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2. PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells

Author

Codarri Deak, Laura, Nicolini, Valeria, Hashimoto, Masao, Karagianni, Maria, Schwalie, Petra C., Lauener, Laura, Varypataki, Eleni Maria, Richard, Marine, Bommer, Esther, Sam, Johannes, Joller, Stefanie, Perro, Mario, Cremasco, Floriana, Kunz, Leo, Yanguez, Emilio, Hüsser, Tamara, Schlenker, Ramona, Mariani, Marisa, Tosevski, Vinko, Herter, Sylvia, Bacac, Marina, Waldhauer, Inja, Colombetti, Sara, Gueripel, Xavier, Wullschleger, Stephan, Tichet, Melanie, Hanahan, Douglas, Kissick, Haydn T., Leclair, Stephane, Freimoser-Grundschober, Anne, Seeber, Stefan, Teichgräber, Volker, Ahmed, Rafi, Klein, Christian, and Umaña, Pablo

Published
2022
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3. The CD33xCD123xCD70 Multispecific CD3-Engaging DARPin MP0533 Induces Selective T Cell–Mediated Killing of AML Leukemic Stem Cells

Author

Bianchi, Matteo, primary, Reichen, Christian, additional, Croset, Amelie, additional, Fischer, Stefanie, additional, Eggenschwiler, Aline, additional, Grübler, Yvonne, additional, Marpakwar, Rajlakshmi, additional, Looser, Thamar, additional, Spitzli, Patricia, additional, Herzog, Christel, additional, Villemagne, Denis, additional, Schiegg, Dieter, additional, Abduli, Liridon, additional, Iss, Chloé, additional, Neculcea, Alexandra, additional, Franchini, Marco, additional, Lekishvili, Tamara, additional, Ragusa, Simone, additional, Zitt, Christof, additional, Kaufmann, Yvonne, additional, Auge, Alienor, additional, Hänggi, Martin, additional, Ali, Waleed, additional, Frasconi, Teresa M., additional, Wullschleger, Stephan, additional, Schlegel, Iris, additional, Matzner, Mirela, additional, Lüthi, Ursina, additional, Schlereth, Bernd, additional, Dawson, Keith M., additional, Kirkin, Vladimir, additional, Ochsenbein, Adrian F., additional, Grimm, Sebastian, additional, Reschke, Nina, additional, Riether, Carsten, additional, Steiner, Daniel, additional, Leupin, Nicolas, additional, and Goubier, Anne, additional

Published
2024
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4. A colorectal cancer classification system that associates cellular phenotype and responses to therapy

Author

Sadanandam, Anguraj, Lyssiotis, Costas A, Homicsko, Krisztian, Collisson, Eric A, Gibb, William J, Wullschleger, Stephan, Ostos, Liliane C Gonzalez, Lannon, William A, Grotzinger, Carsten, Del Rio, Maguy, Lhermitte, Benoit, Olshen, Adam B, Wiedenmann, Bertram, Cantley, Lewis C, Gray, Joe W, and Hanahan, Douglas

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Digestive Diseases, Colo-Rectal Cancer, Cancer, Genetics, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Cetuximab, Colon, Colorectal Neoplasms, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Markers, Humans, Neoplasm Metastasis, Oligonucleotide Array Sequence Analysis, Phenotype, Signal Transduction, Treatment Outcome, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Colorectal cancer (CRC) is a major cause of cancer mortality. Whereas some patients respond well to therapy, others do not, and thus more precise, individualized treatment strategies are needed. To that end, we analyzed gene expression profiles from 1,290 CRC tumors using consensus-based unsupervised clustering. The resultant clusters were then associated with therapeutic response data to the epidermal growth factor receptor-targeted drug cetuximab in 80 patients. The results of these studies define six clinically relevant CRC subtypes. Each subtype shares similarities to distinct cell types within the normal colon crypt and shows differing degrees of 'stemness' and Wnt signaling. Subtype-specific gene signatures are proposed to identify these subtypes. Three subtypes have markedly better disease-free survival (DFS) after surgical resection, suggesting these patients might be spared from the adverse effects of chemotherapy when they have localized disease. One of these three subtypes, identified by filamin A expression, does not respond to cetuximab but may respond to cMET receptor tyrosine kinase inhibitors in the metastatic setting. Two other subtypes, with poor and intermediate DFS, associate with improved response to the chemotherapy regimen FOLFIRI in adjuvant or metastatic settings. Development of clinically deployable assays for these subtypes and of subtype-specific therapies may contribute to more effective management of this challenging disease.

Published
2013

7. Abstract 5037: DARPins as powerful targeting agents for radioligand therapeutics

Author

Bosshart, Andreas, primary, Wullschleger, Stephan, additional, Behe, Martin, additional, Blanc, Alain, additional, Imobersteg, Stefan, additional, Neculcea, Alexandra, additional, Blunschi, Jacqueline, additional, Abduli, Liridon, additional, Schütz, Sarah, additional, Wolter, Julia, additional, Reichen, Christian, additional, Croset, Amelie, additional, Villa, Alessandra, additional, Lizak, Christian, additional, Goubier, Anne, additional, Schibli, Roger, additional, and Steiner, Daniel, additional

Published
2023
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10. Supplementary Table 3 from A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

Author

Sadanandam, Anguraj, primary, Wullschleger, Stephan, primary, Lyssiotis, Costas A., primary, Grötzinger, Carsten, primary, Barbi, Stefano, primary, Bersani, Samantha, primary, Körner, Jan, primary, Wafy, Ismael, primary, Mafficini, Andrea, primary, Lawlor, Rita T., primary, Simbolo, Michele, primary, Asara, John M., primary, Bläker, Hendrik, primary, Cantley, Lewis C., primary, Wiedenmann, Bertram, primary, Scarpa, Aldo, primary, and Hanahan, Douglas, primary

Published
2023
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11. Data from A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

Author

Sadanandam, Anguraj, primary, Wullschleger, Stephan, primary, Lyssiotis, Costas A., primary, Grötzinger, Carsten, primary, Barbi, Stefano, primary, Bersani, Samantha, primary, Körner, Jan, primary, Wafy, Ismael, primary, Mafficini, Andrea, primary, Lawlor, Rita T., primary, Simbolo, Michele, primary, Asara, John M., primary, Bläker, Hendrik, primary, Cantley, Lewis C., primary, Wiedenmann, Bertram, primary, Scarpa, Aldo, primary, and Hanahan, Douglas, primary

Published
2023
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14. Supplementary Figures 1 - 6 from A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

Author

Sadanandam, Anguraj, primary, Wullschleger, Stephan, primary, Lyssiotis, Costas A., primary, Grötzinger, Carsten, primary, Barbi, Stefano, primary, Bersani, Samantha, primary, Körner, Jan, primary, Wafy, Ismael, primary, Mafficini, Andrea, primary, Lawlor, Rita T., primary, Simbolo, Michele, primary, Asara, John M., primary, Bläker, Hendrik, primary, Cantley, Lewis C., primary, Wiedenmann, Bertram, primary, Scarpa, Aldo, primary, and Hanahan, Douglas, primary

Published
2023
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15. Supplementary Table 2 from A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

Author

Sadanandam, Anguraj, primary, Wullschleger, Stephan, primary, Lyssiotis, Costas A., primary, Grötzinger, Carsten, primary, Barbi, Stefano, primary, Bersani, Samantha, primary, Körner, Jan, primary, Wafy, Ismael, primary, Mafficini, Andrea, primary, Lawlor, Rita T., primary, Simbolo, Michele, primary, Asara, John M., primary, Bläker, Hendrik, primary, Cantley, Lewis C., primary, Wiedenmann, Bertram, primary, Scarpa, Aldo, primary, and Hanahan, Douglas, primary

Published
2023
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16. Supplementary Table 4 from A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

Author

Sadanandam, Anguraj, primary, Wullschleger, Stephan, primary, Lyssiotis, Costas A., primary, Grötzinger, Carsten, primary, Barbi, Stefano, primary, Bersani, Samantha, primary, Körner, Jan, primary, Wafy, Ismael, primary, Mafficini, Andrea, primary, Lawlor, Rita T., primary, Simbolo, Michele, primary, Asara, John M., primary, Bläker, Hendrik, primary, Cantley, Lewis C., primary, Wiedenmann, Bertram, primary, Scarpa, Aldo, primary, and Hanahan, Douglas, primary

