DECIPHERING THE CONTRIBUTION OF MACROPHAGES TO FOLLICULAR LYMPHOMA PATHOGENESIS: NEW INSIGHTS INTO THERAPY
Bibliographic record
Abstract
Introduction: Follicular Lymphoma (FL) represents the paradigm of a lymphoid neoplasia depending on microenvironment. Early studies by gene expression profiling (GEP) in FL tumor biopsies found that those cases enriched in certain genes expressed mainly in macrophages and Follicular Dendritic Cells (FDC) showed an inferior outcome (Dave et al, NEJM 2004). In the current study we have analyzed the three-way crosstalk of FL-FDC-M2, the correlation of CSF1-R expression, the M-CSF receptor essential for macrophage differentiation, with FL clinical data, and explored the potential antitumor effect of FL-M2 disruption using a specific CSF1-R inhibitor in combination with anti-B cell therapies. Methods: Primary FL cells (n=5) were co-culture (48h) with M2 macrophages at 4:1 ratio, generated from peripheral blood monocytes of healthy donors (100ng/mL M-CSF). Purified B cells (CD20 beads, Miltenyi) were subjected to GEP using HG-U219 microarray (Affymetrix). Data mining analysis was done with GSEA software. IHC analysis of CSF1-R and CD163 expression were performed in FFPE of FL patients (grade 0-2 (n=59) grade 3a-3b (n=28)). In vivo FL-FDC mouse model was generated by sc inoculation of the FL cell lines RL or WSU-FSCCL w/wo the FDC non-immortalized cell line HK in SCID mice. Results: In vivo, FDC significantly increased FL cell lines tumorigenicity (p<0.001), being these FL-FDC co-xenografts highly infiltrated with mouse M2 macrophages (CD206+). Remarkably, macrophage depletion (liposomal clodronate) significantly (p< 0.001) decreased tumor growth, supporting the contribution of macrophages to FL progression. Cell culture supernatants from FL-FDC co-cultures were enriched in pro-angiogenic factors and in the macrophage-attractant CCL2, favoring in vitro monocyte recruitment to the tumor. Moreover, primary cultures of FL cells induce monocyte differentiation towards M2-like macrophages (Fig.1). FL viability was significantly increased in FL-M2 co-cultures, and gene sets related to migration, adhesion and invasion were enriched in FL cells (Fig.2). Interestingly, in FL tumor biopsies, while the well-established M2 maker CD163 did not correlate with FL clinical parameters, CSF1-R expression correlated with the histological grade. The CSF1-R inhibitor Pexidartinib (PLX3397) changed M2 integrin profile decreasing their adhesion, and switching the M2 macrophage polarization towards a M1 phenotype (Fig.3). PLX3397 hampers the in vitro pro-survival effect provided by M2 to FL primary cells. In vivo, the simultaneous targeting of FL tumor cells with anti-CD20 Rituximab and Macrophages with PLX3397, led to a cooperative and significant reduction of tumor growth (Fig.4). Keywords: dendritic cells; follicular lymphoma (FL); macrophages.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".