Nair, Reshmi and Lannagan, Tamsin R.M. and Jackstadt, Rene and Andrusaite, Anna and Cole, John and Boyne, Caitlin and Nibbs, Robert J.B. and Sansom, Owen J. and Milling, Simon (2024) Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance. OncoImmunology, 13 (1): 2330194. ISSN 2162-4011
AI Summary:
The study used a genetically engineered mouse model to investigate the therapeutic modulation of immune response in metastatic colorectal cancer. The results showed that co-inhibition of TGF- and PD-L1 signaling enhanced cytotoxic CD8+ T cells and upregulated innate immune response and interferon gene signatures.AI Topics:
Colorectal cancer (CRC) is the third most prevalent cancer worldwide with a high mortality rate (20–30%), especially due to metastasis to adjacent organs. Clinical responses to chemotherapy, radiation, targeted and immunotherapies are limited to a subset of patients making metastatic CRC (mCRC) difficult to treat. To understand the therapeutic modulation of immune response in mCRC, we have used a genetically engineered mouse model (GEMM), “KPN”, which resembles the human ‘CMS4’-like subtype. We show here that transforming growth factor (TGF-β1), secreted by KPN organoids, increases cancer cell proliferation, and inhibits splenocyte activation in vitro. TGF-β1 also inhibits activation of naive but not pre-activated T cells, suggesting differential effects on specific immune cells. In vivo, the inhibition of TGF-β inflames the KPN tumors, causing infiltration of T cells, monocytes and monocytic intermediates, while reducing neutrophils and epithelial cells. Co-inhibition of TGF-β and PD-L1 signaling further enhances cytotoxic CD8+T cells and upregulates innate immune response and interferon gene signatures. However, simultaneous upregulation of cancer-related metabolic genes correlated with limited control of tumor burden and/or progression despite combination treatment. Our study illustrates the importance of using GEMMs to predict better immunotherapies for mCRC.
Nair, Reshmi
Author
Nair, Reshmi and Lannagan, Tamsin R.M. and Jackstadt, Rene and Andrusaite, Anna and Cole, John and Boyne, Caitlin and Nibbs, Robert J.B. and Sansom, Owen J. and Milling, Simon (2024) Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance. OncoImmunology, 13 (1): 2330194. ISSN 2162-4011
See full publications listLannagan, Tamsin R.M.
Author
Malviya, Gaurav and Lannagan, Tamsin R.M. and Johnson, Emma and Mackintosh, Agata and Bielik, Robert and Peters, Adam and Soloviev, Dmitry and Brown, Gavin and Jackstadt, Rene and Nixon, Colin and Gilroy, Kathryn and Campbell, Andrew and Sansom, Owen J. and Lewis, David Y. (2024) Noninvasive stratification of colon cancer by multiplex PET imaging. Clinical Cancer Research, 30 (8). pp. 1518-1529. ISSN 1078-0432
Nair, Reshmi and Lannagan, Tamsin R.M. and Jackstadt, Rene and Andrusaite, Anna and Cole, John and Boyne, Caitlin and Nibbs, Robert J.B. and Sansom, Owen J. and Milling, Simon (2024) Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance. OncoImmunology, 13 (1): 2330194. ISSN 2162-4011
Fetit, Rana and McLaren, Alistair S. and White, Mark and Mills, Megan L. and Falconer, John and Cortes-Lavaud, Xabier and Gilroy, Kathryn and Lannagan, Tamsin R.M. and Ridgway, Rachel A. and Nixon, Colin and Naiker, Varushka and Njunge, Renee and Clarke, Cassie and Whyte, Declan and Kirschner, Kristina and Jackstadt, Rene and Norman, Jim and Carlin, Leo M. and Campbell, Andrew D. and Sansom, Owen J. and Steele, Colin W. (2024) Characterising neutrophil subtypes in cancer using scRNA sequencing demonstrates the importance of IL-1β/CXCR2 axis in generation of metastasis specific neutrophils. Cancer Research Communications, 4 (2). pp. 588-606. ISSN 2767-9764
See full publications listJackstadt, Rene
Author
