{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T22:12:28Z","timestamp":1794262348152,"version":"4.9.0"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"7984","license":[{"start":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T00:00:00Z","timestamp":1696377600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T00:00:00Z","timestamp":1696377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2023,10,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance\n                    <jats:sup>1,2<\/jats:sup>\n                    . The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells\u00a0or immune cells promotes anti-tumour immunity\n                    <jats:sup>3\u20136<\/jats:sup>\n                    . However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2009cell function by enhancing JAK\u2013STAT signalling and reducing T\u2009cell dysfunction. Inhibitors of\u00a0PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\/study\/NCT04777994?term=NCT04777994&amp;rank=1\">NCT04777994<\/jats:ext-link>\n                    ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of\u00a0antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.\n                  <\/jats:p>","DOI":"10.1038\/s41586-023-06575-7","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T12:01:40Z","timestamp":1696420900000},"page":"850-862","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":200,"title":["The PTPN2\/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity"],"prefix":"10.1038","volume":"622","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6872-6209","authenticated-orcid":false,"given":"Christina K.","family":"Baumgartner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hakimeh","family":"Ebrahimi-Nik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6635-3904","authenticated-orcid":false,"given":"Arvin","family":"Iracheta-Vellve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith M.","family":"Hamel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3356-7631","authenticated-orcid":false,"given":"Kira E.","family":"Olander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G. R.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen A.","family":"McGuire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoff T.","family":"Halvorsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3853-9939","authenticated-orcid":false,"given":"Omar I.","family":"Avila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chirag H.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah Y.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5284-721X","authenticated-orcid":false,"given":"Ashwin V.","family":"Kammula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2009-6313","authenticated-orcid":false,"given":"Audrey J.","family":"Muscato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Halliwill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasanthi","family":"Geda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly L.","family":"Klinge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoming","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Duggan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Mu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell D.","family":"Yeary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1733-6702","authenticated-orcid":false,"given":"James C.","family":"Patti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler M.","family":"Balon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Mathew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carey","family":"Backus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5329-3711","authenticated-orcid":false,"given":"Domenick E.","family":"Kennedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angeline","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenton","family":"Longenecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph T.","family":"Klahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cara L.","family":"Hrusch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navasona","family":"Krishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles W.","family":"Hutchins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jax P.","family":"Dunning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marinka","family":"Bulic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Payal","family":"Tiwari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayla J.","family":"Colvin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cun Lan","family":"Chuong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian C.","family":"Kohnle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2987-7581","authenticated-orcid":false,"given":"Matthew G.","family":"Rees","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Boghossian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4269-1404","authenticated-orcid":false,"given":"Melissa","family":"Ronan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5117-5586","authenticated-orcid":false,"given":"Jennifer