bluuebunny/crossref_metadata_2025 huggingface dataset:
Table S3 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: August 2023

Supplementary Table 3: IC50 values for PF-07284892 in cell-based assays
Figure 4 from Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma
Authors: Gopal Raj K. , Vantaku Venkata R. , Panda Apekshya , Reimer Bryn , Rath Sneha , To Tsz-Leung , Fisch Adam S. , Cetinbas Murat , Livneh Maia , Calcaterra Michael J. , Gigliotti Benjamin J. , Pierce Kerry A. , Clish Clary B. , Dias-Santagata Dora , Sadow Peter M. , Wirth Lori J. , Daniels Gilbert H. , Sadreyev Ruslan I. , Calvo Sarah E. , Parangi Sareh , Mootha Vamsi K.
Published: August 2023

Genetics and biochemistry of authentic HCC models. A, Table of mtDNA mutation status and nuclear karyotype of HCC (MGH-HCC1 and NCI-HCC) and normal thyroid (Nthy-ori 3-1; immortalized via SV40 transfection) cell lines. N/A, not applicable. B, Normalized enzymatic activity of complex I and complex IV from cell lines. Mean ± SD; n = 3 from one experiment. C, Normalized cell number in media ± pyruvate. Mean ± SD; n = 2, representative of two experiments. D, OCR and extracellular acidification rate (ECAR) of cell lines from the Seahorse XFe96 Analyzer. Dotted vertical lines show drug injections. Mean ± SD; n = 8–10, representative of 3 experiments. E, Normalized cell number of cell lines in glucose (Glu) or galactose (Gal) ± antimycin. Mean ± SD; n = 3, representative of 3 experiments. F, Tumor volumes (mm3) of NCI-HCC xenografts over time. Mean ± SD; n = 3 from 1 experiment. G and H, H&E (G; scale bar, 100 μm) and EM (H; scale bar, 800 nm) from NCI-HCC xenograft. For B, C, and E, significance tested with an unpaired t test: *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001; ns, P > 0.05. See also Supplementary Fig. S4.
Table S2 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: August 2023

Supplementary Table 2: Phosphatase Profiling of PF-07284892
Figure 3 from Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma
Authors: Gopal Raj K. , Vantaku Venkata R. , Panda Apekshya , Reimer Bryn , Rath Sneha , To Tsz-Leung , Fisch Adam S. , Cetinbas Murat , Livneh Maia , Calcaterra Michael J. , Gigliotti Benjamin J. , Pierce Kerry A. , Clish Clary B. , Dias-Santagata Dora , Sadow Peter M. , Wirth Lori J. , Daniels Gilbert H. , Sadreyev Ruslan I. , Calvo Sarah E. , Parangi Sareh , Mootha Vamsi K.
Published: August 2023

Metabolic signatures of HCC. A, PCA of metabolomics from four mass spectrometry methods in HCC (n = 20) and normal thyroid (n = 14). Hashimoto's, Hashimoto thyroiditis; Min CNV, minimum copy-number variation. B, Volcano plot showing fold change (HCC/normal; x-axis) and adjusted P value (y-axis), with metabolites annotated by name and color. CMP, cytidine monophosphate; IMP, inosine monophosphate. C, Differential abundance of lipids organized by class and sorted by the number of carbons with double bonds (color) and adjusted P values (dot size). Cera, ceramide; DAG, diacylglycerol; LPC, lysoPC; PC, phosphatidylcholine; PE, phosphatidylethanolamine; pls, plasmalogen; SM, sphingomyelin. D, Normalized expression and abundance for enzymes and their metabolic products, respectively, with adjusted P values. Horizontal lines show the mean, and boxes show the standard deviation. See also Supplementary Fig. S3.
Figure 2 from Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma
Authors: Gopal Raj K. , Vantaku Venkata R. , Panda Apekshya , Reimer Bryn , Rath Sneha , To Tsz-Leung , Fisch Adam S. , Cetinbas Murat , Livneh Maia , Calcaterra Michael J. , Gigliotti Benjamin J. , Pierce Kerry A. , Clish Clary B. , Dias-Santagata Dora , Sadow Peter M. , Wirth Lori J. , Daniels Gilbert H. , Sadreyev Ruslan I. , Calvo Sarah E. , Parangi Sareh , Mootha Vamsi K.
Published: August 2023