Published
2023
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18. Supplementary Methods, Figure Legends, Table Legends from A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

Author

Sadanandam, Anguraj, primary, Wullschleger, Stephan, primary, Lyssiotis, Costas A., primary, Grötzinger, Carsten, primary, Barbi, Stefano, primary, Bersani, Samantha, primary, Körner, Jan, primary, Wafy, Ismael, primary, Mafficini, Andrea, primary, Lawlor, Rita T., primary, Simbolo, Michele, primary, Asara, John M., primary, Bläker, Hendrik, primary, Cantley, Lewis C., primary, Wiedenmann, Bertram, primary, Scarpa, Aldo, primary, and Hanahan, Douglas, primary

Published
2023
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19. Supplementary Table 1 from A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

Author

Sadanandam, Anguraj, primary, Wullschleger, Stephan, primary, Lyssiotis, Costas A., primary, Grötzinger, Carsten, primary, Barbi, Stefano, primary, Bersani, Samantha, primary, Körner, Jan, primary, Wafy, Ismael, primary, Mafficini, Andrea, primary, Lawlor, Rita T., primary, Simbolo, Michele, primary, Asara, John M., primary, Bläker, Hendrik, primary, Cantley, Lewis C., primary, Wiedenmann, Bertram, primary, Scarpa, Aldo, primary, and Hanahan, Douglas, primary

Published
2023
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22. MP0533: A Multispecific Darpin CD3 Engager Targeting CD33, CD123, and CD70 for the Treatment of AML and MDS Designed to Selectively Target Leukemic Stem Cells

Author

Bianchi, Matteo, primary, Reichen, Christian, additional, Fischer, Stefanie, additional, Grübler, Yvonne, additional, Eggenschwiler, Aline, additional, Marpakwar, Rajlakshmi, additional, Looser, Thamar, additional, Spitzli, Patricia, additional, Herzog, Christel, additional, Villemagne, Denis, additional, Kaufmann, Yvonne, additional, Auge, Alienor, additional, Hänggi, Martin, additional, Ali, Waleed, additional, Lekishvili, Tamara, additional, Frasconi, Teresa, additional, Wullschleger, Stephan, additional, Zitt, Christof, additional, Franchini, Marco, additional, Croset, Amelie, additional, Watson, Randall, additional, Kirkin, Vladimir, additional, Luethi, Ursina, additional, Ochsenbein, Adrian, additional, Riether, Carsten, additional, Steiner, Daniel, additional, Leupin, Nicolas, additional, and Goubier, Anne, additional

Published
2022
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25. TOR Signaling in Growth and Metabolism

Author

Wullschleger, Stephan, Loewith, Robbie, and Hall, Michael N.

Subjects
Cell research -- Physiological aspects, Cell research -- Analysis, Cell research -- Growth, Autoimmunity -- Physiological aspects, Autoimmunity -- Analysis, Autoimmunity -- Growth, Company growth, Biological sciences
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2006.01.016 Byline: Stephan Wullschleger (1), Robbie Loewith (2), Michael N. Hall (1) Abstract: The target of rapamycin (TOR) is a conserved Ser/Thr kinase that regulates cell growth and metabolism in response to environmental cues. Here, highlighting contributions from studies in model organisms, we review mammalian TOR complexes and the signaling branches they mediate. TOR is part of two distinct multiprotein complexes, TOR complex 1 (TORC1), which is sensitive to rapamycin, and TORC2, which is not. The physiological consequences of mammalian TORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders. Author Affiliation: (1) Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland (2) Department of Molecular Biology, University of Geneva, 30 quai Ernest-Ansermet, CH-1211 Geneve 4, Switzerland

