FIGURE 1 CONSORT diagram and patient disposition. DLT, dose-limiting toxicity; RP2D, recommended phase II dose; P, pembrolizumab; C, cabozantinib. More about this image found in CONSORT diagram and patient disposition. DLT, dose-limiting toxicity; RP2D,...

FIGURE 2 Clinical activity of pembrolizumab and cabozantinib. A, Best percent change from baseline as measured by RECIST 1.1 in all evaluable patients from both phase I and phase II (N = 43). B, Swimmer plot of time on treatment in months for in all evaluable patients from both phase I and phase II (N = 43). ccRCC, clear-cell renal cell carcinoma; nccRCC, non-clear cell renal cell carcinoma; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. More about this image found in Clinical activity of pembrolizumab and cabozantinib. A, Best percent chan...

FIGURE 3 Kaplan–Meier curves of PFS ( A ) and OS ( B ) for all patients treated at the RP2D of pembrolizumab 200 mg i.v. every 3 weeks and cabozantinib 60 mg orally once daily (N = 40). Vertical lines show censored patients. More about this image found in Kaplan–Meier curves of PFS ( A ) and OS ( B ) for all patients treated at t...

FIGURE 1 Schematic of study design and patient deposition. A, Treatment regimen. B, Patient deposition per Consolidated Standards of Reporting Trials guidelines. More about this image found in Schematic of study design and patient deposition. A, Treatment regimen. ...

FIGURE 2 Characteristics of iNKT cells and PD-1⁺CD8⁺ T cells in the cell products were assessed by flow cytometry. A, Gating strategy of iNKT cells identified as CD3⁺TCR Vα24⁺ cells in PBMCs (left) and in cell products after expansion (right). B, The purity of iNKT cells as a percentage in CD3⁺ T cells before and after expansion ex vivo (paired t test). C, Gating strategy of PD-1⁺CD8⁺ T cells. PD-1 FMO was applied to rigorously define the PD-1⁺ cells. D, Memory status of PD-1⁺CD8⁺ T cells before (orange) and after expansion ex vivo (blue) by staining CD27 and CD45RA on cell membrane. E, Staining of CXCR3 and CXCR4 on PD-1⁺CD8⁺ T cells before (orange) and after expansion (blue). More about this image found in Characteristics of iNKT cells and PD-1⁺CD8⁺ T cells i...

FIGURE 3 Clinical records and detections. A, The body temperature of patients recorded each hour for 20 hours after cell infusion. All the records in 59 courses are included here in gray. The mean temperature in each timepoint is shown in black bold. Changes in tumor markers CA19-9 in serum during cellular therapy were shown in B . Impact of cell infusion on the cytokines in serum and key populations of lymphocytes in PBMCs. Quantification of Th1/2/17 cytokines in plasma after cell infusion were analyzed by CBA. All results are displayed in C . Change of IL6 in serum over time are shown in D , on which red dots indicated elevated IL6 levels post infusion. Change of IL6 (left) and IL17A (right) during treatment are shown in E . Changing percentage of CD4⁺ T, CD8⁺ T, B, and NK cells during treatment are assessed by flow cytometry, and data relative to baseline are shown in F , G , H , and I , respectively. Changes in number of IFNγ-secreting cells responding to α-Galcer were also recorded using ELISPOT and are shown in J with increased IFNγ-secreting cells responding to α-Galcer in some patients (solid) and not in others (dotted). More about this image found in Clinical records and detections. A, The body temperature of patients reco...

FIGURE 4 Clinical response and OS data. A, Waterfall plot showing best overall change in sum of diameter of tumor lesions for each patient. Change in sum of tumor diameters by RECIST is compared with baseline. Representative CT images of patient 001 and patient 002 with PR of the sum of lesions ... More about this image found in Clinical response and OS data. A, Waterfall plot showing best overall cha...

FIGURE 1 Schematic of the deconvolution workflow. Diagram of normal OE in the top left colored by cell identity (HBC: yellow; GBC: pink; immature OSN: blue; mature OSN: orange; Sustentacular: green; Bowman's Gland: purple; Olfactory ensheating cell:lime green in lamina propria; immune cells: round... More about this image found in Schematic of the deconvolution workflow. Diagram of normal OE in the top le...

FIGURE 2 Pseudodeconvolution of ONB bulk RNA-seq defines proportions of cell type–specific transcriptomics across low- and high-grade tumors. A, Stacked bar chart depicts predicted proportions of cell types in bulk tumors when mapped to control adult human olfactory mucosa using the deconvolution model. B, Statistical differences in selected ONB cellular composition, based on one-way ANOVA followed by post hoc Tukey test (*, P < 0.05; **, P < 0.01). More about this image found in Pseudodeconvolution of ONB bulk RNA-seq defines proportions of cell type–sp...

FIGURE 3 Patterns of gene expression in the normal differentiating OE. A, Trajectory UMAP depicting differentiation states across pseudotime, in seven normal olfactory mucosa biopsies scRNA-seq from Durante and colleagues, 2020 and Oliva and colleagues, 2021 ( 13, 24 ). B, Heat map showing can... More about this image found in Patterns of gene expression in the normal differentiating OE. A, Trajecto...

FIGURE 4 PRC2 complex expression in ONB. A, PRC2 transcripts in the core complex are mostly upregulated in high-grade ONB. B, EPOP expression is significantly increased in high-grade ONB compared with low grade, with no differences between low and high grade in proteins that form the PRC2.2 complex. For A and B, statistical significance assessed by Kruskal–Wallis test with post hoc Dunn test for multiple comparisons (*, P < 0.05; **, P < 0.01). C, EZH2 is present in basal cells and immature neurons (TUJ1⁺) but not in mature neurons (OMP⁺) in the normal human OE. D, Immunohistochemically, Ki-67⁺ cells are nearly uniformly positive for EZH2 and EED in a grade I ONB. Scale bars in C and D are 50 μm. More about this image found in PRC2 complex expression in ONB. A, PRC2 transcripts in the core complex a...

FIGURE 5 Glandular and olfactory ensheathing cell markers are present in low-grade ONB and are associated with increased survival. A, UMAP visualization of non-tumor olfactory mucosa scRNA-seq data depicts the cell type–specific expression of selected transcripts. PLP1 and S100B are expressed in olfactory ensheathing cells (OEC, red arrow); SOX9 is highly expressed in Bowman's glands (black arrow) and the TRPM5⁺ subset of microvillar cells (blue arrow). Scale bar shows normalized counts. B, Kaplan–Meier survival curves showing significant survival advantage in ONB tumors with higher expression of Bowman's gland and OEC markers. Statistical significance determined by log-rank test. C, SOX9⁺ cells are rarely Ki-67⁺ and do not colocalize with SOX2. In contrast, some SOX2⁺ cells show evidence of proliferation based on Ki-67 staining (arrowheads). D, The presence of S100B⁺ cells in a grade I ONB. Ki-67 costaining confirms the presence of the occasional proliferative S100B⁺ cell (arrowhead). In A, resp = respiratory; RBC = red blood cell; sus = sustentacular; in C and D, scale bar = 50 μm. More about this image found in Glandular and olfactory ensheathing cell markers are present in low-grade O...