Transcriptomic landscape of HCC. A, PCA of HCC and normal thyroid (n = 18 each) RNA-seq. Hashimoto's, Hashimoto thyroiditis; Min CNV, minimum copy-number variation. B, Schematic of HCC clinical features with violin plots of gene expression fold changes (HCC/normal) for related molecular pathways. mtRNA, mitochondrial RNA; TDS, thyroid differentiation score. Significance tested by the Kolmogorov–Smirnov test: **, P < 1.0E−03; ***, P < 1.0E−04; ****, P < 1.0E−05. C, Normalized gene expression for transcripts with adjusted P values. D, Gene set enrichment analysis (GSEA) of the KEGG and HALLMARK pathways ranked by enrichment score with shaded FWER values. (H), HALLMARK gene set; metab, metabolism. E, IHC for proteins from selected pathways in HCC and normal thyroid; scale bars, 200 μm. F, Normalized gene expression for transcripts from selected pathways with adjusted P values. “Synthetic sick genes” refers to knockouts that were synthetic sick with OXPHOS dysfunction (35). Horizontal lines show the mean, and boxes show the standard deviation. See also Supplementary Fig. S2.
Figure 1 from Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma
Authors: Gopal Raj K. , Vantaku Venkata R. , Panda Apekshya , Reimer Bryn , Rath Sneha , To Tsz-Leung , Fisch Adam S. , Cetinbas Murat , Livneh Maia , Calcaterra Michael J. , Gigliotti Benjamin J. , Pierce Kerry A. , Clish Clary B. , Dias-Santagata Dora , Sadow Peter M. , Wirth Lori J. , Daniels Gilbert H. , Sadreyev Ruslan I. , Calvo Sarah E. , Parangi Sareh , Mootha Vamsi K.
Published: August 2023

An HCC cohort with complex I mtDNA mutations and chromosomal losses. A, Clinical cohort of HCC and normal thyroid samples with profiling methods used. CGH, comparative genomic hybridization; primary, primary tumor. B, Mutations in mtDNA organized by complex with allelic fraction >0.2 with CGH-SNP array copy-number profile. See also Supplementary Fig. S1.
Figure S7 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: August 2023

Supplementary Figure 7: PF-07284892 sensitizes a patient with GOPC-ROS1 fusion-positive pancreatic cancer to lorlatinib
Figure S6 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: August 2023

Supplementary Figure 6: PK profiles for patients
Figure S5 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: August 2023

Supplementary Figure 5: Study schema
Supplementary Table 2 from The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study
Authors: LoRusso Patricia , Yamamoto Noboru , Patel Manish R. , Laurie Scott A. , Bauer Todd M. , Geng Junxian , Davenport Teffany , Teufel Michael , Li Jian , Lahmar Mehdi , Gounder Mrinal M.
Published: August 2023

Most common any-cause adverse events by highest CTCAE grade with BI 907828 monotherapy
Figure S4 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: August 2023

Supplementary Figure 4: PF-07284892 combination efficacy in additional oncogenic driver-positive mouse cancer models and monotherapy PK/PD
Figure S2 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: August 2023

Supplementary Figure 2: Intermittent dosing of PF-07284892 preserves efficacy and improves tolerability preclinically
Supplementary Figure 2 from The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study
Authors: LoRusso Patricia , Yamamoto Noboru , Patel Manish R. , Laurie Scott A. , Bauer Todd M. , Geng Junxian , Davenport Teffany , Teufel Michael , Li Jian , Lahmar Mehdi , Gounder Mrinal M.
Published: August 2023

Time on treatment and PFS in all patients enrolled to phase Ia
Supplementary Figure 1 from The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study
Authors: LoRusso Patricia , Yamamoto Noboru , Patel Manish R. , Laurie Scott A. , Bauer Todd M. , Geng Junxian , Davenport Teffany , Teufel Michael , Li Jian , Lahmar Mehdi , Gounder Mrinal M.
Published: August 2023

GDF-15 fold change from baseline for dose-escalation cohorts receiving BI 907828 D1q3w and BI 907828 D1D8q4w
Supplementary Table S1 from Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia
Authors: Kan Winnie L. , Dhagat Urmi , Kaufmann Kerstin B. , Hercus Timothy R. , Nero Tracy L. , Zeng Andy G.X. , Toubia John , Barry Emma F. , Broughton Sophie E. , Gomez Guillermo A. , Benard Brooks A. , Dottore Mara , Cheung Tung Shing Karen S. , Boutzen Héléna , Samaraweera Saumya E. , Simpson Kaylene J. , Jin Liqing , Goodall Gregory J. , Begley C. Glenn , Thomas Daniel , Ekert Paul G. , Tvorogov Denis , D'Andrea Richard J. , Dick John E. , Parker Michael W. , Lopez Angel F.
Published: August 2023

