OCA-B/Pou2af1 Expression in Mouse T Cells Promotes PD-1 Blockade-Induced Autoimmunity but is Dispensable for
Biorxiv : the Preprint Server for Biology
|November 24, 2025
Summary
Targeting the transcription coregulator OCA-B in T cells prevents autoimmune diabetes, including that induced by checkpoint blockade therapy. OCA-B inhibition also preserves anti-tumor immunity, suggesting a therapeutic window for treating autoimmunity.
Area of Science:
- Immunology
- Endocrinology
- Oncology
Background:
- The transcription coregulator OCA-B (Octamer-binding Transcriptional coactivator 2-B) is implicated in T cell responses and autoimmunity.
- OCA-B T cell deletion mitigates spontaneous Type 1 Diabetes (T1D) in non-obese diabetic (NOD) mice.
- The role of OCA-B in checkpoint blockade-induced diabetes and its impact on anti-tumor immunity remains uninvestigated.
Purpose of the Study:
- To investigate the role of OCA-B in T cells in the context of α-PD-1 antibody-induced diabetes in NOD mice.
- To determine the effect of OCA-B deletion in T cells on anti-tumor immune responses during PD-1 blockade therapy.
- To explore OCA-B as a therapeutic target for preventing autoimmunity and immune-related adverse events (irAEs).
Main Methods:
- Genetic deletion of OCA-B in T cells of NOD mice.
- Treatment of mice with α-PD-1 antibodies.
- Assessment of diabetes incidence, insulitis, and salivary/lacrimal gland inflammation.
- Analysis of CD8+ T cell exhaustion markers (TPEX and TEX).
- Evaluation of anti-tumor immune responses in various tumor cell line models.
- Development and administration of small molecule inhibitors targeting Oct1/OCA-B transcription complexes.
Main Results:
- T cell-specific OCA-B deletion fully protected 8-week-old NOD mice and partially protected 12-week-old mice against α-PD-1-induced diabetes.
- Reduced infiltration and inflammation were observed in salivary and lacrimal glands of OCA-B-deleted mice.
- OCA-B deletion blocked the differentiation of progenitor exhausted CD8+ T cells (TPEX) into terminally exhausted CD8+ T cells (TEX).
- OCA-B T cell loss preserved anti-tumor immune responses following PD-1 blockade therapy.
- Administration of Oct1/OCA-B inhibitors blocked diabetes emergence in NOD mice treated with α-PD-1.
Conclusions:
- OCA-B in T cells is critical for the development of both spontaneous and checkpoint blockade-induced autoimmune diabetes.
- Targeting OCA-B can prevent autoimmune diabetes while preserving anti-tumor immunity, indicating a potential therapeutic window.
- OCA-B represents a promising therapeutic target for preventing autoimmune diseases and immune-related adverse events.
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