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1. Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness

Author

Lin, Chun-Pu, Levy, Pierre L., Alflen, Astrid, Apriamashvili, Georgi, Ligtenberg, Maarten A., Vredevoogd, David W., Bleijerveld, Onno B., Alkan, Ferhat, Malka, Yuval, Hoekman, Liesbeth, Markovits, Ettai, George, Austin, Traets, Joleen J.H., Krijgsman, Oscar, van Vliet, Alex, Poźniak, Joanna, Pulido-Vicuña, Carlos Ariel, de Bruijn, Beaunelle, van Hal-van Veen, Susan E., Boshuizen, Julia, van der Helm, Pim W., Díaz-Gómez, Judit, Warda, Hamdy, Behrens, Leonie M., Mardesic, Paula, Dehni, Bilal, Visser, Nils L., Marine, Jean-Christophe, Markel, Gal, Faller, William J., Altelaar, Maarten, Agami, Reuven, Besser, Michal J., and Peeper, Daniel S.

Published
2024
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2. Author Correction: Reversal of pre-existing NGFR-driven tumor and immune therapy resistance

Author

Boshuizen, Julia, Vredevoogd, David W., Krijgsman, Oscar, Ligtenberg, Maarten A., Blankenstein, Stephanie, de Bruijn, Beaunelle, Frederick, Dennie T., Kenski, Juliana C. N., Parren, Mara, Brüggemann, Marieke, Madu, Max F., Rozeman, Elisa A., Song, Ji-Ying, Horlings, Hugo M., Blank, Christian U., van Akkooi, Alexander C. J., Flaherty, Keith T., Boland, Genevieve M., and Peeper, Daniel S.

Published
2023
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3. Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling

Author

Apriamashvili, Georgi, Vredevoogd, David W., Krijgsman, Oscar, Bleijerveld, Onno B., Ligtenberg, Maarten A., de Bruijn, Beaunelle, Boshuizen, Julia, Traets, Joleen J. H., D’Empaire Altimari, Daniela, van Vliet, Alex, Lin, Chun-Pu, Visser, Nils L., Londino, James D., Sanchez-Hodge, Rebekah, Oswalt, Leah E., Altinok, Selin, Schisler, Jonathan C., Altelaar, Maarten, and Peeper, Daniel S.

Published
2022
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5. Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness

Author

Lin, Chun Pu, Levy, Pierre L., Alflen, Astrid, Apriamashvili, Georgi, Ligtenberg, Maarten A., Vredevoogd, David W., Bleijerveld, Onno B., Alkan, Ferhat, Malka, Yuval, Hoekman, Liesbeth, Markovits, Ettai, George, Austin, Traets, Joleen J.H., Krijgsman, Oscar, van Vliet, Alex, Poźniak, Joanna, Pulido-Vicuña, Carlos Ariel, de Bruijn, Beaunelle, van Hal-van Veen, Susan E., Boshuizen, Julia, van der Helm, Pim W., Díaz-Gómez, Judit, Warda, Hamdy, Behrens, Leonie M., Mardesic, Paula, Dehni, Bilal, Visser, Nils L., Marine, Jean Christophe, Markel, Gal, Faller, William J., Altelaar, Maarten, Agami, Reuven, Besser, Michal J., Peeper, Daniel S., Lin, Chun Pu, Levy, Pierre L., Alflen, Astrid, Apriamashvili, Georgi, Ligtenberg, Maarten A., Vredevoogd, David W., Bleijerveld, Onno B., Alkan, Ferhat, Malka, Yuval, Hoekman, Liesbeth, Markovits, Ettai, George, Austin, Traets, Joleen J.H., Krijgsman, Oscar, van Vliet, Alex, Poźniak, Joanna, Pulido-Vicuña, Carlos Ariel, de Bruijn, Beaunelle, van Hal-van Veen, Susan E., Boshuizen, Julia, van der Helm, Pim W., Díaz-Gómez, Judit, Warda, Hamdy, Behrens, Leonie M., Mardesic, Paula, Dehni, Bilal, Visser, Nils L., Marine, Jean Christophe, Markel, Gal, Faller, William J., Altelaar, Maarten, Agami, Reuven, Besser, Michal J., and Peeper, Daniel S.

Abstract

Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction. Besides established regulators, we uncover genes controlling T cell fitness either specifically or commonly upon differential stimulation. Dap5 ablation, ranking highly in all three screens, increases translation while enhancing tumor killing. Loss of Icam1-mediated homotypic T cell clustering amplifies cell expansion and effector functions after both acute and intense stimulation. Lastly, Ctbp1 inactivation induces functional T cell persistence exclusively upon chronic stimulation. Our results functionally annotate fitness regulators based on their unique or shared contribution to traits limiting T cell antitumor activity.