Data collection and refinement statistics for the IL-3R ternary complex crystal structure.
Table S8 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Comparisons in cell type proportions predicted by RCTD between LG and HGPDAC epilesional, jutxalesional, and perilesional spots.
Figure S7 from Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia
Authors: Kan Winnie L. , Dhagat Urmi , Kaufmann Kerstin B. , Hercus Timothy R. , Nero Tracy L. , Zeng Andy G.X. , Toubia John , Barry Emma F. , Broughton Sophie E. , Gomez Guillermo A. , Benard Brooks A. , Dottore Mara , Cheung Tung Shing Karen S. , Boutzen Héléna , Samaraweera Saumya E. , Simpson Kaylene J. , Jin Liqing , Goodall Gregory J. , Begley C. Glenn , Thomas Daniel , Ekert Paul G. , Tvorogov Denis , D'Andrea Richard J. , Dick John E. , Parker Michael W. , Lopez Angel F.
Published: August 2023

Increasing IL3Rα/βc ratios and enforced hexamer signaling lead to reduced differentiation in in vivo engraftments.
Table S7 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Differentially expressed genes between LG, HG, and PDAC samples per region.
Figure S6 from Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia
Authors: Kan Winnie L. , Dhagat Urmi , Kaufmann Kerstin B. , Hercus Timothy R. , Nero Tracy L. , Zeng Andy G.X. , Toubia John , Barry Emma F. , Broughton Sophie E. , Gomez Guillermo A. , Benard Brooks A. , Dottore Mara , Cheung Tung Shing Karen S. , Boutzen Héléna , Samaraweera Saumya E. , Simpson Kaylene J. , Jin Liqing , Goodall Gregory J. , Begley C. Glenn , Thomas Daniel , Ekert Paul G. , Tvorogov Denis , D'Andrea Richard J. , Dick John E. , Parker Michael W. , Lopez Angel F.
Published: August 2023

Increasing IL3Rα/βc ratios lead to hexameric receptor assembly and augmented quiescence.
Figure S5 from Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia
Authors: Kan Winnie L. , Dhagat Urmi , Kaufmann Kerstin B. , Hercus Timothy R. , Nero Tracy L. , Zeng Andy G.X. , Toubia John , Barry Emma F. , Broughton Sophie E. , Gomez Guillermo A. , Benard Brooks A. , Dottore Mara , Cheung Tung Shing Karen S. , Boutzen Héléna , Samaraweera Saumya E. , Simpson Kaylene J. , Jin Liqing , Goodall Gregory J. , Begley C. Glenn , Thomas Daniel , Ekert Paul G. , Tvorogov Denis , D'Andrea Richard J. , Dick John E. , Parker Michael W. , Lopez Angel F.
Published: August 2023

Enrichment of the IL-3R hexamer versus dodecamer gene signature in primitive normal and leukemic stem cells.
Table S5 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Differentially expressed genes between LG and HGPDAC juxtalesional spots.
Figure S4 from Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia
Authors: Kan Winnie L. , Dhagat Urmi , Kaufmann Kerstin B. , Hercus Timothy R. , Nero Tracy L. , Zeng Andy G.X. , Toubia John , Barry Emma F. , Broughton Sophie E. , Gomez Guillermo A. , Benard Brooks A. , Dottore Mara , Cheung Tung Shing Karen S. , Boutzen Héléna , Samaraweera Saumya E. , Simpson Kaylene J. , Jin Liqing , Goodall Gregory J. , Begley C. Glenn , Thomas Daniel , Ekert Paul G. , Tvorogov Denis , D'Andrea Richard J. , Dick John E. , Parker Michael W. , Lopez Angel F.
Published: August 2023

The IL-3R dodecamer activates STAT1 to induce cell differentiation.
Table S3 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

RCTD cell type prediction for all spots in the IPMN ST dataset
Table S24 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Protein panel used for the COMET protocol for cyclic immunofluorescent staining.
Table S23 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Differentially expressed genes by overexpressing NKX6-2 in both the Kras;Gnas and KPC cell lines.
Table S22 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Differentially expressed genes between NKX6-2 overexpressing and control KPC cell lines.
Table S21 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Overlap between genes differentially expressed in the NKX6-2 overexpressing and control Kras;Gnas cell line and genes differentially expressed in NKX6-2 positive and negative epilesional spots from the human LG IPMN dataset.
Table S20 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Overlap between genes differentially expressed in the NKX6-2 overexpressing and control Kras;Gnas cell line and genes differentially expressed in Nkx6-2 positive and negative spots from the Kras;Gnas ST epithelial spots.
Supplementary Tables S1-S12 from Targeting N-linked Glycosylation for the Therapy of Aggressive Lymphomas
Authors: Scheich Sebastian , Chen Jiji , Liu Jiamin , Schnütgen Frank , Enssle Julius C. , Ceribelli Michele , Thomas Craig J. , Choi Jaewoo , Morris Vivian , Hsiao Tony , Nguyen Hang , Wang Boya , Bolomsky Arnold , Phelan James D. , Corcoran Sean , Urlaub Henning , Young Ryan M. , Häupl Björn , Wright George W. , Huang Da Wei , Ji Yanlong , Yu Xin , Xu Weihong , Yang Yandan , Zhao Hong , Muppidi Jagan , Pan Kuan-Ting , Oellerich Thomas , Staudt Louis M.
Published: August 2023

