Suvmax Linked to Intrafollicular Macrophage Infiltration Is Associated with Poor Outcome of Follicular Lymphoma

Recent research has demonstrated that tumor glycolysis plays a significant role in remodeling the immune microenvironment and influences the infiltration of immune cells. In particular, the glucose uptake of immune cells in tumors, especially macrophages, is considerably higher than that of the tumor cells themselves. Standardized Uptake Value maximum (SUVmax) serves as a critical indicator of glucose uptake in tumors and can effectively differentiate between diffuse large B-cell lymphoma transformations in the diagnosis of follicular lymphoma (FL). However, the connection between SUVmax in untransformed FL and the components of the immune microenvironment, along with its implications for chemo-free immunotherapy, remains unexplored. We conducted a retrospective study involving 863 patients with newly diagnosed FL from multiple centers. Our findings revealed that FL patients with an SUVmax ≥ 13 exhibited poorer prognoses, characterized by shorter progression-free survival (PFS) and overall survival (OS). Specifically, an SUVmax ≥ 13 was identified as an independent risk factor for both PFS and OS in these patients. Further analysis indicated a significant correlation between SUVmax ≥ 13 and higher tumor proliferation indices, along with elevated levels of lactate dehydrogenase, a key enzyme associated with glycolysis. Interestingly, this SUVmax threshold did not show a significant association with tumor burden, extra-nodal involvement, disease stratification or FLIPI-2 score. To more accurately investigate the relationship between SUVmax in FL and the immune microenvironment, we employed imaging mass spectrometry (IMC) to analyze lymph nodes from 28 FL patients. We obtained corresponding SUVmax values for these lymph nodes. The results revealed the identification of ten distinct clusters, highlighting that patients with SUVmax ≥ 13 had noticeably higher levels of CD163-negative macrophages and endothelial cells, while the proportion of tumor cells remained relatively unchanged. Interaction analyses further demonstrated that FL cells had significantly increased interactions with CD163-negative macrophages and vascular endothelial cells in patients with SUVmax ≥ 13. In treatment response, the combination of anti-CD20 monoclonal antibody with lenalidomide, known as the R2 regimen, activates macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) and enhances macrophage function, simultaneously inhibiting angiogenesis. Our analysis of 32 patients undergoing the R2 regimen indicated that those with SUVmax ≥ 13 had a significantly lower rate of early progression (POD24 within 24 months) compared to patients with SUVmax < 13 (12.5% vs. 25%). In summary, our results suggest that an SUVmax ≥ 13 is an independent risk factor for poor prognosis in FL patients receiving immunochemotherapy, as it correlates with increased infiltration of intrafollicular macrophages and enhanced angiogenesis. Furthermore, the chemo-free R2 regimen may improve outcomes for patients with SUVmax ≥ 13, although these findings require validation through larger studies and prospective clinical trials.