PMC7446533_01
Radiologic and clinical course of disease. (A) Contrasted computed tomography scans of the chest, abdomen, and pelvis show a metastatic lesion within the right adrenal gland (arrow) before initiation of anti-programmed death ligand 1 (PD-L1) therapy (panel A1), which regressed after 16 cycles of treatment with anti-PD-L1 therapy (panel A2). Repeat computed tomography imaging demonstrated progressive disease in the right adrenal gland before initiation of anti-PD-1 therapy (panel A3), with subsequent improvement after 9 months of anti-PD-1 therapy (panel A4). (B) Timeline of therapies. (C) Sites of biopsies and summary of PD-L1/programmed death ligand 2 (PD-L2) staining. CCRT, concurrent radiotherapy; LNs, lymph nodes; NA, not available.
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Imaging of the face after 6 weeks showed a PR in the RP space, and body imaging after 8 weeks of treatment showed a PR in both the right axilla and right adrenal gland (Fig 1A). Biopsy samples were obtained at the time of diagnosis (biopsy 1), before repeat treatment with anti-PD-L1 (biopsy 2), before treatment with anti-PD-1 (biopsy 3), and after progression anti-PD-1 therapy (biopsy 4; Fig 1B). After his initial disease progression while receiving anti-PD-L1 therapy, repeat biopsy demonstrated no tumor PD-L1 staining (with limited stromal PD-L1 positivity), and PD-L2 remained strongly positive (70%; Fig 1C).
Histology of longitudinal specimens. Representative immunohistochemistry images at pretherapy (biopsy 1), and post-therapy (before second anti-programmed death ligand 1 [PD-L1] course; post-PD-L1 therapy A; biopsy 2), at progression/resistance to PD-L1 therapy (before response to nivolumab; post-PD-L1 therapy B; biopsy 3), and at nivolumab resistance (postnivolumab; biopsy 4). H&E, hematoxylin and eosin; PD-L2, programmed death ligand 2.
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Representative immunohistochemistry samples from each time point are shown in Figure 2.
Molecular analysis of longitudinal tumor specimens. (A) RNA collected from archival tissue blocks were analyzed by nanoString PanCancer Immune Profiling (730 immune-related genes). Normalized data were compared between the post-therapy A (preresistance) and post-therapy B (postresistance) specimens for log2 fold change. Fold change for genes altered by > 2 log2 units (four-fold change) are shown. (B) Genes involved in the interferon-gamma signaling reactome (www.reactome.org; accession: M965) were selected from the PanCancer Immune Profiling gene set and plotted by fold change. This analysis demonstrated a general decrease in interferon-gamma signaling within the tumor microenvironment at disease progression on anti-programmed death ligand 1 (PD-L1). (C) Simplified schematic of known PD-L1/programmed death ligand 2 (PD-L2) interactions. PD-L1 interacts with programmed death 1 (PD-1) and B7-1 (CD80) to promote immune effector cell suppression, whereas PD-L2 can bind PD-1 and RGMb, promoting effector suppression and respiratory tolerance in lung-resident macrophages, respectively. APCs, antigen-presenting cells; COX2, cyclooxygenase-2.
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IL6 and PTGS2 (cyclooxygenase-2; Fig 3A). Interferon-gamma-responsive genes demonstrated a global downregulation in the resistant sample, consistent with the predicted effects of a decrease in T-cell activity in the tumor microenvironment (Fig 3B).