Table S1. Brunello library sgRNA normalized read counts of IRF4 sorted CRISPR screens. Table S2. Segregation score of IRF4 sorted CRISPR screens. Table S3. Glycoproteomics in STT3A or STT3B KO cells. Table S4. Brunello sgRNA Library Normalized Read Counts of CRISPR screens. Table S5. CRISPR screen score of essentiality screens. Table S6. Glycoproteomics after NGI-1 treatment. Table S7.HBL1 and TMD8 Phosphotyrosone Phosphoproteome (pYome). Table S8. TMD8 CD79A-BioID. Table S9. HBL1 CD22 BioID. Table S10. Brunello library sgRNA normalized read counts of NGI-1 drug modified screen (TMD8). Table S11. CRISPR screen score of NGI-1 drug modifier screen. Table S12. TMD8 Drug screen Excess HSA.
Table S18 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Differentially expressed genes between Nkx6-2 positive and negative spots in the Kras;Gnas ST epithelial spots.
Supplementary Figures S1-10 from Targeting N-linked Glycosylation for the Therapy of Aggressive Lymphomas
Authors: Scheich Sebastian , Chen Jiji , Liu Jiamin , Schnütgen Frank , Enssle Julius C. , Ceribelli Michele , Thomas Craig J. , Choi Jaewoo , Morris Vivian , Hsiao Tony , Nguyen Hang , Wang Boya , Bolomsky Arnold , Phelan James D. , Corcoran Sean , Urlaub Henning , Young Ryan M. , Häupl Björn , Wright George W. , Huang Da Wei , Ji Yanlong , Yu Xin , Xu Weihong , Yang Yandan , Zhao Hong , Muppidi Jagan , Pan Kuan-Ting , Oellerich Thomas , Staudt Louis M.
Published: August 2023

Supplemental Figure 1. IRF4-GFP knock-in reporter cell lines. Supplemental Figure 2. IRF4-GFP CRISPR screen in adult T-cell lymphoma and screen controls. Supplemental Figure 3. The OST is essential for DLBCL. Supplemental Figure 4. The role of the OST complex in radiation chimeras. Supplemental Figure 5. The B-cell receptor is glycosylated by the OST complex. Supplemental Figure 6. B-cell receptor deglycosylation leads to higher surface expression. Supplemental Figure 7. B-cell receptor deglycosylation leads to signaling changes in proximal BCR signaling components. Supplemental Figure 8. BCR deglycosylation leads to recruitment of CD22 on the cell surface to the BCR and signaling alterations in GCB DLBCL. Supplemental Figure 9. BCR internalization and My-T-BCR formation in glycosylation deficient cells. Supplemental Figure 10. NGI-1 synergizes with BTK and PI3K inhibitors.
Table S15 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Predicted NKX6-2 targets and transcription factors associated with NKX6-2 expression evaluated by GENIE3.
Table S14 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Genes included in the GIP signature with their corresponding GSEA gene sets and enrichment scores.
Table S13 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Correlation between percentage of NKX6-2 positive nuclei and GATA-6, MUC5AC, TFF1, and VIM protein expression.
Table S10 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Quantification of cell phenotypes in the IPMN microenvironment based on COMET data.
Table S1 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Table containing demographic and clinical patient information
Supporting methods from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Additional details of the Lunaphore COMET protocol and assay information.
Supplementary Figures S1-S13 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: August 2023

