Postdoctoral fellow Brigham and Women's Hospital, Harvard Medical School Boston, Massachusetts, United States
Introduction/Rationale: Aging is associated with an increased risk of cancer and immunosenescence, coinciding with the expansion of Age-associated B cells (ABCs). While T cell checkpoints are well-established targets, the landscape of inhibitory pathways in B cells, how they regulate anti-tumor immunity remain unclear. This study investigates the transcriptional regulation of the checkpoint molecule TIM-1 on ABCs and its impact on anti-tumor immunity.
Methods: We combined multi-tissue single-cell RNA-seq across aging, bulk RNA-seq, ATAC-seq, ChIP-qPCR, and a transcription factor CRISPR screen to identify regulators of TIM-1⁺ ABCs. We generated mice with B cell-specific deletion of the ETS-homologous factor (EHF) and assessed tumor growth, immune infiltration using B16-OVA melanoma and AOM/DSS colon adenocarcinoma models in both young and aged cohorts.
Results: We identified a progressive age-related expansion of TIM-1+ ABCs that co-express multiple inhibitory checkpoints, a phenotype mirrored by B cells in tumor-draining lymph nodes. We found that TLR9 signaling drives this phenotype and identified EHF as the pivotal transcriptional driver. EHF directly binds the Havcr1 (TIM-1) locus to induce expression. B cell-specific EHF deletion selectively eliminated TIM-1+ ABCs, unleashed Th1-skewed immunity, and enhanced CD8+ T cell activity. Consequently, EHF-deficient mice exhibited robust control of colorectal and melanoma tumors. Crucially, this heightened anti-tumor immunity persisted in aged mice, reversing age-associated immune suppression.
Conclusion: These findings define a previously unrecognized TLR9-EHF-TIM-1 checkpoint axis in B cells that emerges with age constraining anti-tumor immunity and age-associated inflammation. Targeting the regulatory function of EHF-driven ABCs provides a mechanistic rationale for novel therapeutic strategies to potentiate cancer immunotherapy, particularly in the elderly population where these cells accumulate.
