OCA-B/Pou2af1 Expression in Mouse T Cells Promotes PD-1 Blockade-Induced Autoimmunity but is Dispensable for...

The transcription coregulator OCA-B promotes CD4 ⁺ T cell memory recall responses and autoimmunity. OCA-B T cell deletion blocks spontaneous T1D onset in non-obese diabetic (NOD) mice and blunts T1D in a subset of more aggressive models. However, the role of OCA-B in diabetes induced by treatment with checkpoint blockade therapies, and the role of OCA-B in the control of tumors with and without α-PD-1 treatment, has not been studied. We show that deletion of OCA-B in T cells fully insulates 8-week-old non-obese diabetic (NOD) mice against α-PD-1 antibody-induced diabetes induction and partially protects 12-week-old mice. Salivary/lacrimal gland infiltration and inflammation were also reduced. Protection was associated with a block in the differentiation of progenitor exhausted CD8 ⁺ T cells (T _PEX ) into terminally exhausted CD8 ⁺ T cells (T _EX ). We show that OCA-B T cell loss preserves anti-tumor immune responses following PD-1 blockade therapy in a variety of tumor cell lines. These findings point to a potential therapeutic window in which pharmaceuticals that target OCA-B could be used to block the emergence of both spontaneous and checkpoint blockade-induced autoimmunity while minimally affecting anti-tumor immune responses. We develop first-in-class small molecule inhibitors of Oct1/OCA-B transcription complexes and show that administration into NOD mice also blocks diabetes emergence following α-PD-1 treatment. These results identify OCA-B as a promising therapeutic target for the prevention of autoimmunity and immune-related adverse events (irAEs).