The transcription co-regulator OCA-B/Pou2af1 differentially controls autoimmunity and tumor immunity 2307240

Introduction Expression of the transcription coregulator OCA-B in T cells is dispensable for primary immune responses but critical for CD4+ memory recall and autoimmune disease. OCA-B deletion in T cells also protects non-obese diabetic (NOD) mice from spontaneous type 1 diabetes (T1D) and blunts T1D in a subset of other more acute models. However, the roles of OCA-B in checkpoint blockade-induced diabetes and anti-tumor immunity have not been studied. Different from primary tumor, tumor relapse/rechallenge shares some similarities with memory responses. The roles of OCA-B in these rarer tumor responses have not been investigated before. Methods We used OCA-B T cell conditional mice to study the role of OCA-B in autoimmunity and anti-tumor immunity. Results Here we show that OCA-B deletion in T cells completely protects 8-week-old and partially protects 12-week-old NOD mice against PD-1 blockade-induced diabetes. Protection was associated with a failure of progenitor exhausted CD8+ cells to mature into pathogenic effectors. In parallel, we show that OCA-B T cell loss does not compromise anti-tumor immunity induced by PD-1 blockade in different immune-hot tumor models. We develop a proof-of-concept small molecule inhibitor of Oct1/OCA-B transcription complexes and show that the administration of this compound into NOD mice completely protects 8-week-old NOD mice from PD-1 blockade-induced diabetes. Using OCA-B reporter mice, we identify a small population of antigen-experienced OCA-B-expressing CD4+ T cells that are CD44-intermediate but otherwise naïve-like. We term these cells Tprogenitor-OCA-B (Tp-oca). Tp-oca cells express SLAMF7 and accumulate during MC38 and chronic infection. Conclusion These findings support OCA-B as a druggable target that could be used for the treatment of autoimmune diseases and checkpoint blockade-induced immune-related adverse events (irAEs). These findings also suggest OCA-B as a novel marker for antigen-experienced naïve-like CD4+ T cells with memory potential.