Figure S1. Spatial maps showing number of genes detected per spot in the 13 samples used for spatial transcriptomics analyses. Figure S2. A) Uniform Manifold Approximation and Projection (UMAP) of all spots collected from the 13 samples by ST. Figure S3. A) Violin plot showing expression of CDX2 and MUC2 in the epilesional compartments of IPMN and PDAC samples. Figure S4. Cell type proportions in LG and HR IPMN compartments determined by RCTD deconvolution. Figure S5. COMET cyclic IF imaging of IPMN. Figure S6. NKX6-2 levels determined by ST and COMET analyses conducted on tissue samples from the same patient. Figure S7. NKX6-2 expression in LG IPMN samples and its associated signature. Figure S8. A) Enrichment plots for gastric REG3A positive cells, main fetal acinar cells, pancreas acinar cells, and ductal cells obtained via GSEA analyses. Figure S9. Spatial transcriptomic analyses of a murine model of IPMN. Figure S10. A) Gene set enrichment analyses (GSEA) of differentially expressed cell type signatures between Nkx6-2+ and Nkx6-2 – spots in the Gnas;Kras mice samples. Figure S11. Nkx6-2 overexpression in a Kras;Gnas cell line. Figure S12. Nkx6-2 overexpression in KPC cell lines. Figure S13. Quantification of the percentage of glandular structures in the tumors derived from Kras;GnasNkx6-2 or control cell lines in littermate (Kras;Gnas, left) mice or immunodeficient nude mice (NuJ, right).
Supplementary Tables S1-S2 from Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma
Authors: Lee Juyeun , Nicosia Michael , Hong Ellen S. , Silver Daniel J. , Li Cathy , Bayik Defne , Watson Dionysios C. , Lauko Adam , Kay Kristen E. , Wang Sabrina Z. , Johnson Sadie , McGraw Mary , Grabowski Matthew M. , Kish Danielle D. , Desai Amar B. , Goodman Wendy A. , Cameron Scott J. , Okada Hideho , Valujskikh Anna , Fairchild Robert L. , Ahluwalia Manmeet S. , Lathia Justin D.
Published: August 2023

Table S1. qPCR primers used for mouse study
Table S2. qPCR primers used for human study
Supplementary Figures S1-S16 from Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma
Authors: Lee Juyeun , Nicosia Michael , Hong Ellen S. , Silver Daniel J. , Li Cathy , Bayik Defne , Watson Dionysios C. , Lauko Adam , Kay Kristen E. , Wang Sabrina Z. , Johnson Sadie , McGraw Mary , Grabowski Matthew M. , Kish Danielle D. , Desai Amar B. , Goodman Wendy A. , Cameron Scott J. , Okada Hideho , Valujskikh Anna , Fairchild Robert L. , Ahluwalia Manmeet S. , Lathia Justin D.
Published: August 2023

Supplementary Fig. S1. Immune cell-dependent survival differences between males and females in murine glioblastoma models.
Supplementary Fig. S2. Mouse syngeneic GBM cell lines do not contain a Y chromosome.
Supplementary Fig. S3. Frequencies of tumor-infiltrating immune cells in SB28 model.
Supplementary Fig. S4. Sex difference in survival in SB28-OVA model and GL261 model.
Supplementary Fig. S5. No sex difference in T cells was observed at an earlier time point.
Supplementary Fig. S6. Male T cells are more exhausted in the GL261 model.
Supplementary Fig. S7. Phenotype of T cells in the periphery does not replicate the sex differences shown in tumor-infiltrating T cells.
Supplementary Fig. S8. Frequencies of exhausted T cell subsets.
Supplementary Fig. S9. PD1 blockade enhanced immune responses
Supplementary Fig. S10. No significant difference in the immune cell composition of bone marrow chimera mice before tumor implantation.
Supplementary Fig. S11. Male and female CD8+ T cells in mixed bone marrow chimera model.
Supplementary Fig. S12. Phenotyping tumor-infiltrating CD8+ T cell from GBM patient tumors.
Supplementary Fig. S13. scRNA-seq analysis of tumor-infiltrating CD8+ T cells from GBM patients.
Supplementary Fig. S14. mRNA expression level of transcription factors in human in vitro exhausted T cells.
Supplementary Fig. S15. Expression level of X chromosome inactivation (XCI) genes in exhausted T cells.
Supplementary Fig. S16. Inhibition of UTX abrogates sex differences in T cell exhaustion.
Supplementary Table 1 from The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer
Authors: Van Emmenis Lucie , Ku Sheng-Yu , Gayvert Kaitlyn , Branch Jonathan R. , Brady Nicholas J. , Basu Subhasree , Russell Michael , Cyrta Joanna , Vosoughi Aram , Sailer Verena , Alnajar Hussein , Dardenne Etienne , Koumis Elena , Puca Loredana , Robinson Brian D. , Feldkamp Michael D. , Winkis Annmarie , Majewski Nathan , Rupnow Brent , Gottardis Marco M. , Elemento Olivier , Rubin Mark A. , Beltran Himisha , Rickman David S.
Published: August 2023

Supplementary Table 1. DESeq2 results of all the pairwise comparisons of the tissue groups outlined in Figure 1.
Supplementary Figure 3 from The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer
Authors: Van Emmenis Lucie , Ku Sheng-Yu , Gayvert Kaitlyn , Branch Jonathan R. , Brady Nicholas J. , Basu Subhasree , Russell Michael , Cyrta Joanna , Vosoughi Aram , Sailer Verena , Alnajar Hussein , Dardenne Etienne , Koumis Elena , Puca Loredana , Robinson Brian D. , Feldkamp Michael D. , Winkis Annmarie , Majewski Nathan , Rupnow Brent , Gottardis Marco M. , Elemento Olivier , Rubin Mark A. , Beltran Himisha , Rickman David S.
Published: August 2023