Published
2024

6. Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness

Author

Sub Biomol.Mass Spect. and Proteomics, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Lin, Chun Pu, Levy, Pierre L., Alflen, Astrid, Apriamashvili, Georgi, Ligtenberg, Maarten A., Vredevoogd, David W., Bleijerveld, Onno B., Alkan, Ferhat, Malka, Yuval, Hoekman, Liesbeth, Markovits, Ettai, George, Austin, Traets, Joleen J.H., Krijgsman, Oscar, van Vliet, Alex, Poźniak, Joanna, Pulido-Vicuña, Carlos Ariel, de Bruijn, Beaunelle, van Hal-van Veen, Susan E., Boshuizen, Julia, van der Helm, Pim W., Díaz-Gómez, Judit, Warda, Hamdy, Behrens, Leonie M., Mardesic, Paula, Dehni, Bilal, Visser, Nils L., Marine, Jean Christophe, Markel, Gal, Faller, William J., Altelaar, Maarten, Agami, Reuven, Besser, Michal J., Peeper, Daniel S., Sub Biomol.Mass Spect. and Proteomics, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Lin, Chun Pu, Levy, Pierre L., Alflen, Astrid, Apriamashvili, Georgi, Ligtenberg, Maarten A., Vredevoogd, David W., Bleijerveld, Onno B., Alkan, Ferhat, Malka, Yuval, Hoekman, Liesbeth, Markovits, Ettai, George, Austin, Traets, Joleen J.H., Krijgsman, Oscar, van Vliet, Alex, Poźniak, Joanna, Pulido-Vicuña, Carlos Ariel, de Bruijn, Beaunelle, van Hal-van Veen, Susan E., Boshuizen, Julia, van der Helm, Pim W., Díaz-Gómez, Judit, Warda, Hamdy, Behrens, Leonie M., Mardesic, Paula, Dehni, Bilal, Visser, Nils L., Marine, Jean Christophe, Markel, Gal, Faller, William J., Altelaar, Maarten, Agami, Reuven, Besser, Michal J., and Peeper, Daniel S.

Published
2024

7. Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

Author

Vredevoogd, David W., Kuilman, Thomas, Ligtenberg, Maarten A., Boshuizen, Julia, Stecker, Kelly E., de Bruijn, Beaunelle, Krijgsman, Oscar, Huang, Xinyao, Kenski, Juliana C.N., Lacroix, Ruben, Mezzadra, Riccardo, Gomez-Eerland, Raquel, Yildiz, Mete, Dagidir, Ilknur, Apriamashvili, Georgi, Zandhuis, Nordin, van der Noort, Vincent, Visser, Nils L., Blank, Christian U., Altelaar, Maarten, Schumacher, Ton N., and Peeper, Daniel S.

Published
2019
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9. Reversal of pre-existing NGFR-driven tumor and immune therapy resistance

Author

Boshuizen, Julia, Vredevoogd, David W., Krijgsman, Oscar, Ligtenberg, Maarten A., Blankenstein, Stephanie, de Bruijn, Beaunelle, Frederick, Dennie T., Kenski, Juliana C. N., Parren, Mara, Brüggemann, Marieke, Madu, Max F., Rozeman, Elisa A., Song, Ji-Ying, Horlings, Hugo M., Blank, Christian U., van Akkooi, Alexander C. J., Flaherty, Keith T., Boland, Genevieve M., and Peeper, Daniel S.

Published
2020
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10. Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors

Author

Boshuizen, Julia, Koopman, Louise A, Krijgsman, Oscar, Shahrabi, Aida, van den Heuvel, Elke Gresnigt-, Ligtenberg, Maarten A, Vredevoogd, David W, Kemper, Kristel, Kuilman, Thomas, Song, Ji-Ying, Pencheva, Nora, Mortensen, Jens Thing, Foppen, Marnix Geukes, Rozeman, Elisa A, Blank, Christian U, Janmaat, Maarten L, Satijn, David, Breij, Esther C W, Peeper, Daniel S, and Parren, Paul W H I

Subjects
Drug therapy, Complications and side effects, Genetic aspects, Research, Dosage and administration, Biopharmaceuticals -- Health aspects -- Dosage and administration -- Complications and side effects, Antibodies -- Health aspects -- Dosage and administration -- Complications and side effects, Melanoma -- Health aspects -- Genetic aspects -- Drug therapy -- Research
Abstract

Author(s): Julia Boshuizen [1]; Louise A Koopman [2]; Oscar Krijgsman [1]; Aida Shahrabi [1]; Elke Gresnigt- van den Heuvel [2]; Maarten A Ligtenberg [1]; David W Vredevoogd [1]; Kristel Kemper [...], Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E. We found that AXL-107-MMAE, as a single agent, displayed potent in vivo anti-tumor activity in patient-derived xenografts, including melanoma, lung, pancreas and cervical cancer. By eliminating distinct populations in heterogeneous melanoma cell pools, AXL-107-MMAE and MAPK pathway inhibitors cooperatively inhibited tumor growth. Furthermore, by inducing AXL transcription, BRAF/MEK inhibitors potentiated the efficacy of AXL-107-MMAE. These findings provide proof of concept for the premise that rationalized combinatorial targeting of distinct populations in heterogeneous tumors may improve therapeutic effect, and merit clinical validation of AXL-107-MMAE in both treatment-naive and drug-resistant cancers in mono- or combination therapy.

Published
2018
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11. Data from Inhibitor of Apoptosis Proteins Antagonist Induces T-cell Proliferation after Cross-Presentation by Dendritic Cells

Author

Hoefsmit, Esmée P., primary, van Royen, Paula T., primary, Rao, Disha, primary, Stunnenberg, Johanna A., primary, Dimitriadis, P., primary, Lieftink, Cor, primary, Morris, Ben, primary, Rozeman, Elisa A., primary, Reijers, Irene L.M., primary, Lacroix, Ruben, primary, Shehwana, Huma, primary, Ligtenberg, Maarten A., primary, Beijersbergen, Roderick L., primary, Peeper, Daniel S., primary, and Blank, Christian U., primary

Published
2023
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12. Supplementary Figures and Table from Inhibitor of Apoptosis Proteins Antagonist Induces T-cell Proliferation after Cross-Presentation by Dendritic Cells