Malviya, Gaurav and Lannagan, Tamsin R.M. and Johnson, Emma and Mackintosh, Agata and Bielik, Robert and Peters, Adam and Soloviev, Dmitry and Brown, Gavin and Jackstadt, Rene and Nixon, Colin and Gilroy, Kathryn and Campbell, Andrew and Sansom, Owen J. and Lewis, David Y. (2024) Noninvasive stratification of colon cancer by multiplex PET imaging. Clinical Cancer Research, 30 (8). pp. 1518-1529. ISSN 1078-0432
Nair, Reshmi and Lannagan, Tamsin R.M. and Jackstadt, Rene and Andrusaite, Anna and Cole, John and Boyne, Caitlin and Nibbs, Robert J.B. and Sansom, Owen J. and Milling, Simon (2024) Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance. OncoImmunology, 13 (1): 2330194. ISSN 2162-4011
Pennel, Kathryn A.F. and Hatthakarnkul, Phimmada and Wood, Colin S. and Lian, Guang-Yu and Al-Badran, Sara and Quinn, Jean A. and Legrini, Assya and Inthagard, Jitwadee and Alexander, Peter G. and van Wyk, Hester and Kurniawan, Ahmad and Hashmi, Umar and Gillespie, Michael A. and Mills, Megan and Ammar, Aula and Hay, Jennifer and Andersen, Ditte and Nixon, Colin and Rebus, Selma and Chang, David K. and Kelly, Caroline and Harkin, Andrea and Graham, Janet and Church, David and Tomlinson, Ian and Saunders, Mark and Iveson, Tim and Lannagan, Tamsin R. M. and Jackstadt, Rene and Maka, Noori and Horgan, Paul G. and Roxburgh, Campbell S. D. and Sansom, Owen J. and McMillan, Donald C. and Steele, Colin W. and Jamieson, Nigel B. and Park, James H. and Roseweir, Antonia K. and Edwards, Joanne (2024) JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors. Journal of Experimental and Clinical Cancer Research, 43: 64. ISSN 1756-9966
See full publications listAndrusaite, Anna
Author
Milling, Simon and Ijaz, Umer Zeeshan and Venieri, Danae and Christidis, George E. and Rattray, Nicholas J. W. and Gounaki, Iosifina and Andrusaite, Anna and Hareendran, Aravind and Knapp, Charles W. and Jones, Alexander X. and Photos-Jones, Effie (2024) Beneficial modulation of the gut microbiome by leachates of Penicillium purpurogenum in the presence of clays: A model for the preparation and efficacy of historical Lemnian Earth. PLoS ONE, 19 (12): e0313090. ISSN 1932-6203
Nair, Reshmi and Lannagan, Tamsin R.M. and Jackstadt, Rene and Andrusaite, Anna and Cole, John and Boyne, Caitlin and Nibbs, Robert J.B. and Sansom, Owen J. and Milling, Simon (2024) Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance. OncoImmunology, 13 (1): 2330194. ISSN 2162-4011
See full publications listCole, John
Author
Ramirez-Guzman, Lizbeth A. and Huang, Wenjing and Cole, John J. and Jorgensen, Heather G. (2024) GAS2 upregulation is a targetable vulnerability in chronic myeloid leukaemia. International Journal of Translational Medicine, 4 (2). pp. 354-368. ISSN 2673-8937
Nair, Reshmi and Lannagan, Tamsin R.M. and Jackstadt, Rene and Andrusaite, Anna and Cole, John and Boyne, Caitlin and Nibbs, Robert J.B. and Sansom, Owen J. and Milling, Simon (2024) Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance. OncoImmunology, 13 (1): 2330194. ISSN 2162-4011
See full publications listBoyne, Caitlin
Author
Nair, Reshmi and Lannagan, Tamsin R.M. and Jackstadt, Rene and Andrusaite, Anna and Cole, John and Boyne, Caitlin and Nibbs, Robert J.B. and Sansom, Owen J. and Milling, Simon (2024) Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance. OncoImmunology, 13 (1): 2330194. ISSN 2162-4011
See full publications listNibbs, Rob
Author
Nair, Reshmi and Lannagan, Tamsin R.M. and Jackstadt, Rene and Andrusaite, Anna and Cole, John and Boyne, Caitlin and Nibbs, Robert J.B. and Sansom, Owen J. and Milling, Simon (2024) Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance. OncoImmunology, 13 (1): 2330194. ISSN 2162-4011
McIntyre, Kirsty and Sherry, Leighann and Stapleton, Genevieve and Latkovskis, Imants and McDonnell, Neil and Nibbs, Rob and Douce, Gillian and Milling, Simon (2023) Can Virtual Reality (VR) enhance students’ learning experience? Journal of Perspectives in Applied Academic Practice, 11 (3). pp. 3-9. ISSN 2051-9788
See full publications listSansom, Owen J.
