Inhibition of Granulocytic Myeloid-Derived Suppressor Cells Overcomes Resistance to Immune Checkpoint Inhibition in LKB1-Deficient Non-Small Cell Lung Cancer.

Autor:	Li R; Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California., Salehi-Rad R; Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.; Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, California., Crosson W; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California., Momcilovic M; Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California., Lim RJ; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California., Ong SL; Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California., Huang ZL; Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California., Zhang T; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California., Abascal J; Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California., Dumitras C; Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California., Jing Z; Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California., Park SJ; Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California., Krysan K; Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California., Shackelford DB; Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California., Tran LM; Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California., Liu B; Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. bliu@mednet.ucla.edu sdubinett@mednet.ucla.edu., Dubinett SM; Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. bliu@mednet.ucla.edu sdubinett@mednet.ucla.edu.; Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, California.; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California.; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2021 Jun 15; Vol. 81 (12), pp. 3295-3308. Date of Electronic Publication: 2021 Apr 14.
DOI:	10.1158/0008-5472.CAN-20-3564
Abstrakt:	LKB1 inactivating mutations are commonly observed in patients with KRAS-mutant non-small cell lung cancer (NSCLC). Although treatment of NSCLC with immune checkpoint inhibitors (ICI) has resulted in improved overall survival in a subset of patients, studies have revealed that co-occurring KRAS/LKB1 mutations drive primary resistance to ICIs in NSCLC. Effective therapeutic options that overcome ICI resistance in LKB1-mutant NSCLC are limited. Here, we report that loss of LKB1 results in increased secretion of the C-X-C motif (CXC) chemokines with an NH2-terminal Glu-Leu-Arg (ELR) motif in premalignant and cancerous cells, as well as in genetically engineered murine models (GEMM) of NSCLC. Heightened levels of ELR + CXC chemokines in LKB1-deficient murine models of NSCLC positively correlated with increased abundance of granulocytic myeloid-derived suppressor cells (G-MDSC) locally within the tumor microenvironment and systemically in peripheral blood and spleen. Depletion of G-MDSCs with antibody or functional inhibition via all-trans-retinoic acid (ATRA) led to enhanced antitumor T-cell responses and sensitized LKB1-deficent murine tumors to PD-1 blockade. Combination therapy with anti-PD-1 and ATRA improved local and systemic T-cell proliferation and generated tumor-specific immunity. Our findings implicate ELR + CXC chemokine-mediated enrichment of G-MDSCs as a potential mediator of immunosuppression in LKB1-deficient NSCLC and provide a rationale for using ATRA in combination with anti-PD-1 therapy in patients with LKB1-deficient NSCLC refractory to ICIs. SIGNIFICANCE: These findings show that accumulation of myeloid-derived suppressor cells in LKB1-deficient non-small cell lung cancer can be overcome via treatment with all-trans-retinoic acid, sensitizing tumors to immunotherapy. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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