The dynamic presence of DTP cells traversing giant cell state in patients with therapy-resistant MCL. (A) Representative H&E imaging and immunohistochemistry staining of giant cells (arrowed) from the PDX sample with resistance to both anti-CD19 CAR T-cell therapy and PBN showing increased GOT2 level. Scale bar, 50 μm. (B) Representative image showing MCL with pleomorphic morphology in patient after IBN treatment. Enlarged lymphoma cells (predominantly >10 micron in nuclear diameter) were observed to have highly irregular nuclear contours, partially open chromatin, occasional distinct nucleolus, and moderate amount of cytoplasm (arrowed). H&E, ×1000 with oil. Scale bar, 20 μm. (C) PCA showing responses to systemic therapies in patients with MCL. (D) Kaplan-Meier analysis showing survival probability of patients with MCL (responsive vs nonresponsive). (E) GSEA-identified signaling pathways regulated in nonresponsive patients and the Giant cell model. Listed pathways featured in Giant cells are ranked by a NES and colored by pathway types; Cox proportional hazards univariate analysis identified enriched pathways in nonresponsive patients with MCL. False discovery rate q values labeled as indicated. Functional categories are labeled as indicated colors. (F) ssGSEA scores of rRNA processing, Giant_UP gene signatures, and Got2 expression in patients with MCL. Kaplan-Meier survival curves using the rRNA processing, Giant_UP signature scores, and Got2 expression (responsive vs nonresponsive to therapies), with log-rank P = .00028, P = .0042, and P = .02, respectively. ∗∗P < .01; ∗∗∗∗P < .0001. NES, normalized enrichment score; PCA, principal component analysis; Pval, P value; ssGSEA, single sample gene set enrichment analysis.