Author
Nair, Reshmi and Lannagan, Tamsin R.M. and Jackstadt, Rene and Andrusaite, Anna and Cole, John and Boyne, Caitlin and Nibbs, Robert J.B. and Sansom, Owen J. and Milling, Simon (2024) Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance. OncoImmunology, 13 (1): 2330194. ISSN 2162-4011
Malla, Sudhir B. and Byrne, Ryan M. and Lafarge, Maxime W. and Corry, Shania M. and Fisher, Natalie C. and Tsantoulis, Petros K. and Mills, Megan L. and Ridgway, Rachel A. and Lannagan, Tamsin R. M. and Najumudeen, Arafath K. and Gilroy, Kathryn L. and Amirkhah, Raheleh and Maguire, Sarah L. and Mulholland, Eoghan J. and Belnoue-Davis, Hayley L. and Grassi, Elena and Viviani, Marco and Rogan, Emily and Redmond, Keara L. and Sakhnevych, Svetlana and McCooey, Aoife J. and Bull, Courtney and Hoey, Emily and Sinevici, Nicoleta and Hall, Holly and Ahmaderaghi, Baharak and Domingo, Enric and Blake, Andrew and Richman, Susan D. and Isella, Claudio and Miller, Crispin and Bertotti, Andrea and Trusolino, Livio and Loughrey, Maurice B. and Kerr, Emma M. and Tejpar, Sabine and S:CORT consortium and Maughan, Timothy S. and Lawler, Mark and Campbell, Andrew D. and Leedham, Simon J. and Koelzer, Viktor H. and Sansom, Owen J. and Dunne, Philip D. (2024) Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer. Nature Genetics, 56 (3). pp. 458-472. ISSN 1061-4036
See full publications listMilling, Simon
Author
Milling, Simon and Ijaz, Umer Zeeshan and Venieri, Danae and Christidis, George E. and Rattray, Nicholas J. W. and Gounaki, Iosifina and Andrusaite, Anna and Hareendran, Aravind and Knapp, Charles W. and Jones, Alexander X. and Photos-Jones, Effie (2024) Beneficial modulation of the gut microbiome by leachates of Penicillium purpurogenum in the presence of clays: A model for the preparation and efficacy of historical Lemnian Earth. PLoS ONE, 19 (12): e0313090. ISSN 1932-6203
MacDonald, Lucy and Elmesmari, Aziza and Somma, Domenico and Frew, Jack and Di Mario, Clara and Madhu, Roopa and Paoletti, Audrey and Simakou, Theodoros and Hardy, Olympia M. and Tolusso, Barbara and Campobasso, Denise and Perniola, Simone and Gessi, Marco and Gigante, Maria Rita and Petricca, Luca and Bruno, Dario and Coletto, Lavinia Agra and Benvenuto, Roberta and Isaacs, John D. and Filby, Andrew and McDonald, David and Sim, Jasmine P.X. and Jamieson, Nigel and Wei, Kevin and D’Agostino, Maria Antonietta and Millar, Neal L. and Milling, Simon and McSharry, Charles and Gremese, Elisa and Affleck, Karen and Baker, Kenneth F. and McInnes, Iain B. and Otto, Thomas D. and Korsunsky, Ilya and Alivernini, Stefano and Kurowska-Stolarska, Mariola (2024) Synovial tissue myeloid dendritic cell subsets exhibit distinct tissue-niche localization and function in health and rheumatoid arthritis. Immunity, 57 (12). 2843-2862.e12. ISSN 1074-7613
Nichols, Ben and Briola, Anny and Logan, Michael and Havlik, Jaroslav and Mascellani, Anna and Gkikas, Konstantinos and Milling, Simon and Ijaz, Umer Zeeshan and Quince, Christopher and Svolos, Vaios and Russell, Richard K. and Hansen, Richard and Gerasimidis, Konstantinos (2024) Gut metabolome and microbiota signatures predict response to treatment with exclusive enteral nutrition in a prospective study in children with active Crohn’s disease. American Journal of Clinical Nutrition, 119 (4). pp. 885-895. ISSN 0002-9165
See full publications listAvailable under License Creative Commons Attribution.
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