Abstract B007: Tissue-Specific B Cell Differentiation Limits Anti-Tumor Efficacy of Radiation and Immunotherapy
Bibliographic record
Abstract
Abstract Despite recent advances in triple-negative breast cancer (TNBC) biology and new therapies, this aggressive subtype remains difficult to treat. A key obstacle is the immunosuppressive tumor microenvironment (TME), often dominated by myeloid cells that impair anti-tumor immunity. Radiation therapy (RT), used as an in-situ vaccine, enhances tumor immunogenicity and has shown promise when combined with immune checkpoint blockade (ICB) in preclinical and clinical settings1-3. We previously found that combining RT with CTLA-4 blockade and a CD40 agonist antibody (CD40a), which activates myeloid cells, led to profound tumor regression and occasional complete responses in a rapidly metastasizing TNBC mouse model4. However, CD40a did not improve control of lung metastases beyond that achieved with RT and CTLA-4 blockade. In tumors, CD40a induced remodeling of dendritic cell and macrophage populations, along with enrichment in B cell–associated gene signatures. As CD40 signaling can promote either effector or regulatory B cell responses depending on context5, we hypothesized that triple therapy induces organ-specific B cell differentiation that may hinder systemic immune control. We first assessed systemic versus local effects of CD40a on B cells in naïve and tumor-bearing (4T1) mice. In both settings, CD40a expanded splenic B cells and increased MHC-II+ expression. In lungs, tumor implantation alone led to increased B cell infiltration, even without CD40a. However, these lung B cells showed reduced activation in untreated tumor-bearing mice, only partially restored by CD40a, suggesting a distinct, potentially immunosuppressive phenotype. To evaluate this in the context of RT + CTLA-4 blockade + CD40a, we analyzed B cells from lungs and tumors via multiparametric flow cytometry and observed that CD40a consistently shifted B cell profiles across compartments. Among B cells, we identified regulatory B cells (Breg) as expressing TIM1, CD138, CD5, CD39, and FasL. CD40a decreased Breg infiltration in tumors but significantly increased it in lungs. In both tissues, Breg marker expression correlated with tumor or lung burden. Given TIM1’s role in IL-10–producing Bregs—and its capacity to suppress T cells independently of IL-10—6-8 we tested a TIM1-blocking antibody in combination with RT + CTLA-4 blockade + CD40a. While TIM1 blockade did not enhance tumor control, it markedly reduced lung Bregs. Our data highlight organ-specific B cell responses following CD40a-based immunotherapy and suggest that lung-resident Bregs may limit systemic immune efficacy. Ongoing work focuses on defining mechanisms of Breg-mediated suppression and, in collaboration with bioengineers, on developing intra-tumoral delivery strategies to reduce systemic immunosuppressive effects of agents like CD40a. 1-PMID: 29180535 2-PMID: 33476307 3-PMID: 30397353 4-PMID: 37620372 5-PMID: 19265127 6-PMID: 25582854 7-PMID: 31511630 8-PMID: 31685302 Citation Format: Maud Charpentier, David Sprott, Sandra Demaria. Tissue-Specific B Cell Differentiation Limits Anti-Tumor Efficacy of Radiation and Immunotherapy [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 B007.
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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 | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 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".