Potent clinical predictive and systemic adjuvant therapeutic value of plasma fractalkine in PD-L1/PD-1 blockade immunotherapy for lung cancer

Abstract

AbstractRecent studies highlight the importance of baseline functional immunity for efficacious immune checkpoint blockade therapies. High-dimensional systemic immune profiling was performed in a discovery cohort of 112 non-small cell lung cancer patients undergoing PD-L1/PD-1 blockade immunotherapy. Responders showed high baseline phenotypic diversity of myeloid cell types in peripheral blood, in which elevated activated monocytic cells and decreased granulocytic phenotypes were potent predictive biomarkers. High-throughput profiling of soluble factors in plasma identified fractalkine (FKN), a chemokine involved in immune chemotaxis and adhesion, as a biomarker of myeloid cell diversity in human patients and in murine models, which was found significantly increased in objective responders. Secreted FKN inhibited adenocarcinoma and squamous cell carcinoma growth in vivo through a prominent contribution of systemic effector NK cells, enhanced tumor infiltration with immunostimulatory immune cells and inhibition of MDSCs within tumors. A synergy between FKN and PD-L1/PD-1 blockade immunotherapy was found in murine lung cancer models refractory to anti-PD-L1/anti-PD-1 treatment. Transcriptional data from 515 human lung adenocarcinoma samples independently confirmed the results from the discovery cohort. Importantly, recombinant FKN and tumor expressed-FKN were efficacious in delaying tumor growth in vivo with significant abscopal effects, indicating a potential therapeutic use of FKN in combination with immunotherapies.One Sentence SummarySerum fractalkine as a biomarker of response to immune checkpoint blockade.