Author

Hoefsmit, Esmée P., primary, van Royen, Paula T., primary, Rao, Disha, primary, Stunnenberg, Johanna A., primary, Dimitriadis, P., primary, Lieftink, Cor, primary, Morris, Ben, primary, Rozeman, Elisa A., primary, Reijers, Irene L.M., primary, Lacroix, Ruben, primary, Shehwana, Huma, primary, Ligtenberg, Maarten A., primary, Beijersbergen, Roderick L., primary, Peeper, Daniel S., primary, and Blank, Christian U., primary

Published
2023
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13. Figure S3 from Cripto-1 Plasmid DNA Vaccination Targets Metastasis and Cancer Stem Cells in Murine Mammary Carcinoma

Author

Witt, Kristina, primary, Ligtenberg, Maarten A., primary, Conti, Laura, primary, Lanzardo, Stefania, primary, Ruiu, Roberto, primary, Wallmann, Tatjana, primary, Tufvesson-Stiller, Helena, primary, Chambers, Benedict J., primary, Rolny, Charlotte, primary, Lladser, Alvaro, primary, Lundqvist, Andreas, primary, Cavallo, Federica, primary, and Kiessling, Rolf, primary

Published
2023
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14. Data from Cripto-1 Plasmid DNA Vaccination Targets Metastasis and Cancer Stem Cells in Murine Mammary Carcinoma

Author

Witt, Kristina, primary, Ligtenberg, Maarten A., primary, Conti, Laura, primary, Lanzardo, Stefania, primary, Ruiu, Roberto, primary, Wallmann, Tatjana, primary, Tufvesson-Stiller, Helena, primary, Chambers, Benedict J., primary, Rolny, Charlotte, primary, Lladser, Alvaro, primary, Lundqvist, Andreas, primary, Cavallo, Federica, primary, and Kiessling, Rolf, primary

Published
2023
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15. Table S1 from Cripto-1 Plasmid DNA Vaccination Targets Metastasis and Cancer Stem Cells in Murine Mammary Carcinoma

Author

Witt, Kristina, primary, Ligtenberg, Maarten A., primary, Conti, Laura, primary, Lanzardo, Stefania, primary, Ruiu, Roberto, primary, Wallmann, Tatjana, primary, Tufvesson-Stiller, Helena, primary, Chambers, Benedict J., primary, Rolny, Charlotte, primary, Lladser, Alvaro, primary, Lundqvist, Andreas, primary, Cavallo, Federica, primary, and Kiessling, Rolf, primary

Published
2023
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16. Supplementary Data from Cooperative Targeting of Immunotherapy-Resistant Melanoma and Lung Cancer by an AXL-Targeting Antibody–Drug Conjugate and Immune Checkpoint Blockade

Author

Boshuizen, Julia, primary, Pencheva, Nora, primary, Krijgsman, Oscar, primary, Altimari, Daniela D'Empaire, primary, Castro, Patricia Garrido, primary, de Bruijn, Beaunelle, primary, Ligtenberg, Maarten A., primary, Gresnigt-Van den Heuvel, Elke, primary, Vredevoogd, David W., primary, Song, Ji-Ying, primary, Visser, Nils, primary, Apriamashvili, Georgi, primary, Janmaat, Maarten L., primary, Plantinga, Theo S., primary, Franken, Patrick, primary, Houtkamp, Mischa, primary, Lingnau, Andreas, primary, Jure-Kunkel, Maria, primary, and Peeper, Daniel S., primary

Published
2023
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17. Supplementary Figures from Predictive Immune-Checkpoint Blockade Classifiers Identify Tumors Responding to Inhibition of PD-1 and/or CTLA-4

Author

Krijgsman, Oscar, primary, Kemper, Kristel, primary, Boshuizen, Julia, primary, Vredevoogd, David W., primary, Rozeman, Elisa A., primary, Ibanez Molero, Sofia, primary, de Bruijn, Beaunelle, primary, Cornelissen-Steijger, Paulien, primary, Shahrabi, Aida, primary, Del Castillo Velasco-Herrera, Martin, primary, Song, Ji-Ying, primary, Ligtenberg, Maarten A., primary, Kluin, Roelof J.C., primary, Kuilman, Thomas, primary, Ross-Macdonald, Petra, primary, Haanen, John B.A.G., primary, Adams, David J., primary, Blank, Christian U., primary, and Peeper, Daniel S., primary

Published
2023
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18. Data from Cooperative Targeting of Immunotherapy-Resistant Melanoma and Lung Cancer by an AXL-Targeting Antibody–Drug Conjugate and Immune Checkpoint Blockade

Author

Boshuizen, Julia, primary, Pencheva, Nora, primary, Krijgsman, Oscar, primary, Altimari, Daniela D'Empaire, primary, Castro, Patricia Garrido, primary, de Bruijn, Beaunelle, primary, Ligtenberg, Maarten A., primary, Gresnigt-Van den Heuvel, Elke, primary, Vredevoogd, David W., primary, Song, Ji-Ying, primary, Visser, Nils, primary, Apriamashvili, Georgi, primary, Janmaat, Maarten L., primary, Plantinga, Theo S., primary, Franken, Patrick, primary, Houtkamp, Mischa, primary, Lingnau, Andreas, primary, Jure-Kunkel, Maria, primary, and Peeper, Daniel S., primary

Published
2023
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19. Inhibitor of Apoptosis Proteins Antagonist Induces T-cell Proliferation after Cross-Presentation by Dendritic Cells

