Abstract PR-06: Disrupting TACI signaling to restore immune balance: harnessing translational opportunities at the intersection of cancer and autoimmunity
Bibliographic record
Abstract
Abstract Background: Chronic lymphocytic leukemia (CLL) and systemic lupus erythematosus (SLE) represent opposing failures of immune regulation—tumor-driven suppression versus unchecked autoreactivity—yet both exploit the BAFF/APRIL–TACI (TNFRSF13B) axis. Continuous TACI engagement activates NF-κB signaling, promoting leukemic cell survival and rescuing autoreactive B cells from deletion. While therapies such as BTK and BCL-2 inhibitors shrink CLL tumors, they often impair immune competence; similarly, broad B-cell depletion in SLE curbs autoantibodies but heightens infection risk. A strategy that dismantles pathogenic B-cell programs while sparing protective immunity remains urgently needed. Aim: To assess whether genetic or antibody-mediated TACI blockade (i) suppresses CLL progression and restores anti-tumor immunity, and (ii) re-establishes self-tolerance across lupus models. Methods: Cancer arm: Eµ-TCL1 CLL cells, with or without TACI, were transplanted into wild-type mice (n ≥ 4/group); tumor burden, cytokines, and T-cell subsets were analyzed by flow cytometry. Microarray and real-time PCR profiled the transcriptional impact of TACI loss. Primary human CLL samples (≥ 4) underwent migration assays, T-cell co-culture ± anti-TACI antibody, and CRISPR-mediated TACI knockdown before NSG mouse engraftment. Autoimmunity arm: TACI deletion was introduced into BAFF-Tg, Lyn-/-, and Sanroque mice (n ≥ 4/strain). Plasma-cell frequencies, germinal-center dynamics, Tfh activity, autoantibody titers, renal pathology, and serum cytokines were assessed. Safety endpoints included weight, hematology, and vaccine-response assays. Results: TACI loss restrained pathogenic B-cell programs across both disease contexts. In CLL, mice engrafted with TACI-/- cells showed delayed disease progression, lower tumor incidence, normalized IL-6/IL-10 levels, and restored T-cell subsets versus TACI+/+ controls. TACI-deficient CLL cells downregulated IL-10, TNF, PD-L1, and PD-L2, restored immunoglobulin levels, and re-established T-cell–dependent antigen responses. Mechanistically, TACI enhanced CLL cell migration and splenic homing, promoting an immunosuppressive microenvironment; findings were validated in primary CLL cells and PDX models. In lupus models, TACI deletion restored B-cell homeostasis. BAFF-Tg TACI-/- mice exhibited normal plasma-cell frequencies and reduced autoantibodies and IFN-γ. Lyn-/- TACI-/- mice showed fewer plasma cells, lower cytokine production, and preserved renal structure. Sanroque TACI-/- mice displayed corrected Tfh activity and normalized autoantibody levels. Protective immune responses were maintained across all models without overt immunodeficiency. Conclusion: TACI blockade restores immune balance by impairing leukemic B-cell survival and migration while preserving humoral responses. Simultaneously, it re-establishes tolerance and prevents end-organ damage in lupus. These findings support TACI inhibition as a cross-disease therapeutic strategy unifying cancer immunotherapy and autoimmunity control. Citation Format: Yong Sheng, Beatriz Garcillán, M Arifur Rahman, William A. Figgett, SiLing Yang, Yukli Freedman, Eden H. Whitlock, Nicholas H. Weber, Fabienne Mackay. Disrupting TACI signaling to restore immune balance: harnessing translational opportunities at the intersection of cancer and autoimmunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr PR-06.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".