Published
2006

28. PD-1-cisIL-2R agonism yields better effectors from stem-like CD8+T cells

Author

Codarri Deak, Laura, Nicolini, Valeria, Hashimoto, Masao, Karagianni, Maria, Schwalie, Petra C., Lauener, Laura, Varypataki, Eleni Maria, Richard, Marine, Bommer, Esther, Sam, Johannes, Joller, Stefanie, Perro, Mario, Cremasco, Floriana, Kunz, Leo, Yanguez, Emilio, Hüsser, Tamara, Schlenker, Ramona, Mariani, Marisa, Tosevski, Vinko, Herter, Sylvia, Bacac, Marina, Waldhauer, Inja, Colombetti, Sara, Gueripel, Xavier, Wullschleger, Stephan, Tichet, Melanie, Hanahan, Douglas, Kissick, Haydn T., Leclair, Stephane, Freimoser-Grundschober, Anne, Seeber, Stefan, Teichgräber, Volker, Ahmed, Rafi, Klein, Christian, and Umaña, Pablo

Abstract

Expansion and differentiation of antigen-experienced PD-1+TCF-1+stem-like CD8+T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade1–4. Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of ‘better effector’ CD8+T cells similar to those generated in an acute infection5. IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor β- and γ-chain (IL-2Rβγ)-biased agonists are currently being developed6–10. Here we show that IL-2Rβγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cisto PD-1. Cisbinding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell recovers the ability to differentiate stem-like CD8+T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.

Published
2022
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33. A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

Author

Sadanandam, Anguraj, primary, Wullschleger, Stephan, additional, Lyssiotis, Costas A., additional, Grötzinger, Carsten, additional, Barbi, Stefano, additional, Bersani, Samantha, additional, Körner, Jan, additional, Wafy, Ismael, additional, Mafficini, Andrea, additional, Lawlor, Rita T., additional, Simbolo, Michele, additional, Asara, John M., additional, Bläker, Hendrik, additional, Cantley, Lewis C., additional, Wiedenmann, Bertram, additional, Scarpa, Aldo, additional, and Hanahan, Douglas, additional

Published
2015
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34. Biodiversity and microbial safety of artisanal Malian sour milk fènè and development of adapted starter cultures for controlled production

Author

Wullschleger, Stephan M., Meile, Leo, and Lacroix, Christophe

Subjects
MILK FERMENTATION, FERMENTED MILK PRODUCTS, SOUR MILK PRODUCTS (DAIRYING), MALI (WESTERN AFRICA). REPUBLIC OF MALI, LEBENSMITTEL-SICHERHEIT + LEBENSMITTEL-ÜBERWACHUNG + LEBENSMITTEL-KONTROLLE + LEBENSMITTEL-CHEMIE (ÖFFENTLICHES GESUNDHEITSWESEN), MICROBIOLOGY OF MILK AND MILK PRODUCTS (DAIRYING), LEBENSMITTELHYGIENE (HUMANERNÄHRUNG), MIKROBIELLE LEBENSMITTELZUSÄTZE, STARTER- UND SCHUTZKULTUREN (LEBENSMITTELINDUSTRIE), Chemical engineering, MILCHSÄUERUNG, SAUERMILCHPRODUKTE UND FERMENTIERTE MILCHPRODUKTE (MILCHPRODUKTION), MICROBIAL FOOD ADDITIVES, PROTECTIVE AND STARTER CULTURES (FOOD INDUSTRY), MIKROBIOLOGIE VON MILCH UND MILCHPRODUKTEN (MILCHPRODUKTION), FOOD HYGIENE + FOOD SANITATION (HUMAN NUTRITION), FOOD INSPECTION + FOOD CHEMISTRY + FOOD SAFETY (PUBLIC HEALTH), MALI (WESTAFRIKA). REPUBLIK MALI, ddc:660, FOS: Chemical engineering
Published
2009
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42. Mutation of the PDK1 PH Domain Inhibits Protein Kinase B/Akt, Leading to Small Size and Insulin Resistance

Author

Bayascas, Jose R., primary, Wullschleger, Stephan, additional, Sakamoto, Kei, additional, García-Martínez, Juan M., additional, Clacher, Carol, additional, Komander, David, additional, van Aalten, Daan M. F., additional, Boini, Krishna M., additional, Lang, Florian, additional, Lipina, Christopher, additional, Logie, Lisa, additional, Sutherland, Calum, additional, Chudek, John A., additional, van Diepen, Janna A., additional, Voshol, Peter J., additional, Lucocq, John M., additional, and Alessi, Dario R., additional

Published
2008
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46. How moderate changes in Akt T-loop phosphorylation impact on tumorigenesis and insulin resistance

Author

Wullschleger, Stephan, Sakamoto, Kei, Johnstone, Lana, Duce, Suzanne, Fleming, Stewart, and Alessi, Dario R.

