Figure 4.
Microenvironmental dynamics during anti-PD1 therapy. (A) Volcano plot showing the most significant changes in gene expression comparing rebiopsies with pretreatment Hodgkin lymphoma (HL) samples, using the NanoString PanCancer Immune Profiling Panel. The fold change of gene expression (FC) is plotted against the P value. Genes highlighted in red have an FC < −2 and a P value < .05, whereas genes highlighted in yellow have an FC > 2 and a P value < .05. The graph also shows the expression changes of a group of known HRSC genes. (B) Most significant differentially expressed genes comparing rebiopsies with pretreatment samples. (C) Analysis of gene-expression changes for a group of genes associated with the Tr1 phenotype (left panel), for FoxP3 as a marker for Tregs (middle panel), and for macrophage genes (right panel) in samples from reactive lymph nodes (LN), HL pretreatment samples, and the relative rebiopsies. *P < .05, **P < .005, Student t test. (D) WSI analysis of CD68 and PD-L1 in HL pretreatment samples and the relative rebiopsies. The difference in CD68 expression was not significant, whereas PD-L1 showed a significant reduction in expression (P = .0276, 2-tailed paired Student t test). Red lines represent the mean values. (E) Analysis of gene-expression changes for PDCD1 (PD1) and CD274 (PD-L1) in paired samples from a r/r cHL cohort with progressive disease/relapse during anti-PD1 therapy. *P < .05, Student t test. (F) Immunohistochemical image analysis of PD1 and PD-L1 in samples from the same cohort as in (E). Increase in PD1+ staining was analyzed by WSI and was not significant (P = .0667, 2-tailed paired Student t test). PD-L1 was analyzed on image sections by manually removing HRSCs in the program before analysis, and measuring of PD-L1 staining was only done on macrophages. The decrease in PD-L1 staining was significant (P = .0184, 2-tailed paired Student t test). Red lines are mean values. Representative images of HRSCs and surrounding TME in r/r cHL samples with progressive disease/relapse during anti-PD1 therapy stained with an anti-PD1 (G-H) or an anti–PD-L1 (I-J) antibody. (G,I) r/r cHL prior to anti-PD1 treatment. (H,J) Relapse during anti-PD1 treatment. Scale bars, 25 µm. ns, not significant.

Microenvironmental dynamics during anti-PD1 therapy. (A) Volcano plot showing the most significant changes in gene expression comparing rebiopsies with pretreatment Hodgkin lymphoma (HL) samples, using the NanoString PanCancer Immune Profiling Panel. The fold change of gene expression (FC) is plotted against the P value. Genes highlighted in red have an FC < −2 and a P value < .05, whereas genes highlighted in yellow have an FC > 2 and a P value < .05. The graph also shows the expression changes of a group of known HRSC genes. (B) Most significant differentially expressed genes comparing rebiopsies with pretreatment samples. (C) Analysis of gene-expression changes for a group of genes associated with the Tr1 phenotype (left panel), for FoxP3 as a marker for Tregs (middle panel), and for macrophage genes (right panel) in samples from reactive lymph nodes (LN), HL pretreatment samples, and the relative rebiopsies. *P < .05, **P < .005, Student t test. (D) WSI analysis of CD68 and PD-L1 in HL pretreatment samples and the relative rebiopsies. The difference in CD68 expression was not significant, whereas PD-L1 showed a significant reduction in expression (P = .0276, 2-tailed paired Student t test). Red lines represent the mean values. (E) Analysis of gene-expression changes for PDCD1 (PD1) and CD274 (PD-L1) in paired samples from a r/r cHL cohort with progressive disease/relapse during anti-PD1 therapy. *P < .05, Student t test. (F) Immunohistochemical image analysis of PD1 and PD-L1 in samples from the same cohort as in (E). Increase in PD1+ staining was analyzed by WSI and was not significant (P = .0667, 2-tailed paired Student t test). PD-L1 was analyzed on image sections by manually removing HRSCs in the program before analysis, and measuring of PD-L1 staining was only done on macrophages. The decrease in PD-L1 staining was significant (P = .0184, 2-tailed paired Student t test). Red lines are mean values. Representative images of HRSCs and surrounding TME in r/r cHL samples with progressive disease/relapse during anti-PD1 therapy stained with an anti-PD1 (G-H) or an anti–PD-L1 (I-J) antibody. (G,I) r/r cHL prior to anti-PD1 treatment. (H,J) Relapse during anti-PD1 treatment. Scale bars, 25 µm. ns, not significant.

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