Author

Hoefsmit, Esmée P., primary, van Royen, Paula T., additional, Rao, Disha, additional, Stunnenberg, Johanna A., additional, Dimitriadis, P., additional, Lieftink, Cor, additional, Morris, Ben, additional, Rozeman, Elisa A., additional, Reijers, Irene L.M., additional, Lacroix, Ruben, additional, Shehwana, Huma, additional, Ligtenberg, Maarten A., additional, Beijersbergen, Roderick L., additional, Peeper, Daniel S., additional, and Blank, Christian U., additional

Published
2023
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20. MeVa2.1.dOVA and MeVa2.2.dOVA: two novel BRAFV600E-driven mouse melanoma cell lines to study tumor immune resistance

Author

Rao, Disha, primary, Lacroix, Ruben, additional, Rooker, Alex, additional, Gomes, Tainá, additional, Stunnenberg, Johanna A., additional, Valenti, Mesele, additional, Dimitriadis, Petros, additional, Lin, Chun-Pu, additional, de Bruijn, Beaunelle, additional, Krijgsman, Oscar, additional, Ligtenberg, Maarten A., additional, Peeper, Daniel S., additional, and Blank, Christian U., additional

Published
2022
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21. 979 Compound screen identifies inhibitor of apoptosis proteins (IAP) antagonist as an inducer of T cell proliferation after cross-presentation by dendritic cells

Author

Hoefsmit, Esmee, primary, Royen, Paula van, additional, Rao, Disha, additional, Stunnenberg, Johanna, additional, Dimitriadis, Petros, additional, Lieftink, Cor, additional, Morris, Ben, additional, Rozeman, Elisa, additional, Reijers, Irene, additional, Lacroix, Ruben, additional, Shehwana, Huma, additional, Ligtenberg, Maarten, additional, Beijersbergen, Roderick, additional, Peeper, Daniel, additional, and Blank, Christian, additional

Published
2022
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22. Renal cell carcinoma escapes NK cell‐mediated immune surveillance through the downregulation of DNAM‐1.

Author

Tong, Le, Kremer, Veronika, Neo, Shi Yong, Liu, Yaxuan, Chen, Yi, Wagner, Arnika Kathleen, Yang, Ying, Chen, Ziqing, Seitz, Christina, Tobin, Nicholas Patrick, Ligtenberg, Maarten Alexander, Alici, Evren, Chen, Xinsong, Haglund, Felix, Seliger, Barbara, Harmenberg, Ulrika, Colón, Eugenia, Plogell, Ann‐Helén Scherman, Liu, Lisa Lei, and Lundqvist, Andreas

Published
2023
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23. RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells

Author

Zhang, Zhengkui, primary, Kong, Xiangjun, additional, Ligtenberg, Maarten A., additional, van Hal-van Veen, Susan E., additional, Visser, Nils L., additional, de Bruijn, Beaunelle, additional, Stecker, Kelly, additional, van der Helm, Pim W., additional, Kuilman, Thomas, additional, Hoefsmit, Esmée P., additional, Vredevoogd, David W., additional, Apriamashvili, Georgi, additional, Baars, Beau, additional, Voest, Emile E., additional, Klarenbeek, Sjoerd, additional, Altelaar, Maarten, additional, and Peeper, Daniel S., additional

Published
2022
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24. RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells

Author

Zhang, Zhengkui, Kong, Xiangjun, Ligtenberg, Maarten A., van Hal-van Veen, Susan E., Visser, Nils L., de Bruijn, Beaunelle, Stecker, Kelly, van der Helm, Pim W., Kuilman, Thomas, Hoefsmit, Esmée P., Vredevoogd, David W., Apriamashvili, Georgi, Baars, Beau, Voest, Emile E., Klarenbeek, Sjoerd, Altelaar, Maarten, Peeper, Daniel S., Zhang, Zhengkui, Kong, Xiangjun, Ligtenberg, Maarten A., van Hal-van Veen, Susan E., Visser, Nils L., de Bruijn, Beaunelle, Stecker, Kelly, van der Helm, Pim W., Kuilman, Thomas, Hoefsmit, Esmée P., Vredevoogd, David W., Apriamashvili, Georgi, Baars, Beau, Voest, Emile E., Klarenbeek, Sjoerd, Altelaar, Maarten, and Peeper, Daniel S.

Abstract

Tumor escape mechanisms for immunotherapy include deficiencies in antigen presentation, diminishing adaptive CD8+ T cell antitumor activity. Although innate natural killer (NK) cells are triggered by loss of MHC class I, their response is often inadequate. To increase tumor susceptibility to both innate and adaptive immune elimination, we performed parallel genome-wide CRISPR-Cas9 knockout screens under NK and CD8+ T cell pressure. We identify all components, RNF31, RBCK1, and SHARPIN, of the linear ubiquitination chain assembly complex (LUBAC). Genetic and pharmacologic ablation of RNF31, an E3 ubiquitin ligase, strongly sensitizes cancer cells to NK and CD8+ T cell killing. This occurs in a tumor necrosis factor (TNF)-dependent manner, causing loss of A20 and non-canonical IKK complexes from TNF receptor complex I. A small-molecule RNF31 inhibitor sensitizes colon carcinoma organoids to TNF and greatly enhances bystander killing of MHC antigen-deficient tumor cells. These results merit exploration of RNF31 inhibition as a clinical pharmacological opportunity for immunotherapy-refractory cancers.