Supplementary Figure 3. A. Western blot analysis results showing the expression of CELSR3 following CELSR3 or GFP knock-out in the indicated NEPC PDO xenograft tumors for each of the mice (m) that were part of the experiment as described for Figure 3. B. Graphic representation of the percentage of orthotopic NEPC PDO xenograft clones that were engineered with either sgCELSR3 or sgGFP CRISPR-Cas9 that formed macro-metastatic lesions at the indicated region of the mice. C. and D. H&E and IHC staining of the indicated markers.
Supplementary Figure 2 from The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer
Authors: Van Emmenis Lucie , Ku Sheng-Yu , Gayvert Kaitlyn , Branch Jonathan R. , Brady Nicholas J. , Basu Subhasree , Russell Michael , Cyrta Joanna , Vosoughi Aram , Sailer Verena , Alnajar Hussein , Dardenne Etienne , Koumis Elena , Puca Loredana , Robinson Brian D. , Feldkamp Michael D. , Winkis Annmarie , Majewski Nathan , Rupnow Brent , Gottardis Marco M. , Elemento Olivier , Rubin Mark A. , Beltran Himisha , Rickman David S.
Published: August 2023

Supplementary Figure 2. Percentage of RHAMM positive cells that were detected using IHC in the indicate tumor type or benign prostate tissue.
Supplementary Figure 1 from The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer
Authors: Van Emmenis Lucie , Ku Sheng-Yu , Gayvert Kaitlyn , Branch Jonathan R. , Brady Nicholas J. , Basu Subhasree , Russell Michael , Cyrta Joanna , Vosoughi Aram , Sailer Verena , Alnajar Hussein , Dardenne Etienne , Koumis Elena , Puca Loredana , Robinson Brian D. , Feldkamp Michael D. , Winkis Annmarie , Majewski Nathan , Rupnow Brent , Gottardis Marco M. , Elemento Olivier , Rubin Mark A. , Beltran Himisha , Rickman David S.
Published: August 2023

Supplementary Figure 1. A. Log fold change ratio (y axis) and mean average expression (x axis) for each gene expression measurements from the bulk RNA-seq data from NEPC tumors compared to locally advanced prostate cancer (PCa) in two samples across all genes (left) or stratified by the indicated annotations for the encoded proteins (right). B. CELSR3 mRNA expression is limited in normal human tissues. mRNA expression measured using RT-PCR and analyzed using the DDCt method with values normalized to 22Rv1 expression (=1) for all tissues. C. Representative IHC staining for CEACAM5 in three different NEPC patient-derived organoids (10x (upper row) and 40x (lower row) magnification).
FIGURE 5 from The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer
Authors: Van Emmenis Lucie , Ku Sheng-Yu , Gayvert Kaitlyn , Branch Jonathan R. , Brady Nicholas J. , Basu Subhasree , Russell Michael , Cyrta Joanna , Vosoughi Aram , Sailer Verena , Alnajar Hussein , Dardenne Etienne , Koumis Elena , Puca Loredana , Robinson Brian D. , Feldkamp Michael D. , Winkis Annmarie , Majewski Nathan , Rupnow Brent , Gottardis Marco M. , Elemento Olivier , Rubin Mark A. , Beltran Himisha , Rickman David S.
Published: August 2023

CELSR3 is a target for T-cell redirection therapeutics. A, CELSR3xCD3 bs-mAb directs T-cell mediated cytotoxicity in CELSR3(+) TCCSUP NLR and PM154 NLR but not CELSR3(−) DU145 NLR, TCCSUP CELSR3 KO cell lines. 5:1 (exp. 1) or 10:1 (exp. 2) pan T cells to tumor cells were added to each well along with CELSR3xCD3 bs-mAb and imaged using the IncuCyte S3 platform. Maximum cell lysis occurred by day 7 timepoint. At least three biological replicates were analyzed from one independent experiment. B, Cell surface expression of CELSR3 on tumor cell lines determined by quantitative flow cytometry and calculated from at least 10,000 events per sample. Dotted line denotes assay lower limit of detection.
FIGURE 3 from The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer
Authors: Van Emmenis Lucie , Ku Sheng-Yu , Gayvert Kaitlyn , Branch Jonathan R. , Brady Nicholas J. , Basu Subhasree , Russell Michael , Cyrta Joanna , Vosoughi Aram , Sailer Verena , Alnajar Hussein , Dardenne Etienne , Koumis Elena , Puca Loredana , Robinson Brian D. , Feldkamp Michael D. , Winkis Annmarie , Majewski Nathan , Rupnow Brent , Gottardis Marco M. , Elemento Olivier , Rubin Mark A. , Beltran Himisha , Rickman David S.
Published: August 2023