Abstract

The Akt signalling pathway plays vital roles in controlling cellular responses to insulin as well as in proliferation and survival. Inhibition of Akt signalling leads to insulin resistance and type 2 diabetes, whereas hyperactivation of Akt promotes tumorigenesis. In this study, we investigate how modest changes in the activity of the Akt signalling pathway, to an extent that might be achieved by drug treatment, would impact on insulin resistance and tumorigenesis. Using insulin-resistant PDK1K465E/K465E PH domain knock-in mice, we found that introducing the PTEN+/− mutation to slightly stimulate Akt restored normal insulin sensitivity. Introducing the PDK1K465E/K465E PH domain knock-in mutation into cancer-prone PTEN+/− mice, lowered Akt activity only by about 50%, but led to a delay in tumour onset of ∼4 months in a broad range of tumours. This was also accompanied by slower growth of B cell follicular lymphomas, as monitored by magnetic resonance imaging. Our findings imply that signal transduction inhibitors that lead to a modest reduction in Akt activity would not only delay onset of tumours possessing elevated phosphoinositide 3-kinase pathway activity but would also reduce the growth rate of developed tumours.

Published
2011
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48. Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor- reactive CD8+T cells and reprogramming macrophages

Author

Tichet, Melanie, Wullschleger, Stephan, Chryplewicz, Agnieszka, Fournier, Nadine, Marcone, Rachel, Kauzlaric, Annamaria, Homicsko, Krisztian, Deak, Laura Codarri, Umana, Pablo, Klein, Christian, and Hanahan, Douglas

Subjects
modulation, normalization, tolerance, antigen, pd-l1, expression, interleukin-2, immunotherapy, differentiation, cd8(+) t-cells
Abstract

Immunotherapies have shown remarkable, albeit tumor-selective, therapeutic benefits in the clinic. Most pa-tients respond transiently at best, highlighting the importance of understanding mechanisms underlying resistance. Herein, we evaluated the effects of the engineered immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer that is resistant to checkpoint and other immunotherapies. PD1-IL2v utilizes anti-PD-1 as a targeting moiety fused to an immuno-stimulatory IL-2 cytokine variant (IL2v) to precisely deliver IL2v to PD-1+ T cells in the tumor microenvironment. PD1-IL2v elicited substantial infiltration by stem-like CD8+ T cells, resulting in tumor regression and enhanced survival in mice. Combining anti-PD-L1 with PD1-IL2v sustained the response phase, improving therapeutic efficacy both by reprogram-ming immunosuppressive tumor-associated macrophages and enhancing T cell receptor (TCR) immune repertoire diversity. These data provide a rationale for clinical trials to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, particularly in immunotherapy-resistant tumors infiltrated with PD-1+ stem-like T cells.

49. Myeloid Cells Orchestrate Systemic Immunosuppression, Impairing the Efficacy of Immunotherapy against HPV + Cancers.

Author

Galliverti G, Wullschleger S, Tichet M, Murugan D, Zangger N, Horton W, Korman AJ, Coussens LM, Swartz MA, and Hanahan D

Subjects
Animals, CTLA-4 Antigen antagonists & inhibitors, Disease Models, Animal, Drug Synergism, Female, Humans, Immunosuppression Therapy, Immunotherapy methods, Mice, Myeloid Cells drug effects, Nanoparticles administration & dosage, Papillomavirus E7 Proteins immunology, Papillomavirus E7 Proteins metabolism, Papillomavirus Infections drug therapy, Papillomavirus Infections virology, Papillomavirus Vaccines administration & dosage, Programmed Cell Death 1 Receptor antagonists & inhibitors, Tumor Microenvironment, Uterine Cervical Neoplasms drug therapy, Uterine Cervical Neoplasms pathology, Uterine Cervical Neoplasms virology, Antineoplastic Agents, Immunological pharmacology, CD8-Positive T-Lymphocytes immunology, Myeloid Cells immunology, Papillomaviridae immunology, Papillomavirus Infections immunology, Papillomavirus Vaccines immunology, Uterine Cervical Neoplasms immunology
Abstract