Published
2022

25. RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells

Author

Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Zhang, Zhengkui, Kong, Xiangjun, Ligtenberg, Maarten A., van Hal-van Veen, Susan E., Visser, Nils L., de Bruijn, Beaunelle, Stecker, Kelly, van der Helm, Pim W., Kuilman, Thomas, Hoefsmit, Esmée P., Vredevoogd, David W., Apriamashvili, Georgi, Baars, Beau, Voest, Emile E., Klarenbeek, Sjoerd, Altelaar, Maarten, Peeper, Daniel S., Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Zhang, Zhengkui, Kong, Xiangjun, Ligtenberg, Maarten A., van Hal-van Veen, Susan E., Visser, Nils L., de Bruijn, Beaunelle, Stecker, Kelly, van der Helm, Pim W., Kuilman, Thomas, Hoefsmit, Esmée P., Vredevoogd, David W., Apriamashvili, Georgi, Baars, Beau, Voest, Emile E., Klarenbeek, Sjoerd, Altelaar, Maarten, and Peeper, Daniel S.

Published
2022

26. RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells

Author

Externen Med. Onco, Cancer, Zhang, Zhengkui, Kong, Xiangjun, Ligtenberg, Maarten A., van Hal-van Veen, Susan E., Visser, Nils L., de Bruijn, Beaunelle, Stecker, Kelly, van der Helm, Pim W., Kuilman, Thomas, Hoefsmit, Esmée P., Vredevoogd, David W., Apriamashvili, Georgi, Baars, Beau, Voest, Emile E., Klarenbeek, Sjoerd, Altelaar, Maarten, Peeper, Daniel S., Externen Med. Onco, Cancer, Zhang, Zhengkui, Kong, Xiangjun, Ligtenberg, Maarten A., van Hal-van Veen, Susan E., Visser, Nils L., de Bruijn, Beaunelle, Stecker, Kelly, van der Helm, Pim W., Kuilman, Thomas, Hoefsmit, Esmée P., Vredevoogd, David W., Apriamashvili, Georgi, Baars, Beau, Voest, Emile E., Klarenbeek, Sjoerd, Altelaar, Maarten, and Peeper, Daniel S.

Published
2022

28. RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells

Author

Zhang, Zhengkui, Kong, Xiangjun, Ligtenberg, Maarten A., van Hal-van Veen, Susan E., Visser, Nils L., de Bruijn, Beaunelle, Stecker, Kelly, van der Helm, Pim W., Kuilman, Thomas, Hoefsmit, Esmée P., Vredevoogd, David W., Apriamashvili, Georgi, Baars, Beau, Voest, Emile E., Klarenbeek, Sjoerd, Altelaar, Maarten, Peeper, Daniel S., Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Afd Biomol.Mass Spect. and Proteomics, and Biomolecular Mass Spectrometry and Proteomics

Subjects
function-based genome-wide screens, Ubiquitin-Protein Ligases, NF-KAPPA-B, T cells, NK cells, Research & Experimental Medicine, ESCAPE, Biochemistry, immunotherapy resistance, General Biochemistry, Genetics and Molecular Biology, ACTIVATION, NATURAL-KILLER-CELLS, INFLAMMATION, CLASS-I, SUPPRESSES, Science & Technology, COMPLEX, Biochemistry, Genetics and Molecular Biology(all), Tumor Necrosis Factor-alpha, Ubiquitination, bystander killing, Cell Biology, CANCER, Killer Cells, Natural, Medicine, Research & Experimental, Tumor Escape, Life Sciences & Biomedicine, Genetics and Molecular Biology(all), ACQUIRED-RESISTANCE
Abstract

Tumor escape mechanisms for immunotherapy include deficiencies in antigen presentation, diminishing adaptive CD8+ T cell antitumor activity. Although innate natural killer (NK) cells are triggered by loss of MHC class I, their response is often inadequate. To increase tumor susceptibility to both innate and adaptive immune elimination, we performed parallel genome-wide CRISPR-Cas9 knockout screens under NK and CD8+ T cell pressure. We identify all components, RNF31, RBCK1, and SHARPIN, of the linear ubiquitination chain assembly complex (LUBAC). Genetic and pharmacologic ablation of RNF31, an E3 ubiquitin ligase, strongly sensitizes cancer cells to NK and CD8+ T cell killing. This occurs in a tumor necrosis factor (TNF)-dependent manner, causing loss of A20 and non-canonical IKK complexes from TNF receptor complex I. A small-molecule RNF31 inhibitor sensitizes colon carcinoma organoids to TNF and greatly enhances bystander killing of MHC antigen-deficient tumor cells. These results merit exploration of RNF31 inhibition as a clinical pharmacological opportunity for immunotherapy-refractory cancers. ispartof: CELL REPORTS MEDICINE vol:3 issue:6 ispartof: location:United States status: published

Published
2021

30. Predictive Immune-Checkpoint Blockade Classifiers Identify Tumors Responding to Inhibition of PD-1 and/or CTLA-4

Author

Krijgsman, Oscar, primary, Kemper, Kristel, additional, Boshuizen, Julia, additional, Vredevoogd, David W., additional, Rozeman, Elisa A., additional, Ibanez Molero, Sofia, additional, de Bruijn, Beaunelle, additional, Cornelissen-Steijger, Paulien, additional, Shahrabi, Aida, additional, Del Castillo Velasco-Herrera, Martin, additional, Song, Ji-Ying, additional, Ligtenberg, Maarten A., additional, Kluin, Roelof J.C., additional, Kuilman, Thomas, additional, Ross-Macdonald, Petra, additional, Haanen, John B.A.G., additional, Adams, David J., additional, Blank, Christian U., additional, and Peeper, Daniel S., additional

