CD40L and IL-4 suppress NK cell-mediated antibody-dependent cellular cytotoxicity through the HLA-E:NKG2A axis
Bibliographic record
Abstract
Abstract Background Anti-CD20 antibodies are first-line treatments for B cell malignancies. Natural killer (NK) cells are important mediators of anti-CD20 antibody efficacy in humans through antibody-dependent cellular cytotoxicity (ADCC). In B cell malignancies, the lymph nodes are a critical site of pathology and the T cell-derived signals CD40L and IL-4 within the lymph node microenvironment can mediate tumour proliferation, survival and resistance to pro-apoptotic therapy. CD40L and IL-4 have recently been shown to inhibit NK cell activation against chronic lymphocytic leukaemia (CLL) cells via the HLA-E:NKG2A immune checkpoint axis. However, the effect of these signals on NK cell-mediated ADCC of malignant B cells is unclear. Methods Using a combination of clinical samples, murine models, flow cytometry, immunoblotting, immunohistochemistry, ELISA, bioinformatics and functional assays, we examined the impact of lymph node-mimicking conditions on NK cell-mediated ADCC against malignant B cells. Exogenous CD40L and IL-4 were used to mimic T-B cell interactions in 2D malignant B cell cultures, in addition to a 3D spheroid model of T cell-dependent CLL proliferation. Results CD40L and IL-4 increased HLA-E expression on the surface of primary CLL cells and non-Hodgkin’s lymphoma (NHL) cell lines, and this decreased NK cell-mediated ADCC via ligation of the inhibitory receptor NKG2A. High HLA-E surface expression was observed in lymph node FFPE sections of CLL and NHL patients and in a 3D ex vivo lymph node-mimicking model of CLL. NKG2A blockade potentiated NK cell-mediated ADCC against malignant B cells treated with CD40L and IL-4 and improved anti-CD20 antibody therapy in a murine model of B cell lymphoma. Conclusion These results reveal a novel mechanism of resistance to anti-CD20 therapy in B cell malignancies and demonstrate that the combination of anti-NKG2A with anti-CD20 could improve the treatment of patients with CLL or NHL.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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".