A, Quantitative RT-PCR of mRNA expression of CELSR3 following stable expression of hairpin molecules targeting CELSR3 (shCELSR3) or control non-targeting hairpin molecules (shCTL) in the NEPC PDO WCM154. B, Left: Representative images of migrated NEPC PDO WMC154 cells 4 or 48 hours postseeding using Corning FluoroBlok cell culture inserts. Right: Average and SD of the cell counts from the cell migration assays at 4, 18, 24, and 48 hours postseeding. The data are a summary from three plane views per biological replicate were counted at 4, 18, 24, and 48 hours postseeding. *, P < 104; **, P < 106; ***, P < 107; ****, P < 108 (Student t tests). C, Protein levels and proliferation curves of NEPC PDO WCM154 organoids following CRISPR/Cas9 KO using guide RNAs targeting CELSR3 (sgCELSR3) or GFP (sgGFP) as a control. D, Western blot analysis results showing the expression of the indicated NEPC markers following CELSR3 KO as described in C.
FIGURE 1 from The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer
Authors: Van Emmenis Lucie , Ku Sheng-Yu , Gayvert Kaitlyn , Branch Jonathan R. , Brady Nicholas J. , Basu Subhasree , Russell Michael , Cyrta Joanna , Vosoughi Aram , Sailer Verena , Alnajar Hussein , Dardenne Etienne , Koumis Elena , Puca Loredana , Robinson Brian D. , Feldkamp Michael D. , Winkis Annmarie , Majewski Nathan , Rupnow Brent , Gottardis Marco M. , Elemento Olivier , Rubin Mark A. , Beltran Himisha , Rickman David S.
Published: August 2023

A, Schematic of the bioinformatics pipeline that was used to analyze bulk RNA-seq data with the aim of identifying cell surface protein encoding genes specifically enriched in CRPC and NEPC compared with localized prostate cancer (PCA), benign prostate (Prost.) and across the different normal tissues that are represented in the GTEx database. B, Heat map summarizing the average expression levels of the indicated genes from RNA-seq data from the normal tissue from the GTEX database, benign prostate, prostate cancer, CRPC, or NEPC tumors from our cohort. Box plot showing distribution of expression of the indicated gene (C) or CDH2 transcript isoform (D) based on RNA-seq data from the clinical cohort of normal tissue from GTEX, benign prostate, prostate cancer, CRPC, or NEPC. Box represents 25%–75% percentile with median denoted as a line. Whiskers extend ± 1.5× interquartile range. Datapoints that lie outside the whiskers are plotted individually.
Figure S4 from Synergism Between IL21 and Anti-PD-1 Combination Therapy is Underpinned by the Coordinated Reprogramming of the Immune Cellular Network in the Tumor Microenvironment
Authors: Wu Shaoxian , Huang Hao , Sun Runzi , Gao David Shihong , Ye Fan , Huang Jianing , Li Ella , Ni Andrew , Lu Kevin GuoKai , Chen Kong , Jiang Jingting , Morel Penelope A. , Zhong Ziyang , Lu Binfeng
Published: August 2023

Supplementary Figure 4. IL21-anti-HSA and PD-1 mAbs synergy at the proliferation is due to upregulation of IL21R by PD-1 mAbs treatment and IL21 directly promotes proliferation on IL21R+ CD8+ T cells.
Figure S1 from Synergism Between IL21 and Anti-PD-1 Combination Therapy is Underpinned by the Coordinated Reprogramming of the Immune Cellular Network in the Tumor Microenvironment
Authors: Wu Shaoxian , Huang Hao , Sun Runzi , Gao David Shihong , Ye Fan , Huang Jianing , Li Ella , Ni Andrew , Lu Kevin GuoKai , Chen Kong , Jiang Jingting , Morel Penelope A. , Zhong Ziyang , Lu Binfeng
Published: August 2023

Supplementary Figure 1. Distribution of CD4+ T cell subsets.
FIGURE 7 from Synergism Between IL21 and Anti-PD-1 Combination Therapy is Underpinned by the Coordinated Reprogramming of the Immune Cellular Network in the Tumor Microenvironment
Authors: Wu Shaoxian , Huang Hao , Sun Runzi , Gao David Shihong , Ye Fan , Huang Jianing , Li Ella , Ni Andrew , Lu Kevin GuoKai , Chen Kong , Jiang Jingting , Morel Penelope A. , Zhong Ziyang , Lu Binfeng
Published: August 2023