Published
2021
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33. Cooperative Targeting of Immunotherapy-Resistant Melanoma and Lung Cancer by an AXL-Targeting Antibody–Drug Conjugate and Immune Checkpoint Blockade

Author

Boshuizen, Julia, primary, Pencheva, Nora, additional, Krijgsman, Oscar, additional, Altimari, Daniela D'Empaire, additional, Castro, Patricia Garrido, additional, de Bruijn, Beaunelle, additional, Ligtenberg, Maarten A., additional, Gresnigt-Van den Heuvel, Elke, additional, Vredevoogd, David W., additional, Song, Ji-Ying, additional, Visser, Nils, additional, Apriamashvili, Georgi, additional, Janmaat, Maarten L., additional, Plantinga, Theo S., additional, Franken, Patrick, additional, Houtkamp, Mischa, additional, Lingnau, Andreas, additional, Jure-Kunkel, Maria, additional, and Peeper, Daniel S., additional

Published
2021
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34. PREDICTIVE IMMUNE CHECKPOINT BLOCKADE CLASSIFIERS DISTINGUISHING MONO- VERSUS COMBINATION THERAPY REQUIREMENT

Author

Krijgsman, Oscar, primary, Kemper, Kristel, additional, Boshuizen, Julia, additional, Vredevoogd, David W., additional, Rozeman, Elisa A., additional, Ibanez Molero, Sofia, additional, de Bruijn, Beaunelle, additional, Cornelissen-Steijger, Paulien, additional, Shahrabi, Aida, additional, Velasco-Herrera, Martin Del Castillo, additional, Song, Ji-Ying, additional, Ligtenberg, Maarten A., additional, Kluin, Roelof J.C., additional, Kuilman, Thomas, additional, Ross-MacDonald, Petra, additional, Haanen, John, additional, Adams, David J., additional, Blank, Christian, additional, and Peeper, Daniel S., additional

Published
2020
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35. Loss of Ubiquitin Ligase STUB1 Amplifies IFNγ-R1/JAK1 Signaling and Sensitizes Tumors to IFNγ

Author

Apriamashvili, Georgi, primary, Vredevoogd, David W., additional, Krijgsman, Oscar, additional, Bleijerveld, Onno B., additional, Ligtenberg, Maarten A., additional, de Bruijn, Beaunelle, additional, Boshuizen, Julia, additional, Altimari, Daniela D’Empaire, additional, Visser, Nils L., additional, Londino, James D., additional, Altelaar, Maarten, additional, and Peeper, Daniel S., additional

Published
2020
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36. Correction: Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

Author

Vredevoogd, David W, Kuilman, Thomas, Ligtenberg, Maarten A, Boshuizen, Julia, Stecker, Kelly E, de Bruijn, Beaunelle, Krijgsman, Oscar, Huang, Xinyao, Kenski, Juliana C N, Lacroix, Ruben, Mezzadra, Riccardo, Gomez-Eerland, Raquel, Yildiz, Mete, Dagidir, Ilknur, Apriamashvili, Georgi, Zandhuis, Nordin, van der Noort, Vincent, Visser, Nils L, Blank, Christian U, Altelaar, Maarten, Schumacher, Ton N, Peeper, Daniel S, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, and Inorganic Chemistry and Catalysis

Abstract

(Cell 178, 585–599.e1–e15; July 25, 2019)

Published
2020

37. Correction: Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

Author

Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Inorganic Chemistry and Catalysis, Vredevoogd, David W, Kuilman, Thomas, Ligtenberg, Maarten A, Boshuizen, Julia, Stecker, Kelly E, de Bruijn, Beaunelle, Krijgsman, Oscar, Huang, Xinyao, Kenski, Juliana C N, Lacroix, Ruben, Mezzadra, Riccardo, Gomez-Eerland, Raquel, Yildiz, Mete, Dagidir, Ilknur, Apriamashvili, Georgi, Zandhuis, Nordin, van der Noort, Vincent, Visser, Nils L, Blank, Christian U, Altelaar, Maarten, Schumacher, Ton N, Peeper, Daniel S, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Inorganic Chemistry and Catalysis, Vredevoogd, David W, Kuilman, Thomas, Ligtenberg, Maarten A, Boshuizen, Julia, Stecker, Kelly E, de Bruijn, Beaunelle, Krijgsman, Oscar, Huang, Xinyao, Kenski, Juliana C N, Lacroix, Ruben, Mezzadra, Riccardo, Gomez-Eerland, Raquel, Yildiz, Mete, Dagidir, Ilknur, Apriamashvili, Georgi, Zandhuis, Nordin, van der Noort, Vincent, Visser, Nils L, Blank, Christian U, Altelaar, Maarten, Schumacher, Ton N, and Peeper, Daniel S

Published
2020

38. Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

Author

Vredevoogd, David W., primary, Kuilman, Thomas, additional, Ligtenberg, Maarten A., additional, Boshuizen, Julia, additional, Stecker, Kelly E., additional, de Bruijn, Beaunelle, additional, Krijgsman, Oscar, additional, Huang, Xinyao, additional, Kenski, Juliana C.N., additional, Lacroix, Ruben, additional, Mezzadra, Riccardo, additional, Gomez-Eerland, Raquel, additional, Yildiz, Mete, additional, Dagidir, Ilknur, additional, Apriamashvili, Georgi, additional, Zandhuis, Nordin, additional, van der Noort, Vincent, additional, Visser, Nils L., additional, Blank, Christian U., additional, Altelaar, Maarten, additional, Schumacher, Ton N., additional, and Peeper, Daniel S., additional

