SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation

• DOI: 10.1136/jitc-2020-001496
• Publication Date: 2021-03-03T16:43:49Z
• Authors: Esther Redin; Irati Garmendia; Teresa Lozano; Diego Serrano; Yaiza Senent; Miriam Redrado; Maria Villalba; Carlos E De Andrea; Francisco Exposito; Daniel Ajona; Sergio Ortiz-Espi...; Ana Remirez; Cristina Bertolo; Cristina Sainz; Juana Garcia-Pedrero; Ruben Pio; Juan Lasarte; Jackeline Agorreta; Luis M Montuenga; Alfonso Calvo
• Keywords: Lung Neoplasms; Mice, 129 Strain; Programmed Cell Death 1 Receptor; Dasatinib; T-Lymphocytes, Regulatory; Mice; 03 medical and health sciences; Lymphocytes, Tumor-Infiltrating; 0302 clinical medicine; Lung neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Animals; Humans; Lymphocytes; Immune Checkpoint Inhibitors; Protein Kinase Inhibitors; RC254-282; Cell Proliferation; Clinical/Translational Cancer Immunotherapy; Proto-Oncogene Proteins c-yes; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Drug evaluation; Preclinical; Phenotype; Tumor microenvironment; Drug Resistance, Neoplasm; Tumor-infiltrating; Female; Signal Transduction

The use of immune-checkpoint inhibitors has drastically improved the management patients with non-small cell lung cancer (NSCLC), but innate and acquired resistances are hurdles needed to be solved. Immunomodulatory drugs that can reinvigorate immune cytotoxic activity, in combination antiprogrammed death 1 (PD-1) antibody, a great promise overcome resistance. We evaluated impact SRC family kinases (SFKs) on NSCLC prognosis, immunomodulatory effect SFK inhibitor dasatinib, anti-PD-1, clinically relevant mouse models NSCLC.A cohort from University Clinic Navarra (n=116) was used study infiltrates by multiplex immunofluorescence (mIF) YES1 protein expression tumor samples. Publicly available resources (TCGA, Km Plotter, CIBERSORT) were patient's survival based SFKs infiltrates. Syngeneic 393P UNSCC680AJ for vivo drug testing.Among members, showed highest association poor prognosis. Patients high levels also infiltration CD4+/FOXP3+ cells (regulatory T (Tregs)), suggesting an immunosuppressive phenotype. After testing panel murine lines, selected studies. In model, dasatinib+anti-PD-1 treatment resulted synergistic 87% regressions development immunological memory impeded growth when mice rechallenged. depletion experiments further CD8+ CD4+ necessary therapeutic combination. antitumor activity accompanied very significant decrease number Tregs, which validated mIF sections. effects milder similar model. vitro assays, we demonstrated dasatinib blocks proliferation transforming factor beta-driven conversion effector into Tregs through targeting phospholymphocyte-specific tyrosine kinase downstream effectors pSTAT5 pSMAD3.YES1 is associated increased numbers NSCLC. Dasatinib synergizes anti-PD-1 impair experimental models. This provides preclinical rationale combined PD-1/programmed death-ligand blockade improve outcomes