{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T08:26:26Z","timestamp":1793262386007,"version":"4.5.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T00:00:00Z","timestamp":1595462400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T00:00:00Z","timestamp":1595462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"ASTAR","award":["H18\/01\/a0\/018"],"award-info":[{"award-number":["H18\/01\/a0\/018"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Imaging Biol"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Purpose<\/jats:title>\n<jats:p>Immune checkpoint inhibitor (ICI) monotherapy and combination regimens are being actively pursued as strategies to improve durable response rates in cancer patients. However, the biology surrounding combination therapies is not well understood and may increase the likelihood of immune-mediated adverse events. Accurate stratification of ICI response by non-invasive PET imaging may help ensure safe therapy management across a wide number of cancer phenotypes.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Procedures<\/jats:title>\n<jats:p>We have assessed the ability of a fluorine-labelled peptide, [<jats:sup>18<\/jats:sup>F]AlF-mNOTA-GZP, targeting granzyme B, to stratify ICI response in two syngeneic models of colon cancer, CT26 and MC38. <jats:italic>In vivo<\/jats:italic> tumour uptake of [<jats:sup>18<\/jats:sup>F]AlF-mNOTA-GZP following ICI monotherapy, or in combination with PD-1 was characterised and correlated with changes in tumour-associated immune cell populations.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>[<jats:sup>18<\/jats:sup>F]AlF-<jats:italic>m<\/jats:italic>NOTA-GZP showed good predictive ability and correlated well with changes in tumour-associated T cells, especially CD8+ T cells; however, overall uptake and response to monotherapy or combination therapies was very different in the CT26 and MC38 tumours, likely due to the immunostimulatory environment imbued by the MSI-high phenotype in MC38 tumours.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>[<jats:sup>18<\/jats:sup>F]AlF-<jats:italic>m<\/jats:italic>NOTA-GZP uptake correlates well with changes in CD8+ T cell populations and is able to stratify tumour response to a range of ICIs administered as monotherapies or in combination. However, tracer uptake can be significantly affected by preexisting phenotypic abnormalities potentially confusing data interpretation.<\/jats:p>\n<\/jats:sec>","DOI":"10.1007\/s11307-020-01519-3","type":"journal-article","created":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T16:03:45Z","timestamp":1595520225000},"page":"1392-1402","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Granzyme B PET Imaging of Immune Checkpoint Inhibitor Combinations in Colon Cancer Phenotypes"],"prefix":"10.1007","volume":"22","author":[{"given":"J. L.","family":"Goggi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. X.","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. V.","family":"Hartimath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Jieu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. Y.","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Boominathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. Y.","family":"Yuen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. X.","family":"Chin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. R.","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Larbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. M.","family":"Chacko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Renia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Johannes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0156-8082","authenticated-orcid":false,"given":"Edward G.","family":"Robins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,23]]},"reference":[{"issue":"2","key":"1519_CR1","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1158\/2326-6066.CIR-13-0078","volume":"1","author":"JR