Published
2020
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39. Cancer Neoepitopes for Immunotherapy: Discordance Between Tumor-Infiltrating T Cell Reactivity and Tumor MHC Peptidome Display

Author

Wickström, Stina L., primary, Lövgren, Tanja, additional, Volkmar, Michael, additional, Reinhold, Bruce, additional, Duke-Cohan, Jonathan S., additional, Hartmann, Laura, additional, Rebmann, Janina, additional, Mueller, Anja, additional, Melief, Jeroen, additional, Maas, Roeltje, additional, Ligtenberg, Maarten, additional, Hansson, Johan, additional, Offringa, Rienk, additional, Seliger, Barbara, additional, Poschke, Isabel, additional, Reinherz, Ellis L., additional, and Kiessling, Rolf, additional

Published
2019
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41. Cancer Neoepitopes for Immunotherapy : Discordance Between Tumor-Infiltrating T Cell Reactivity and Tumor MHC Peptidome Display

Author

Wickstrom, Stina L., Lövgren, Tanja, Volkmar, Michael, Reinhold, Bruce, Duke-Cohan, Jonathan S., Hartmann, Laura, Rebmann, Janina, Mueller, Anja, Melief, Jeroen, Maas, Roeltje, Ligtenberg, Maarten, Hansson, Johan, Offringa, Rienk, Seliger, Barbara, Poschke, Isabel, Reinherz, Ellis L., Kiessling, Rolf, Wickstrom, Stina L., Lövgren, Tanja, Volkmar, Michael, Reinhold, Bruce, Duke-Cohan, Jonathan S., Hartmann, Laura, Rebmann, Janina, Mueller, Anja, Melief, Jeroen, Maas, Roeltje, Ligtenberg, Maarten, Hansson, Johan, Offringa, Rienk, Seliger, Barbara, Poschke, Isabel, Reinherz, Ellis L., and Kiessling, Rolf

Abstract

Tumor-infiltrating lymphocytes (TIL) are considered enriched for T cells recognizing shared tumor antigens or mutation-derived neoepitopes. We performed exome sequencing and HLA-A*02:01 epitope prediction from tumor cell lines from two HLA-A2-positive melanoma patients whose TIL displayed strong tumor reactivity. The potential neoepitopes were screened for recognition using autologous TIL by immunological assays and presentation on tumor major histocompatibility complex class I (MHC-I) molecules by Poisson detection mass spectrometry (MS). TIL from the patients recognized 5/181 and 3/49 of the predicted neoepitopes, respectively. MS screening detected 3/181 neoepitopes on tumor MHC-I from the first patient but only one was also among those recognized by TIL. Consequently, TIL enriched for neoepitope specificity failed to recognize tumor cells, despite being activated by peptides. For the second patient, only after IFN-gamma treatment of the tumor cells was one of 49 predicted neoepitopes detected by MS, and this coincided with recognition by TIL sorted for the same specificity. Importantly, specific T cells could be expanded from patient and donor peripheral blood mononuclear cells (PBMC) for all neoepitopes recognized by TIL and/or detected on tumor MHC-I. In summary, stimulating the appropriate inflammatory environment within tumors may promote neoepitope MHC presentation while expanding T cells in blood may circumvent lack of specific TIL. The discordance in detection between physical and functional methods revealed here can be rationalized and used to improve neoantigen-targeted T cell immunotherapy.

Published
2019
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42. Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

Author

Afd Biomol.Mass Spect. and Proteomics, Sub Analysis begr. 01-01-2014, Inorganic Chemistry and Catalysis, Biomolecular Mass Spectrometry and Proteomics, Vredevoogd, David W., Kuilman, Thomas, Ligtenberg, Maarten A., Boshuizen, Julia, Stecker, Kelly E., de Bruijn, Beaunelle, Krijgsman, Oscar, Huang, Xinyao, Kenski, Juliana C.N., Lacroix, Ruben, Mezzadra, Riccardo, Gomez-Eerland, Raquel, Yildiz, Mete, Dagidir, Ilknur, Apriamashvili, Georgi, Zandhuis, Nordin, van der Noort, Vincent, Visser, Nils L., Blank, Christian U., Altelaar, Maarten, Schumacher, Ton N., Peeper, Daniel S., Afd Biomol.Mass Spect. and Proteomics, Sub Analysis begr. 01-01-2014, Inorganic Chemistry and Catalysis, Biomolecular Mass Spectrometry and Proteomics, Vredevoogd, David W., Kuilman, Thomas, Ligtenberg, Maarten A., Boshuizen, Julia, Stecker, Kelly E., de Bruijn, Beaunelle, Krijgsman, Oscar, Huang, Xinyao, Kenski, Juliana C.N., Lacroix, Ruben, Mezzadra, Riccardo, Gomez-Eerland, Raquel, Yildiz, Mete, Dagidir, Ilknur, Apriamashvili, Georgi, Zandhuis, Nordin, van der Noort, Vincent, Visser, Nils L., Blank, Christian U., Altelaar, Maarten, Schumacher, Ton N., and Peeper, Daniel S.

