10.01 Effective solid tumor therapy through enhanced recruitment and immune suppression shielded T cells

Background CAR T cell therapy remains ineffective in solid tumors. Scarce infiltration and suppression at the tumor site are two notable limitations. regulatory (Treg) cells capable of suppressing effective anti-tumor responses through inhibitory factors such as transforming growth factor β (TGF-β). Treg expressing C-C chemokine receptor 8 (CCR8) have been found to accumulate correlate with poor prognosis breast cancer. We postulated that CCR8 could be exploited redirect effector while a dominant-negative TGF-β 2 (DNR) can simultaneously shield them from TGF-β. Materials Methods DNR expressed murine human upon retroviral transduction. (TCR) chimeric antigen (CAR) specific models systems were utilized. qPCR, IF microscopy, ELISA cancer genome atlas (TCGA) database used steps ligand identification hypothesis generation. employed flow cytometry multi-photon intra-vital microscopy interrogate infiltration, proliferation phenotype products. Mechanistically, CRISPR was dissect role CCL1-CCR8 positive feedback loop therapy. Results identified an vivo pancreatic model cancer, gene upregulated infiltrated lymphocytes compared accumulated spleen. In this same model, CCL1 detected explants. secreted activated potentiates for + recruitment site. The introduction receptors primary improved migration towards capacity presence Besides these effects, did not further impact memory or secretome CCR8-driven sustained synergized TGF-β-shielding conferred by therapeutic efficacy, allowing rejection otherwise completely resistant Conclusions conclude combination CCR8- DNR-transduction into antigen-specific exploit critical biological axes render tumors Beyond TGF-β, relieving other immunosuppressive may sustain mechanism improve anti-tumoral function CCR8+ ACT. This approach extended Treg-rich entities where limited intra-tumoral prevent success. Furthermore, axis heralds potential target efficacy immunotherapies beyond Disclosure Information B.L. Cadilha: None. M.R. Benmebarek: K. Dorman: A. Oner: T. Lorenzini: H. Obeck: S. Stoiber: D. Huynh: F. Märkl: M. Seifert: Manske: Endres: Kobold: