CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors

• 成果类型: Article
• 署名作者: Skoulidis, Ferdinandos; Araujo, Haniel A.; Minh Truong Do; Qian, Yu; Sun, Xin; Cobo, Ana Galan; Le, John T.; Montesion, Meagan; Palmer, Rachael; Jahchan, Nadine; Juan, Joseph M.; Min, Chengyin; Yu, Yi; Pan, Xuewen; Arbour, Kathryn C.; Vokes, Natalie; Schmidt, Stephanie T.; Molkentine, David; Owen, Dwight H.; Memmott, Regan; Patil, Pradnya D.; Marmarelis, Melina E.; Awad, Mark M.; Murray, Joseph C.; Hellyer, Jessica A.; Gainor, Justin F.; Dimou, Anastasios; Bestvina, Christine M.; Shu, Catherine A.; Riess, Jonathan W.; Blakely, Collin M.; Pecot, Chad, V; Mezquita, Laura; Tabbo, Fabrizio; Scheffler, Matthias; Digumarthy, Subba; Mooradian, Meghan J.; Sacher, Adrian G.; Lau, Sally C. M.; Saltos, Andreas N.; Rotow, Julia; Johnson, Rocio Perez; Liu, Corinne; Stewart, Tyler; Goldberg, Sarah B.; Killam, Jonathan; Walther, Zenta; Schalper, Kurt; Davies, Kurtis D.; Woodcock, Mark G.; Anagnostou, Valsamo; Marrone, Kristen A.; Forde, Patrick M.; Ricciuti, Biagio; Venkatraman, Deepti; Van Allen, Eliezer M.; Cummings, Amy L.; Goldman, Jonathan W.; Shaish, Hiram; Kier, Melanie; Katz, Sharyn; Aggarwal, Charu; Ni, Ying; Azok, Joseph T.; Segal, Jeremy; Ritterhouse, Lauren; Neal, Joel W.; Lacroix, Ludovic; Elamin, Yasir Y.; Negrao, Marcelo, V; Le, Xiuning; Lam, Vincent K.; Lewis, Whitney E.; Kemp, Haley N.; Carter, Brett; Roth, Jack A.; Swisher, Stephen; Lee, Richard; Zhou, Teng; Poteete, Alissa; Kong, Yifan; Takehara, Tomohiro; Paula, Alvaro Guimaraes; Cuentas, Edwin R. Parra; Behrens, Carmen; Wistuba, Ignacio I.; Zhang, Jianjun; Blumenschein, George R.; Gay, Carl; Byers, Lauren A.; Gibbons, Don L.; Tsao, Anne; Lee, J. Jack; Bivona, Trever G.; Camidge, D. Ross; Gray, Jhannelle E.; Lieghl, Natasha; Levy, Benjamin; Brahmer, Julie R.; Garassino, Marina C.; Gandara, David R.; Garon, Edward B.; Rizvi, Naiyer A.; Scagliotti, Giorgio Vittorio; Wolf, Jurgen; Planchard, David; Besse, Benjamin; Herbst, Roy S.; Wakelee, Heather A.; Pennell, Nathan A.; Shaw, Alice T.; Janne, Pasi A.; Carbone, David P.; Hellmann, Matthew D.; Rudin, Charles M.; Albacker, Lee; Mann, Helen; Zhu, Zhou; Lai, Zhongwu; Stewart, Ross; Peters, Solange; Johnson, Melissa L.; Wong, Kwok K.; Huang, Alan; Winslow, Monte M.; Rosen, Michael J.; Winters, Ian P.; Papadimitrakopoulou, Vassiliki A.; Cascone, Tina; Jewsbury, Philip; Heymach, John, V
• 署名单位: University of Texas System; UTMD Anderson Cancer Center; Foundation Medicine; Memorial Sloan Kettering Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University System of Ohio; Ohio State University; James Cancer Hospital & Solove Research Institute; Cleveland Clinic Foundation; University of Pennsylvania; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Johns Hopkins University; Johns Hopkins Medicine; Stanford University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Mayo Clinic; University of Chicago; Columbia University; University of California System; University of California Davis; University of California System; University of California San Francisco; University of North Carolina; University of North Carolina Chapel Hill; University of Barcelona; Hospital Clinic de Barcelona; University of Cologne; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; H Lee Moffitt Cancer Center & Research Institute; Memorial Sloan Kettering Cancer Center; University of California System; University of California San Diego; Yale University; Northwell Health; North Shore University Hospital; Yale University; University of Colorado System; University of Colorado Anschutz Medical Campus; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; Icahn School of Medicine at Mount Sinai; University of Chicago; UNICANCER; Gustave Roussy; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Colorado System; University of Colorado Anschutz Medical Campus; University of Colorado Denver; University of Turin; Novartis; Novartis USA; AstraZeneca; AstraZeneca; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); Tennessee Oncology; Sarah Cannon Research Institute; Pfizer; Pfizer USA
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4465
• DOI: 10.1038/s41586-024-07943-7
• 发表日期: 2024-11-14
• 页码: 462-+
• 关键词: cooccurring genomic alterations; nivolumab plus ipilimumab; cell lung-cancer; nrf2 activation; checkmate 9la; kras; expression; adenocarcinoma; chemotherapy; mutations

摘要

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial(3). Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1 was the strongest genomic predictor of dual ICB efficacy-a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1 and STK11 alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8(+) cytotoxic T cells, but relative sparing of CD4(+) effector subsets. Dual ICB potently engaged CD4(+) effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4(+) and CD8(+) T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations.