Vascular phenotype as predictive markers of CAR-T cell therapy response in patients with diffuse large B-cell lymphoma

Chimeric antigen receptor-T-cell therapy is effective in approximately 50% of patients with diffuse large B-cell lymphoma. We tested the hypothesis that CAR-T responsiveness could be predicted by quantitatively assessing the expression of inflammation-induced adhesion molecules that favour the homing of T cells (E-Selectin, intercellular adhesion molecule -1 or vascular cell adhesion molecule-1) on intratumoral microvascular endothelial cells lining flat venules or peripheral node addressin+ high endothelial venules. We analysed 18 pretreatment tumour samples with known clinical outcomes by cyclic immunofluorescence of pretreatment FFPE biopsies using machine learning algorithms on images in QuPath across serial stains. The same sections were also examined for the number of pretreatment CD8+ T cells and expression of some T-cell receptors for EC adhesion molecules (α4-Integrin, L-Selectin and P-Selectin glycoprotein ligand). We discovered an increase in VCAM-1 and E-Selectin expression in ECs lining flat venules, a correlation with CD8+ T-cell adhesion molecule receptor expression, and an unexpected decrease in ICAM-1 expression in ECs lining high endothelial venules among responders. The utility of VCAM-1 expression in intratumoral ECs as a predictive biomarker for responsiveness to CAR-T therapy suggested by this pilot study requires replication with a larger series for validation.