Published
2019

43. Cripto-1 Plasmid DNA Vaccination Targets Metastasis and Cancer Stem Cells in Murine Mammary Carcinoma

Author

Witt, Kristina, primary, Ligtenberg, Maarten A., additional, Conti, Laura, additional, Lanzardo, Stefania, additional, Ruiu, Roberto, additional, Wallmann, Tatjana, additional, Tufvesson-Stiller, Helena, additional, Chambers, Benedict J., additional, Rolny, Charlotte, additional, Lladser, Alvaro, additional, Lundqvist, Andreas, additional, Cavallo, Federica, additional, and Kiessling, Rolf, additional

Published
2018
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44. Abstract A77: Cripto-1 vaccination elicits protective immune response to metastatic breast cancer and breast cancer stem cells

Author

Witt, Kristina, primary, Ligtenberg, Maarten Alexander, additional, Conti, Laura, additional, Lanzardo, Stefania, additional, Ruiu, Roberto, additional, Tufvesson-Stiller, Helena, additional, Ostling, Jeanette, additional, Rolny, Charlotte, additional, Lladser, Alvaro, additional, Lundqvist, Andreas, additional, Cavallo, Federica, additional, and Kiessling, Rolf, additional

Published
2018
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46. Coexpressed Catalase Protects Chimeric Antigen Receptor-Redirected T Cells as well as Bystander Cells from Oxidative Stress-Induced Loss of Antitumor Activity

Author

Ligtenberg, Maarten A., Mougiakakos, Dimitrios, Mukhopadhyay, Madhura, Witt, Kristina, Lladser, Alvaro, Chmielewski, Markus, Riet, Tobias, Abken, Hinrich, Kiessling, Rolf, Ligtenberg, Maarten A., Mougiakakos, Dimitrios, Mukhopadhyay, Madhura, Witt, Kristina, Lladser, Alvaro, Chmielewski, Markus, Riet, Tobias, Abken, Hinrich, and Kiessling, Rolf

Abstract

Treatment of cancer patients by adoptive T cell therapy has yielded promising results. In solid tumors, however, T cells encounter a hostile environment, in particular with increased inflammatory activity as a hallmark of the tumor milieu that goes along with abundant reactive oxygen species (ROS) that substantially impair antitumor activity. We present a strategy to render antitumor T cells more resilient toward ROS by coexpressing catalase along with a tumor specific chimeric Ag receptor (CAR) to increase their antioxidative capacity by metabolizing H2O2. In fact, T cells engineered with a bicistronic vector that concurrently expresses catalase, along with the CAR coexpressing catalase (CAR-CAT), performed superior over CAR T cells as they showed increased levels of intracellular catalase and had a reduced oxidative state with less ROS accumulation in both the basal state and upon activation while maintaining their antitumor activity despite high H2O2 levels. Moreover, CAR-CAT T cells exerted a substantial bystander protection of nontransfected immune effector cells as measured by CD3 zeta chain expression in bystander T cells even in the presence of high H2O2 concentrations. Bystander NK cells, otherwise ROS sensitive, efficiently eliminate their K562 target cells under H2O2-induced oxidative stress when admixed with CAR-CAT T cells. This approach represents a novel means for protecting tumor-infiltrating cells from tumor-associated oxidative stress-mediated repression.

Published
2016

49. Genetic engineering of human NK cells to express CXCR2 improves migration to renal cell carcinoma.

Author

Kremer, Veronika, Ligtenberg, Maarten, Zendehdel, Rosa, Seitz, Christina, Duivenvoorden, Annet, Wennerberg, Erik, Colón, Eugenia, Scherman-Plogell, Ann-Helén, and Lundqvist, Andreas

Subjects
*CANCER treatment, *RENAL cell carcinoma, *GENETIC engineering, *KILLER cells
Abstract

Background: Adoptive natural killer (NK) cell transfer is being increasingly used as cancer treatment. However, clinical responses have so far been limited to patients with hematological malignancies. A potential limiting factor in patients with solid tumors is defective homing of the infused NK cells to the tumor site. Chemokines regulate the migration of leukocytes expressing corresponding chemokine receptors. Various solid tumors, including renal cell carcinoma (RCC), readily secrete ligands for the chemokine receptor CXCR2. We hypothesize that infusion of NK cells expressing high levels of the CXCR2 chemokine receptor will result in increased influx of the transferred NK cells into tumors, and improved clinical outcome in patients with cancer. Methods: Blood and tumor biopsies from 14 primary RCC patients were assessed by flow cytometry and chemokine analysis. Primary NK cells were transduced with human CXCR2 using a retroviral system. CXCR2 receptor functionality was determined by Calcium flux and NK cell migration was evaluated in transwell assays. Results: We detected higher concentrations of CXCR2 ligands in tumors compared with plasma of RCC patients. In addition, CXCL5 levels correlated with the intratumoral infiltration of CXCR2-positive NK cells. However, tumor-infiltrating NK cells from RCC patients expressed lower CXCR2 compared with peripheral blood NK cells. Moreover, healthy donor NK cells rapidly lost their CXCR2 expression upon in vitro culture and expansion. Genetic modification of human primary NK cells to re-express CXCR2 improved their ability to specifically migrate along a chemokine gradient of recombinant CXCR2 ligands or RCC tumor supernatants compared with controls. The enhanced trafficking resulted in increased killing of target cells. In addition, while their functionality remained unchanged compared with control NK cells, CXCR2-transduced NK cells obtained increased adhesion properties and formed more conjugates with target cells. Conclusions: To increase the success of NK cell-based therapies of solid tumors, it is of great importance to promote their homing to the tumor site. In this study, we show that stable engineering of human primary NK cells to express a chemokine receptor thereby enhancing their migration is a promising strategy to improve anti-tumor responses following adoptive transfer of NK cells. [ABSTRACT FROM AUTHOR]

Published
2017
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