Cancers induced by human papillomaviruses (HPV) should be responsive to immunotherapy by virtue of expressing the immunogenic oncoproteins E6/E7. However, advanced forms of cervical cancer, driven by HPV, are poorly responsive to immune response-enhancing treatments involving therapeutic vaccination against these viral neoantigens. Leveraging a transgenic mouse model of HPV-derived cancers, K14HPV16/H2b, we demonstrated that a potent nanoparticle-based E7 vaccine, but not a conventional "liquid" vaccine, induced E7 tumor antigen-specific CD8 + T cells in cervical tumor-bearing mice. Vaccination alone or in combination with anti-PD-1/anti-CTLA4 did not elicit tumor regression nor increase CD8 + T cells in the tumor microenvironment (TME), suggesting the presence of immune-suppressive barriers. Patients with cervical cancer have poor dendritic cell functions, have weak cytotoxic lymphocyte responses, and demonstrate an accumulation of myeloid cells in the periphery. Here, we illustrated that myeloid cells in K14HPV16/H2b mice possess potent immunosuppressive activity toward antigen-presenting cells and CD8 + T cells, dampening antitumor immunity. These immune-inhibitory effects inhibited synergistic effects of combining our oncoprotein vaccine with immune checkpoint-blocking antibodies. Our data highlighted a link between HPV-induced cancers, systemic amplification of myeloid cells, and the detrimental effects of myeloid cells on CD8 + T-cell activation and recruitment into the TME. These results established immunosuppressive myeloid cells in lymphoid organs as an HPV + cancer-induced means of circumventing tumor immunity that will require targeted abrogation to enable the induction of efficacious antitumor immune responses., (©2019 American Association for Cancer Research.)

Published
2020
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50. Quantitative MRI establishes the efficacy of PI3K inhibitor (GDC-0941) multi-treatments in PTEN-deficient mice lymphoma.

Author

Wullschleger S, García-Martínez JM, and Duce SL

Subjects
Animals, Cell Line, Tumor, Disease Models, Animal, Female, Head and Neck Neoplasms enzymology, Head and Neck Neoplasms pathology, Longitudinal Studies, Lymphoma, B-Cell enzymology, Lymphoma, B-Cell pathology, Lymphoma, Follicular enzymology, Lymphoma, Follicular pathology, Magnetic Resonance Imaging methods, Mice, Mice, Inbred C57BL, Mice, Transgenic, Enzyme Inhibitors pharmacology, Head and Neck Neoplasms drug therapy, Indazoles pharmacology, Lymphoma, B-Cell drug therapy, Lymphoma, Follicular drug therapy, PTEN Phosphohydrolase deficiency, Phosphoinositide-3 Kinase Inhibitors, Sulfonamides pharmacology
Abstract

Aim: To assess the efficacy of multiple treatment of phosphatidylinositol-3-kinase (PI3K) inhibitor on autochthonous tumours in phosphatase and tensin homologue (Pten)-deficient genetically engineered mouse cancer models using a longitudinal magnetic resonance imaging (MRI) protocol., Materials and Methods: Using 3D MRI, B-cell follicular lymphoma growth was quantified in a Pten(+/-)Lkb1(+/hypo) mouse line, before, during and after repeated treatments with a PI3K inhibitor GDC-0941 (75 mg/kg)., Results: Mean pre-treatment linear tumour growth rate was 16.5±12.8 mm(3)/week. Repeated 28-day GDC-0941 administration, with 21 days 'off-treatment', induced average tumour regression of 41±7%. Upon cessation of the second treatment (which was not permanently cytocidal), tumours re-grew with an average linear growth rate of 40.1±15.5 mm(3)/week. There was no evidence of chemoresistance., Conclusion: This protocol can accommodate complex dosing schedules, as well as combine different cancer therapies. It reduces biological variability problems and resulted in a 10-fold reduction in mouse numbers compared with terminal assessment methods. It is ideal for preclinical efficacy studies and for phenotyping molecularly characterized mouse models when investigating gene function.

Published
2012

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