Brahmer","year":"2013","unstructured":"Brahmer JR, Pardoll DM (2013) Immune checkpoint inhibitors: making immunotherapy a reality for the treatment of lung cancer. Cancer Immunol Res 1(2):85\u201391","journal-title":"Cancer Immunol Res"},{"key":"1519_CR2","doi-asserted-by":"publisher","unstructured":"Llosa NJ, Luber B, Siegel N, Awan AH, Oke T, Zhu Q, Bartlett BR, Aulakh LK, Thompson ED, Jaffee EM, Durham JN, Sears CL, Le DT, Diaz\u00a0Jr LA, Pardoll DM,\u00a0 Wang H, Housseau F and Anders RA (2019)\u00a0Immunopathologic stratification of colorectal cancer for checkpoint blockade immunotherapy. Cancer Immunol Res.\u00a0https:\/\/doi.org\/10.1158\/2326-6066.CIR-18-0927","DOI":"10.1158\/2326-6066.CIR-18-0927"},{"issue":"4","key":"1519_CR3","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/nrc3239","volume":"12","author":"DM Pardoll","year":"2012","unstructured":"Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252\u2013264","journal-title":"Nat Rev Cancer"},{"issue":"9","key":"1519_CR4","doi-asserted-by":"publisher","first-page":"3335","DOI":"10.1172\/JCI83871","volume":"125","author":"Y Yang","year":"2015","unstructured":"Yang Y (2015) Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest 125(9):3335\u20133337","journal-title":"J Clin Invest"},{"key":"1519_CR5","doi-asserted-by":"publisher","first-page":"453","DOI":"10.3389\/fimmu.2019.00453","volume":"10","author":"DO Khair","year":"2019","unstructured":"Khair DO, Bax HJ, Mele S, Crescioli S, Pellizzari G, Khiabany A, Nakamura M, Harris RJ, French E, Hoffmann RM, Williams IP, Cheung A, Thair B, Beales CT, Touizer E, Signell AW, Tasnova NL, Spicer JF, Josephs DH, Geh JL, MacKenzie Ross A, Healy C, Papa S, Lacy KE, Karagiannis SN (2019) Combining immune checkpoint inhibitors: established and emerging targets and strategies to improve outcomes in melanoma. Front Immunol 10:453","journal-title":"Front Immunol"},{"key":"1519_CR6","first-page":"100420","volume":"25","author":"L Michel","year":"2019","unstructured":"Michel L, Rassaf T, Totzeck M (2019) Cardiotoxicity from immune checkpoint inhibitors. Int J Cardiol Heart Vasc 25:100420","journal-title":"Int J Cardiol Heart Vasc"},{"issue":"2","key":"1519_CR7","doi-asserted-by":"publisher","DOI":"10.1136\/esmoopen-2018-000482","volume":"4","author":"HC Puhr","year":"2019","unstructured":"Puhr HC, Ilhan-Mutlu A (2019) New emerging targets in cancer immunotherapy: the role of LAG3. ESMO Open 4(2):e000482","journal-title":"ESMO Open"},{"key":"1519_CR8","doi-asserted-by":"publisher","first-page":"7005","DOI":"10.2147\/OTT.S170385","volume":"11","author":"Y He","year":"2018","unstructured":"He Y, Cao J, Zhao C, Li X, Zhou C, Hirsch FR (2018) TIM-3, a promising target for cancer immunotherapy. OncoTargets Ther 11:7005\u20137009","journal-title":"OncoTargets Ther"},{"key":"1519_CR9","doi-asserted-by":"crossref","unstructured":"Solinas C, Migliori E, De Silva P, Willard-Gallo K (2019) LAG3: The biological processes that motivate targeting this immune checkpoint molecule in human cancer. Cancers 11(8):1213","DOI":"10.3390\/cancers11081213"},{"issue":"6","key":"1519_CR10","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1038\/nm.3179","volume":"19","author":"N Gagliani","year":"2013","unstructured":"Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, Guo B, Herbert D'BR, Bulfone A, Trentini F, di Serio C, Bacchetta R, Andreani M, Brockmann L, Gregori S, Flavell RA, Roncarolo MG (2013) Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 19(6):739\u2013746","journal-title":"Nat Med"},{"key":"1519_CR11","doi-asserted-by":"publisher","first-page":"34","DOI":"10.3389\/fonc.2015.00034","volume":"5","author":"SN Linch","year":"2015","unstructured":"Linch SN, McNamara MJ, Redmond WL (2015) OX40 agonists and combination immunotherapy: putting the pedal to the metal. Front Oncol 5:34","journal-title":"Front Oncol"},{"issue":"12","key":"1519_CR12","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/j.trecan.2019.10.006","volume":"5","author":"I Catalano","year":"2019","unstructured":"Catalano I, Grassi E, Bertotti A, Trusolino L (2019) Immunogenomics of colorectal tumors: facts and hypotheses on an evolving saga. Trends Cancer 5(12):779\u2013788","journal-title":"Trends Cancer"},{"issue":"6","key":"1519_CR13","doi-asserted-by":"publisher","first-page":"8509","DOI":"10.1002\/jcp.27782","volume":"234","author":"B Farhood","year":"2019","unstructured":"Farhood B, Najafi M, Mortezaee K (2019) CD8(+) cytotoxic T lymphocytes in cancer immunotherapy: a review. J Cell Physiol 234(6):8509\u20138521","journal-title":"J Cell Physiol"},{"key":"1519_CR14","doi-asserted-by":"crossref","unstructured":"Seo JW, Tavare R, Mahakian LM, Silvestrini MT, Tam S, Ingham ES, Salazar FB, Borowsky AD, Wu AM, Ferrara KW (2018) CD8(+) T-cell density imaging with (64)cu-labeled Cys-diabody informs immunotherapy protocols. Clin Cancer Res 24(20):4976\u20134987","DOI":"10.1158\/1078-0432.CCR-18-0261"},{"issue":"10","key":"1519_CR15","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.2967\/jnumed.116.173930","volume":"57","author":"BM Larimer","year":"2016","unstructured":"Larimer BM, Wehrenberg-Klee E, Caraballo A, Mahmood U (2016) Quantitative CD3 PET imaging predicts tumor growth response to anti-CTLA-4 therapy. J Nucl Med 57(10):1607\u20131611","journal-title":"J Nucl Med"},{"issue":"4","key":"1519_CR16","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1158\/1078-0432.CCR-18-2407","volume":"25","author":"BM Larimer","year":"2019","unstructured":"Larimer BM, Bloch E, Nesti S, Austin EE, Wehrenberg-Klee E, Boland G, Mahmood U (2019) The effectiveness of checkpoint inhibitor combinations and administration timing can be measured by granzyme B PET imaging. Clin Cancer Res 25(4):1196\u20131205","journal-title":"Clin Cancer Res"},{"issue":"9","key":"1519_CR17","doi-asserted-by":"publisher","first-page":"2318","DOI":"10.1158\/0008-5472.CAN-16-3346","volume":"77","author":"BM Larimer","year":"2017","unstructured":"Larimer BM, Wehrenberg-Klee E, Dubois F, Mehta A, Kalomeris T, Flaherty K, Boland G, Mahmood U (2017) Granzyme B PET imaging as a predictive biomarker of immunotherapy response. Cancer Res 77(9):2318\u20132327","journal-title":"Cancer Res"},{"key":"1519_CR18","doi-asserted-by":"crossref","unstructured":"Goggi JL, Hartimath SV, Hwang Y, Tan YX, Khanapur S, Ramasamy B, Jiang L, Yong FF, Cheng P, Tan PW, Husaini MAR, Yuen TY, Jieu B, Chacko AM, Larbi A, Renia L, Johannes C, Robins EG (2020) Examining immunotherapy response using multiple radiotracers. Mol Imaging Biol 22:993\u20131002","DOI":"10.1007\/s11307-020-01477-w"},{"key":"1519_CR19","doi-asserted-by":"crossref","unstructured":"Fersing C, Bouhlel A, Cantelli C, Garrigue P, Lisowski V, Guillet B (2019) A comprehensive review of non-covalent radiofluorination approaches using aluminum [(18)F]fluoride: will [(18)F]AlF replace (68)Ga for metal chelate labeling? Molecules 24(16):2866","DOI":"10.3390\/molecules24162866"},{"key":"1519_CR20","doi-asserted-by":"crossref","unstructured":"Evrard C, Tachon G, Randrian V, Karayan-Tapon L, Tougeron D (2019) Microsatellite instability: diagnosis, heterogeneity, discordance, and clinical impact in colorectal cancer. Cancers 11(10):1567","DOI":"10.3390\/cancers11101567"},{"issue":"3","key":"1519_CR21","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1007\/BF00300234","volume":"24","author":"MM Tomayko","year":"1989","unstructured":"Tomayko MM, Reynolds CP (1989) Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol 24(3):148\u2013154","journal-title":"Cancer Chemother Pharmacol"},{"key":"1519_CR22","doi-asserted-by":"crossref","unstructured":"McBride WJ, Sharkey RM, Karacay H, D'Souza CA, Rossi EA, Laverman P, Chang C-H, Boerman OC and Goldenberg DM (2009) A novel method of 18F radiolabeling for PET. J Nucl Med 50(6):991\u2013998","DOI":"10.2967\/jnumed.108.060418"},{"issue":"2","key":"1519_CR23","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1172\/JCI122216","volume":"129","author":"D