PD-1 ICB in KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.
Insights
STK11/LKB1 mutations in non-small cell lung cancer (NSCLC) impede immune checkpoint blockade (ICB) therapy by reducing TCF1+ CD8 T cells. Targeting AXL restores T cell function and ICB response in NSCLC.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- STK11/LKB1 mutations are linked to poor responses to immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC).
- STK11/LKB1 mutations lead to a lack of TCF1-expressing CD8 T cells, contributing to ICB resistance.
Purpose of the Study:
- To investigate the mechanism of ICB resistance in STK11/LKB1-mutant NSCLC.
- To identify therapeutic strategies to overcome ICB resistance in STK11/LKB1-mutant NSCLC.
Main Methods:
- Utilized syngeneic murine lung adenocarcinoma models (KP and KPL) and humanized mice with NSCLC xenografts.
- Investigated the role of AXL inhibition in modulating the tumor microenvironment and T cell responses.
- Assessed clinical response to combination therapy (bemcentinib and pembrolizumab) in NSCLC patients with STK11/LKB1 mutations.
Main Results:
- STK11/LKB1 mutations in NSCLC result in an absence of TCF1+ CD8 T cells, causing resistance to ICB.
- Systemic AXL inhibition promotes type I interferon secretion, expanding TCF1+ PD-1+ CD8 T cells and restoring ICB sensitivity.
- Combination therapy with bemcentinib and pembrolizumab showed objective clinical response in NSCLC patients with STK11/LKB1 mutations.
Conclusions:
- AXL is a critical targetable driver of immune suppression in STK11/LKB1-mutant NSCLC.
- Targeting AXL represents a promising therapeutic strategy to enhance ICB efficacy in this patient population.
