Th144 - Thyroid Cells from Normal and Autoimmune Thyroid Glands Suppress upon Contact T Lymphocyte Proliferation -but Not Cytokine Production- revealing a Inhibitory Activity Independent of PD-1/PD-L1

Daniel Alvarez-Sierra – Post-Doct, Cellular Biology, Physiology and Immunology, Universitat Autonoma de Batcelona; Nerea Sanchez-Gaona – PhD Student, Infectious diseases, Vall Hebron Institute de Recerca (VHR); Maria Cruz Cobo – PhD Stident, Hematology, University of Geneve; Alba Escriche – Cellular Plasticity and Cancer Group – Vall Hebron Oncology Institute (VHIO); Maria Abad – Principal Investigator, Plasticity and Cancer Group, Vall Hebron Oncology Institute (VHIO); Aroa Gomez-Brey – Consultant, Intensive Care Unit, Hospital Universitari Vall Hebron; Irene Bello-Rodriguez – Consultant, Thoracic Surgery, Hospital Universitari Vall Hebron; Enric Caubet – Consultant, Surgery, Hospital Universitari Vall Hebron; Oscar Gonzalez – Consultant, Surgery, Hospital Universitari Vall Hebron; Carles Zafon – Consultant, Endocrinology, Hospital Universitari Vall Hebron; Carmela Iglesias-Felip – Consultant, Histopathology, Hospital Universitari Vall Hebron; Pablo Moreno – Consultant, Surgery, Hospital Universitari Bellvitge; Anna Petit-Montserrat – Consultant, Histopathology, Hospital Universitari Bellvitge; Marco Fernandez-Sanmartin – Scientific Officer, Flow Cytometry, Institute Investigacio Sanitaria Germans Trias i Pujol (IGTP); Monica Martinez-Gallo – Consultant, Immunology, Hospital Universitari Vall Hebron; Ricardo Pujol Borrell – Emeritus Professor, Cell Biology, Physiology and Immunology, Universitat Autónoma de Barcelona

Abstract Text: Immune Checkpoint Receptors include a number of inhibitory receptors that limit tissue damage during immune responses; blocking PD-1/PD-L1 checkpoint receptor axis led to a paradigm shift in cancer immunotherapy but also to autoimmune adverse effects, prominently thyroid autoimmunity. Although PD-L1 expression by human thyroid follicular cells (TFCs) of autoimmune glands was previously reported by our group, the effects of the direct interaction between T cells and thyroid cells expressing PD-L1 was not been investigated.
Here we report that autologous primary TFCs, but not transformed TFCs, strongly inhibit CD4 and CD8 T cell proliferation but no cytokine production. Cocultures using of 0.4 μm pore transwell inserts and/or saturating concentrations of anti-PD-1 blocking antibody (Nivolumab, Opdivo®) demonstrated that this effect was not mediated by PD-1/PD-L1 pathway. Beta galactosidase analysis excluded culture-induced senescence as an explanation. High resolution flow cytometry demonstrated that autologous TFC/T cells coculture induces the expansion of several subsets of double negative (DN) T cells characterized by high expression of activation markers and negative immune checkpoints. scRNA-seq demonstrated that dissociated TFC express numerous candidate molecules for mediating this immune regulatory activity, including CD40, E-Cadherin, LGALS3 or TIGIT ligands. These ligands directly or through the generation of a suppressor population of DN T cells are most likely the responsible of TFC in vitro immunosuppressive activity. These results contribute to reveal the complex network of inhibitory mechanism that operate at the tissue level to restrain autoimmunity but also point to pathways, other that PD-1/PD-L1, that can contribute to tumor evasion.