Kumar","year":"2019","unstructured":"Kumar D, Lisok A, Dahmane E, McCoy M, Shelake S, Chatterjee S, Allaj V, Sysa-Shah P, Wharram B, Lesniak WG, Tully E, Gabrielson E, Jaffee EM, Poirier JT, Rudin CM, Gobburu JVS, Pomper MG, Nimmagadda S (2019) Peptide-based PET quantifies target engagement of PD-L1 therapeutics. J Clin Invest 129(2):616\u2013630","journal-title":"J Clin Invest"},{"key":"1519_CR24","doi-asserted-by":"crossref","unstructured":"Lesniak WG, Mease RC, Chatterjee S, Kumar D, Lisok A, Wharram B, Kalagadda VR, Emens LA, Pomper MG, Nimmagadda S (2019) Development of [(18)F]FPy-WL12 as a PD-L1 specific PET imaging peptide. Mol Imaging 18:1536012119852189","DOI":"10.1177\/1536012119852189"},{"issue":"6","key":"1519_CR25","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1084\/jem.20182395","volume":"216","author":"JM Fritz","year":"2019","unstructured":"Fritz JM, Lenardo MJ (2019) Development of immune checkpoint therapy for cancer. J Exp Med 216(6):1244\u20131254","journal-title":"J Exp Med"},{"issue":"6","key":"1519_CR26","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1038\/s41590-019-0346-9","volume":"20","author":"DV Sawant","year":"2019","unstructured":"Sawant DV, Yano H, Chikina M, Zhang Q, Liao M, Liu C, Callahan DJ, Sun Z, Sun T, Tabib T, Pennathur A, Corry DB, Luketich JD, Lafyatis R, Chen W, Poholek AC, Bruno TC, Workman CJ, Vignali DAA (2019) Adaptive plasticity of IL-10(+) and IL-35(+) Treg cells cooperatively promotes tumor T cell exhaustion. Nat Immunol 20(6):724\u2013735","journal-title":"Nat Immunol"},{"key":"1519_CR27","doi-asserted-by":"crossref","unstructured":"Mlecnik B, Van den Eynde M, Bindea G, Church SE, Vasaturo A, Fredriksen T, et al. Comprehensive intrametastatic immune quantification and major impact of immunoscore on survival. J Natl Cancer Instit. 2018;110(1)","DOI":"10.1093\/jnci\/djx123"},{"issue":"25","key":"1519_CR28","doi-asserted-by":"publisher","first-page":"2500","DOI":"10.1056\/NEJMc1713444","volume":"377","author":"M Yarchoan","year":"2017","unstructured":"Yarchoan M, Hopkins A, Jaffee EM (2017) Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 377(25):2500\u20132501","journal-title":"N Engl J Med"},{"issue":"1\u20132","key":"1519_CR29","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.cell.2014.12.033","volume":"160","author":"MS Rooney","year":"2015","unstructured":"Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N (2015) Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160(1\u20132):48\u201361","journal-title":"Cell"},{"key":"1519_CR30","doi-asserted-by":"publisher","first-page":"15659","DOI":"10.1038\/srep15659","volume":"5","author":"CW Kang","year":"2015","unstructured":"Kang CW, Dutta A, Chang LY, Mahalingam J, Lin YC, Chiang JM, Hsu CY, Huang CT, Su WT, Chu YY, Lin CY (2015) Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer. Sci Rep 5:15659","journal-title":"Sci Rep"}],"container-title":["Molecular Imaging and Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11307-020-01519-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11307-020-01519-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11307-020-01519-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T23:27:34Z","timestamp":1626996454000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11307-020-01519-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,23]]},"references-count":30,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,10]]}},"alternative-id":["1519"],"URL":"https:\/\/doi.org\/10.1007\/s11307-020-01519-3","relation":{},"ISSN":["1536-1632","1860-2002"],"issn-type":[{"value":"1536-1632","type":"print"},{"value":"1860-2002","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,23]]},"assertion":[{"value":"23 July 2020","order":1,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"The authors declare no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}