AXL Targeting Restores PD-1 Blockade Sensitivity of STK11/LKB1 Mutant NSCLC Through Expansion of TCF1+ CD8 T Cells

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dc.contributor.advisorAkbay, Esra A.en
dc.contributor.committeeMemberDeBerardinis, Ralph J.en
dc.contributor.committeeMemberFu, Yang-Xinen
dc.contributor.committeeMemberBrekken, Rolf A.en
dc.contributor.committeeMemberMinna, John D.en
dc.contributor.committeeMemberAguilera, Todd A.en
dc.creatorLi, Huiyuen
dc.creator.orcid0000-0002-1977-3981
dc.date.accessioned2024-01-11T20:19:34Z
dc.date.available2024-01-11T20:19:34Z
dc.date.created2021-12
dc.date.issuedDecember 2021
dc.date.submittedDecember 2021
dc.date.updated2024-01-11T20:19:34Z
dc.description.abstractMutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB) for unknown reasons. We found that introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically, this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype that was recapitulated in human STK11/LKB1 mutant NSCLCs. We found that systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expands tumor-associated TCF1+ PD-1+ CD8 T cells, restoring therapeutic response to PD-1 ICB for KPL tumors. This effect was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. Anecdotal NSCLC patients with STK11/LKB1 mutant tumors also demonstrated responses to the combination of AXL inhibitor bemcentinib and pembrolizumab. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1417098562
dc.identifier.urihttps://hdl.handle.net/2152.5/10227
dc.language.isoenen
dc.subjectAdenocarcinoma of Lungen
dc.subjectCarcinoma, Non-Small-Cell Lungen
dc.subjectCD8-Positive T-Lymphocytesen
dc.subjectLung Neoplasmsen
dc.subjectProtein Kinasesen
dc.subjectProto-Oncogene Proteinsen
dc.titleAXL Targeting Restores PD-1 Blockade Sensitivity of STK11/LKB1 Mutant NSCLC Through Expansion of TCF1+ CD8 T Cellsen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCancer Biologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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