Combination therapy synergistically promoted monocyte to the M1 trajectory in the TME. A, Pseudotime plot of macrophage subsets constructed by Monocle 3. B, UMAP showing macrophages, neutrophils, and monocytes. C, Bar plot of the proportions of the above cell subsets. D, Dot plot showing expression levels of Il21r on different macrophage subsets under different treatment conditions. E–G, Heat map showing the expression of selected DEG in monocytes, TAM1, TAM2 cells under different treatment conditions.
FIGURE 3 from Synergism Between IL21 and Anti-PD-1 Combination Therapy is Underpinned by the Coordinated Reprogramming of the Immune Cellular Network in the Tumor Microenvironment
Authors: Wu Shaoxian , Huang Hao , Sun Runzi , Gao David Shihong , Ye Fan , Huang Jianing , Li Ella , Ni Andrew , Lu Kevin GuoKai , Chen Kong , Jiang Jingting , Morel Penelope A. , Zhong Ziyang , Lu Binfeng
Published: August 2023

Systemic injection of IL21-anti-HSA promoted tumor site–focused antitumor activities. A, Diagram of the experimental protocol. C57BL/6 mice were injected intraperitoneally with FTY720 the day before tumor inoculation, and injected every other day. The next day, mice were inoculated with MC38 colon adenocarcinoma cells subcutaneously, and 5 days later, IL21-anti-HSA was injected intraperitoneally. Treatments were given every 4 days for a total of four treatments. Mouse tumor growth curves (n = 4–5) were drawn. B, Mouse tumor growth curve. C–F, The tumor growth curve of a single mouse in the above different treatment groups. Data are presented as mean ± SEM, and two-way ANOVA test was used to compare statistical differences in tumor growth curves between different groups. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.
FIGURE 1 from Synergism Between IL21 and Anti-PD-1 Combination Therapy is Underpinned by the Coordinated Reprogramming of the Immune Cellular Network in the Tumor Microenvironment
Authors: Wu Shaoxian , Huang Hao , Sun Runzi , Gao David Shihong , Ye Fan , Huang Jianing , Li Ella , Ni Andrew , Lu Kevin GuoKai , Chen Kong , Jiang Jingting , Morel Penelope A. , Zhong Ziyang , Lu Binfeng
Published: August 2023

IL21 is produced by both CXCR5+ Tfh cells and hyperactivated/exhausted CD4+ T cells in the TME. A and B, Dot plots and UMAPs showing the expression of selected genes in different CD4+ T-cell subsets in integrated human cancer tissues. C and D, Dot plots and UMAPs showing the expression of selected genes in different CD4+ T-cell subsets in mouse MC38 colon adenocarcinoma tumors. E, UMAP plot showing imputed expression of selected genes constructed by ArchR.
Data from Synergism Between IL21 and Anti-PD-1 Combination Therapy is Underpinned by the Coordinated Reprogramming of the Immune Cellular Network in the Tumor Microenvironment
Authors: Wu Shaoxian , Huang Hao , Sun Runzi , Gao David Shihong , Ye Fan , Huang Jianing , Li Ella , Ni Andrew , Lu Kevin GuoKai , Chen Kong , Jiang Jingting , Morel Penelope A. , Zhong Ziyang , Lu Binfeng
Published: August 2023

T cell–stimulating cytokines and immune checkpoint inhibitors (ICI) are an ideal combination for increasing response rates of cancer immunotherapy. However, the results of clinical trials have not been satisfying. It is important to understand the mechanism of synergy between these two therapeutic modalities. Here, through integrated analysis of multiple single-cell RNA sequencing (scRNA-seq) datasets of human tumor-infiltrating immune cells, we demonstrate that IL21 is produced by tumor-associated T follicular helper cells and hyperactivated/exhausted CXCL13+CD4+ T cells in the human tumor microenvironment (TME). In the mouse model, the hyperactivated/exhausted CD4+ T cell–derived IL21 enhances the helper function of CD4+ T cells that boost CD8+ T cell–mediated immune responses during PD-1 blockade immunotherapy. In addition, we demonstrated that IL21’s antitumor activity did not require T-cell trafficking. Using scRNA-seq analysis of the whole tumor-infiltrating immune cells, we demonstrated that IL21 treatment in combination with anti-PD-1 blockade synergistically drives tumor antigen–specific CD8+ T cells to undergo clonal expansion and differentiate toward the hyperactive/exhausted functional state in the TME. In addition, IL21 treatment and anti-PD-1 blockade synergistically promote dendritic cell (DC) activation and maturation to mature DC as well as monocyte to type 1 macrophage (M1) differentiation in the TME. Furthermore, the combined treatment reprograms the immune cellular network by reshaping cell-cell communication in the TME. Our study establishes unique mechanisms of synergy between IL21 and PD-1–based ICI in the TME through the coordinated promotion of type 1 immune responses.
Significance:
This study reveals how cytokine and checkpoint inhibitor therapy can be combined to increase the efficacy of cancer immunotherapy.