A.","family":"Roth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6847-7065","authenticated-orcid":false,"given":"Meng-Ju","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliette S. M. T.","family":"Suermondt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0384-1097","authenticated-orcid":false,"given":"Nelson H.","family":"Knudsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Collins K.","family":"Cheruiyot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0947-8284","authenticated-orcid":false,"given":"Debattama R.","family":"Sen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel K.","family":"Griffin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0113-2403","authenticated-orcid":false,"given":"Todd R.","family":"Golub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3867-0416","authenticated-orcid":false,"given":"Nabeel","family":"El-Bardeesy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua H.","family":"Decker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magali","family":"Guffroy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey","family":"Fossey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Trusk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Im-Meng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcia N.","family":"Paddock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4084-0093","authenticated-orcid":false,"given":"Elliot P.","family":"Farney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Matulenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clay","family":"Beauregard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M.","family":"Frost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7383-5573","authenticated-orcid":false,"given":"Kathleen B.","family":"Yates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8161-9715","authenticated-orcid":false,"given":"Philip R.","family":"Kym","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1336-413X","authenticated-orcid":false,"given":"Robert T.","family":"Manguso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,10,4]]},"reference":[{"key":"6575_CR1","doi-asserted-by":"crossref","unstructured":"Hugo, W. et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35\u201344 (2016).","DOI":"10.1016\/j.cell.2016.02.065"},{"key":"6575_CR2","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1200\/EDBK_240837","volume":"39","author":"CM Fares","year":"2019","unstructured":"Fares, C. M., Van Allen, E. M., Drake, C. G., Allison, J. P. & Hu-Lieskovan, S. Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients? Am. Soc. Clin. Oncol. Educ. Book 39, 147\u2013164 (2019).","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"6575_CR3","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/nature23270","volume":"547","author":"RT Manguso","year":"2017","unstructured":"Manguso, R. T. et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 547, 413\u2013418 (2017).","journal-title":"Nature"},{"key":"6575_CR4","doi-asserted-by":"publisher","first-page":"e103637","DOI":"10.15252\/embj.2019103637","volume":"39","author":"F Wiede","year":"2020","unstructured":"Wiede, F. et al. PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours. EMBO J. 39, e103637 (2020).","journal-title":"EMBO J."},{"key":"6575_CR5","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1038\/s41590-019-0480-4","volume":"20","author":"MW LaFleur","year":"2019","unstructured":"LaFleur, M. W. et al. PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity. Nat. Immunol. 20, 1335\u20131347 (2019).","journal-title":"Nat. Immunol."},{"key":"6575_CR6","doi-asserted-by":"publisher","first-page":"107957","DOI":"10.1016\/j.celrep.2020.107957","volume":"32","author":"M Flosbach","year":"2020","unstructured":"Flosbach, M. et al. PTPN2 deficiency enhances programmed T cell expansion and survival capacity of activated T cells. Cell Rep. 32, 107957 (2020).","journal-title":"Cell Rep."},{"key":"6575_CR7","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1016\/S0960-9822(02)00697-8","volume":"12","author":"PD Simoncic","year":"2002","unstructured":"Simoncic, P. D., Lee-Loy, A., Barber, D. L., Tremblay, M. L. & McGlade, C. J. The T cell protein tyrosine phosphatase is a negative regulator of Janus family kinases 1 and 3. Curr. Biol. 12, 446\u2013453 (2002).","journal-title":"Curr. Biol."},{"key":"6575_CR8","doi-asserted-by":"publisher","first-page":"5662","DOI":"10.1128\/MCB.22.16.5662-5668.2002","volume":"22","author":"J ten Hoeve","year":"2002","unstructured":"ten Hoeve, J. et al. Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol. Cell. Biol. 22, 5662\u20135668 (2002).","journal-title":"Mol. Cell. Biol."},{"key":"6575_CR9","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1182\/blood.V106.11.418.418","volume":"106","author":"IS Lossos","year":"2005","unstructured":"Lossos, I. S., Lu, X. & Tiganis, T. PTPN2, distinctively expressed in GCB-like and ABC-like DLBCL, is the nuclear phosphatase of STAT6. Blood 106, 418\u2013418 (2005).","journal-title":"Blood"},{"key":"6575_CR10","doi-asserted-by":"publisher","first-page":"1968","DOI":"10.1053\/j.gastro.2020.07.040","volume":"159","author":"M Parlato","year":"2020","unstructured":"Parlato, M. et al. Loss-of-function mutation in PTPN2 causes aberrant activation of JAK signaling via STAT and very early onset intestinal inflammation. Gastroenterology 159, 1968\u20131971.e4 (2020).","journal-title":"Gastroenterology"},{"key":"6575_CR11","doi-asserted-by":"crossref","unstructured":"Wiede, F. et al. PTP1B is an intracellular checkpoint that limits T-cell and CAR T-cell anti-tumor immunity. Cancer Discov. 12, 752\u2013773 (2022).","DOI":"10.1158\/2159-8290.CD-21-0694"},{"key":"6575_CR12","doi-asserted-by":"publisher","first-page":"4758","DOI":"10.1172\/JCI59492","volume":"121","author":"F Wiede","year":"2011","unstructured":"Wiede, F. et al. T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. J. Clin. Invest. 121, 4758\u20134774 (2011).","journal-title":"J. Clin. Invest."},{"key":"6575_CR13","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1038\/s41586-020-2265-1","volume":"583","author":"JED Thaventhiran","year":"2020","unstructured":"Thaventhiran, J. E. D. et al. Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature 583, 90\u201395 (2020).","journal-title":"Nature"},{"key":"6575_CR14","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1038\/nrd.2018.201","volume":"17","author":"A Mullard","year":"2018","unstructured":"Mullard, A. Phosphatases start shedding their stigma of undruggability. Nat. Rev. Drug Discov. 17, 847\u2013849 (2018).","journal-title":"Nat. Rev. Drug Discov."},{"key":"6575_CR15","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1021\/acs.accounts.6b00537","volume":"50","author":"Z-Y Zhang","year":"2017","unstructured":"Zhang, Z.-Y. Drugging the undruggable: therapeutic potential of targeting protein tyrosine phosphatases. Acc. Chem. Res. 50, 122\u2013129 (2017).","journal-title":"Acc. Chem. Res."},{"key":"6575_CR16","doi-asserted-by":"publisher","first-page":"2333","DOI":"10.1021\/jm901090b","volume":"53","author":"AP Combs","year":"2010","unstructured":"Combs, A. P. Recent advances in the discovery of competitive protein tyrosine phosphatase 1B inhibitors for the treatment of diabetes, obesity, and cancer. J. Med. Chem. 53, 2333\u20132344 (2010).","journal-title":"J. Med. Chem."},{"key":"6575_CR17","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1038\/nature18621","volume":"535","author":"Y-NP Chen","year":"2016","unstructured":"Chen, Y.-N. P. et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature 535, 148\u2013152 (2016).","journal-title":"Nature"},{"key":"6575_CR18","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545\u201315550 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"6575_CR19","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1038\/nbt.3460","volume":"34","author":"C Yu","year":"2016","unstructured":"Yu, C. et al. High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines. Nat. Biotechnol. 34, 419\u2013423 (2016).","journal-title":"Nat. Biotechnol."},{"key":"6575_CR20","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1038\/nature07201","volume":"454","author":"R Medzhitov","year":"2008","unstructured":"Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428\u2013435 (2008).","journal-title":"Nature"},{"key":"6575_CR21","doi-asserted-by":"publisher","first-page":"3457","DOI":"10.1182\/blood-2003-09-3153","volume":"103","author":"KM Heinonen","year":"2004","unstructured":"Heinonen, K. M. et al. T-cell protein tyrosine phosphatase deletion results in progressive systemic inflammatory disease. Blood 103, 3457\u20133464 (2004).","journal-title":"Blood"},{"key":"6575_CR22","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1084\/jem.186.5.683","volume":"186","author":"KE You-Ten","year":"1997","unstructured":"You-Ten, K. E. et al. Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase\u2013deficient mice. J. Exp. Med. 186, 683\u2013693 (1997).","journal-title":"J. Exp. Med."},{"key":"6575_CR23","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/nature05911","volume":"447","author":"Wellcome Trust Case Control Consortium.","year":"2007","unstructured":"Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661\u2013678 (2007).","journal-title":"Nature"},{"key":"6575_CR24","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1097\/CJI.0000000000000408","volume":"45","author":"SL Lambert","year":"2022","unstructured":"Lambert, S. L. et al. Association of baseline and pharmacodynamic biomarkers with outcomes in patients treated with the PD-1 inhibitor budigalimab. J. Immunother. 45, 167\u2013179 (2022).","journal-title":"J. Immunother."},{"key":"6575_CR25","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/S0092-8674(00)81683-9","volume":"100","author":"D Hanahan","year":"2000","unstructured":"Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57\u201370 (2000).","journal-title":"Cell"},{"key":"6575_CR26","first-page":"1486","volume":"58","author":"BA Pulaski","year":"1998","unstructured":"Pulaski, B. A. & Ostrand-Rosenberg, S. Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines. Cancer Res. 58, 1486\u20131493 (1998).","journal-title":"Cancer Res."},{"key":"6575_CR27","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.1038\/s41590-022-01315-x","volume":"23","author":"J Dubrot","year":"2022","unstructured":"Dubrot, J. et al. In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer. Nat. Immunol. 23, 1495\u20131506 (2022).","journal-title":"Nat. Immunol."},{"key":"6575_CR28","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.4049\/jimmunol.127.5.1754","volume":"127","author":"N Hanna","year":"1981","unstructured":"Hanna, N. & Burton, R. C. Definitive evidence that natural killer (NK) cells inhibit experimental tumor metastases in vivo. J. Immunol. 127, 1754\u20131758 (1981).","journal-title":"J. Immunol."},{"key":"6575_CR29","first-page":"929","volume":"65","author":"JE Talmadge","year":"1980","unstructured":"Talmadge, J. E., Meyers, K. M., Prieur, D. J. & Starkey, J. R. Role of natural killer cells in tumor growth and metastasis: C57BL\/6 normal and beige mice. J. Natl Cancer Inst. 65, 929\u2013935 (1980).","journal-title":"J. Natl Cancer Inst."},{"key":"6575_CR30","doi-asserted-by":"publisher","first-page":"4483","DOI":"10.1158\/0008-5472.CAN-14-3499","volume":"75","author":"D Anz","year":"2015","unstructured":"Anz, D. et al. Suppression of intratumoral CCL22 by type I interferon inhibits migration of regulatory T cells and blocks cancer progression. Cancer Res. 75, 4483\u20134493 (2015).","journal-title":"Cancer Res."},{"key":"6575_CR31","doi-asserted-by":"publisher","first-page":"e22057","DOI":"10.7554\/eLife.22057","volume":"6","author":"A Madi","year":"2017","unstructured":"Madi, A. et al. T cell receptor repertoires of mice and humans are clustered in similarity networks around conserved public CDR3 sequences. eLife 6, e22057 (2017).","journal-title":"eLife"},{"key":"6575_CR32","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1038\/s41587-020-0505-4","volume":"38","author":"H Huang","year":"2020","unstructured":"Huang, H., Wang, C., Rubelt, F., Scriba, T. J. & Davis, M. M. Analyzing the Mycobacterium tuberculosis immune response by T-cell receptor clustering with GLIPH2 and genome-wide antigen screening. Nat. Biotechnol. 38, 1194\u20131202 (2020).","journal-title":"Nat. Biotechnol."},{"key":"6575_CR33","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1038\/s41590-019-0312-6","volume":"20","author":"BC Miller","year":"2019","unstructured":"Miller, B. C. et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326\u2013336 (2019).","journal-title":"Nat. Immunol."},{"key":"6575_CR34","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nature19330","volume":"537","author":"SJ Im","year":"2016","unstructured":"Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417\u2013421 (2016).","journal-title":"Nature"},{"key":"6575_CR35","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.cell.2018.10.038","volume":"175","author":"M Sade-Feldman","year":"2018","unstructured":"Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998\u20131013.e20 (2018).","journal-title":"Cell"},{"key":"6575_CR36","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/s41586-019-1325-x","volume":"571","author":"O Khan","year":"2019","unstructured":"Khan, O. et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571, 211\u2013218 (2019).","journal-title":"Nature"},{"key":"6575_CR37","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/s41586-022-05257-0","volume":"610","author":"M Hashimoto","year":"2022","unstructured":"Hashimoto, M. et al. PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program. Nature 610, 173\u2013181 (2022).","journal-title":"Nature"},{"key":"6575_CR38","doi-asserted-by":"publisher","unstructured":"Beltra, J.-C. et al. Enhanced STAT5a activation rewires exhausted CD8 T cells during chronic stimulation to acquire a hybrid durable effector like state. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/2022.10.03.509766 (2022).","DOI":"10.1101\/2022.10.03.509766"},{"key":"6575_CR39","doi-asserted-by":"publisher","first-page":"2101","DOI":"10.1182\/blood-2007-06-096297","volume":"111","author":"JA Wofford","year":"2008","unstructured":"Wofford, J. A., Wieman, H. L., Jacobs, S. R., Zhao, Y. & Rathmell, J. C. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood 111, 2101\u20132111 (2008).","journal-title":"Blood"},{"key":"6575_CR40","doi-asserted-by":"publisher","first-page":"16601","DOI":"10.1073\/pnas.1003457107","volume":"107","author":"TW Hand","year":"2010","unstructured":"Hand, T. W. et al. Differential effects of STAT5 and PI3K\/AKT signaling on effector and memory CD8 T-cell survival. Proc. Natl Acad. Sci. USA 107, 16601\u201316606 (2010).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"6575_CR41","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1038\/s41590-019-0403-4","volume":"20","author":"C Yao","year":"2019","unstructured":"Yao, C. et al. Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection. Nat. Immunol. 20, 890\u2013901 (2019).","journal-title":"Nat. Immunol."},{"key":"6575_CR42","doi-asserted-by":"publisher","first-page":"4781","DOI":"10.1182\/blood-2005-12-4818","volume":"107","author":"MR Betts","year":"2006","unstructured":"Betts, M. R. et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107, 4781\u20134789 (2006).","journal-title":"Blood"},{"key":"6575_CR43","doi-asserted-by":"publisher","first-page":"1857","DOI":"10.1158\/1078-0432.CCR-06-1905","volume":"13","author":"MO Butler","year":"2007","unstructured":"Butler, M. O. et al. Long-lived antitumor CD8+ lymphocytes for adoptive therapy generated using an artificial antigen-presenting cell. Clin. Cancer Res. 13, 1857\u20131867 (2007).","journal-title":"Clin. Cancer Res."},{"key":"6575_CR44","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1056\/NEJMoa1604958","volume":"375","author":"JM Zaretsky","year":"2016","unstructured":"Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819\u2013829 (2016).","journal-title":"N. Engl. J. Med."},{"key":"6575_CR45","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1158\/2159-8290.CD-16-1223","volume":"7","author":"DS Shin","year":"2017","unstructured":"Shin, D. S. et al. Primary resistance to PD-1 blockade mediated by JAK1\/2 mutations. Cancer Discov. 7, 188\u2013201 (2017).","journal-title":"Cancer Discov."},{"key":"6575_CR46","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01062-w","volume":"8","author":"M Sade-Feldman","year":"2017","unstructured":"Sade-Feldman, M. et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat. Commun. 8, 1136 (2017).","journal-title":"Nat. Commun."},{"key":"6575_CR47","doi-asserted-by":"publisher","first-page":"1259","DOI":"10.1016\/j.cell.2017.10.001","volume":"171","author":"N McGranahan","year":"2017","unstructured":"McGranahan, N. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171, 1259\u20131271.e11 (2017).","journal-title":"Cell"},{"key":"6575_CR48","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.immuni.2019.01.006","volume":"50","author":"C-CS Pai","year":"2019","unstructured":"Pai, C.-C. S. et al. Clonal deletion of tumor-specific T cells by interferon-\u03b3 confers therapeutic resistance to combination immune checkpoint blockade. Immunity 50, 477\u2013492.e8 (2019).","journal-title":"Immunity"},{"key":"6575_CR49","unstructured":"Halvorsen, G. T., Frost, J. M. & Kym, P. R. Protein tyrosine phosphatase inhibitors and methods of use thereof. US patent 10,851,073 B2 (2020)."},{"key":"6575_CR50","unstructured":"Farney, E. et al. Protein tyrosine phosphotase inhibitors and methods of use thereof. World patent 2019, 246513 A1 (2019)."},{"key":"6575_CR51","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1124\/dmd.106.012294","volume":"35","author":"JC Kalvass","year":"2007","unstructured":"Kalvass, J. C., Maurer, T. S. & Pollack, G. M. Use of plasma and brain unbound fractions to assess the extent of brain distribution of 34 drugs: comparison of unbound concentration ratios to in vivo p-glycoprotein efflux ratios. Drug Metab. Dispos. 35, 660\u2013666 (2007).","journal-title":"Drug Metab. Dispos."},{"key":"6575_CR52","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","volume":"30","author":"AM Bolger","year":"2014","unstructured":"Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114\u20132120 (2014).","journal-title":"Bioinformatics"},{"key":"6575_CR53","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/nbt.3519","volume":"34","author":"NL Bray","year":"2016","unstructured":"Bray, N. L., Pimentel, H., Melsted, P. & Pachter, L. Near-optimal probabilistic RNA-seq quantification. Nat. Biotechnol. 34, 525\u2013527 (2016).","journal-title":"Nat. Biotechnol."},{"key":"6575_CR54","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).","journal-title":"Genome Biol."},{"key":"6575_CR55","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","volume":"1","author":"A Liberzon","year":"2015","unstructured":"Liberzon, A. et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 1, 417\u2013425 (2015).","journal-title":"Cell Syst."},{"key":"6575_CR56","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1038\/s43018-019-0018-6","volume":"1","author":"SM Corsello","year":"2020","unstructured":"Corsello, S. M. et al. Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling. Nat. Cancer\u00a01, 235\u2013248 (2020).","journal-title":"Nat. Cancer"},{"key":"6575_CR57","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1382-0","volume":"19","author":"FA Wolf","year":"2018","unstructured":"Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15 (2018).","journal-title":"Genome Biol."},{"key":"6575_CR58","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","volume":"16","author":"I Korsunsky","year":"2019","unstructured":"Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289\u20131296 (2019).","journal-title":"Nat. Methods"},{"key":"6575_CR59","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41592-018-0303-9","volume":"16","author":"V Ntranos","year":"2019","unstructured":"Ntranos, V., Yi, L., Melsted, P. & Pachter, L. A discriminative learning approach to differential expression analysis for single-cell RNA-seq. Nat. Methods 16, 163\u2013166 (2019).","journal-title":"Nat. Methods"},{"key":"6575_CR60","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1038\/nature14404","volume":"523","author":"S Spranger","year":"2015","unstructured":"Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic \u03b2-catenin signalling prevents anti-tumour immunity. Nature 523, 231\u2013235 (2015).","journal-title":"Nature"},{"key":"6575_CR61","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1038\/nmeth.3364","volume":"12","author":"DA Bolotin","year":"2015","unstructured":"Bolotin, D. A. et al. MiXCR: software for comprehensive adaptive immunity profiling. Nat. Methods 12, 380\u2013381 (2015).","journal-title":"Nat. Methods"},{"key":"6575_CR62","doi-asserted-by":"publisher","first-page":"358","DOI":"10.17796\/1053-4628-41.5.358","volume":"41","author":"N Tickotsky","year":"2017","unstructured":"Tickotsky, N., Petel, R., Araki, R. & Moskovitz, M. Caries progression rate in primary teeth: a retrospective study. J. Clin. Pediatr. Dent. 41, 358\u2013361 (2017).","journal-title":"J. Clin. Pediatr. Dent."},{"key":"6575_CR63","doi-asserted-by":"publisher","first-page":"e1008555","DOI":"10.1371\/journal.ppat.1008555","volume":"16","author":"M Zhao","year":"2020","unstructured":"Zhao, M. et al. Rapid in vitro generation of bona fide exhausted CD8+ T cells is accompanied by Tcf7 promotor methylation. PLoS Pathog. 16, e1008555 (2020).","journal-title":"PLoS Pathog."}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41586-023-06575-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-023-06575-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-023-06575-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T19:03:33Z","timestamp":1698260613000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41586-023-06575-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,4]]},"references-count":63,"journal-issue":{"issue":"7984","published-print":{"date-parts":[[2023,10,26]]}},"alternative-id":["6575"],"URL":"https:\/\/doi.org\/10.1038\/s41586-023-06575-7","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.742802078.793601193","asserted-by":"object"}]},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,4]]},"assertion":[{"value":"15 July 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 October 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This manuscript stems from a collaboration between the Broad Institute, AbbVie and Calico Sciences. Equal financial support for the design and study conduct for this research were provided by AbbVie and Calico. R.T.M. and K.B.Y. receive research funding from Calico Life Sciences. C.K.B., K.M.H., K.A.M., K.H., K.L.K., R.D., L.M., R.M., C.\u00a0Backus, D.E.K., A.C., J.T.K., C.L.H., C.W.H., J.P.D., M.B., J.H.D., Y.Y., M.G., S.F., P.\u00a0Trusk, W.Q., Q.S., E.P.F., M.A.M., J.M.F. and P.R.K. are employees of AbbVie. P.G. was an employee of AbbVie at the time she contributed to the manuscript and is now an employee of Bristol Myers Squibb. Z.X. was an employee of AbbVie at the time he contributed to the manuscript and is now an employee of Ipsen Therapeutics. K.L. was an employee of AbbVie at the time he contributed to the manuscript. N.K. was an employee of AbbVie at the time he contributed to the manuscript and is now an employee of Pfizer. G.T.H. is a deceased author who was an employee of AbbVie at the time of the study. A.I.-V. was an employee of the Broad Institute at the time he contributed to the manuscript and is now an employee of Monte Rosa Therapeutics. M.N.P., C.H.P., I.-M.S. and Y.L. are employees of Calico Life Sciences. T.R.G. has paid scientific advisory roles and equity in Dewpoint Therapeutics and Anji Pharmaceuticals, holds founder\u2019s equity in Sherlock Biosciences, is a paid advisor to Braidwell and has research funding from Bayer HealthCare, Calico Life Sciences and Novo Holdings. R.T.M. has received consulting or speaking fees from Bristol Myers Squibb, Gilead Sciences and Immunai Therapeutics, has equity ownership in OncoRev, and receives research funding from Calico Life Sciences. C.\u00a0Beauregard was an employee of Calico Life Sciences at the time he contributed to the manuscript and is now an employee of Vir Biotechnology. AbbVie, Calico Life Sciences and the Broad Institute participated in the interpretation of data, review and approval of the publication. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}