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

Ferdinandos Skoulidis (), Haniel A. Araujo, Minh Truong Do, Yu Qian, Xin Sun, Ana Galan Cobo, John T. Le, Meagan Montesion, Rachael Palmer, Nadine Jahchan, Joseph M. Juan, Chengyin Min, Yi Yu, Xuewen Pan, Kathryn C. Arbour, Natalie Vokes, Stephanie T. Schmidt, David Molkentine, Dwight H. Owen, Regan Memmott, Pradnya D. Patil, Melina E. Marmarelis, Mark M. Awad, Joseph C. Murray, Jessica A. Hellyer, Justin F. Gainor, Anastasios Dimou, Christine M. Bestvina, Catherine A. Shu, Jonathan W. Riess, Collin M. Blakely, Chad V. Pecot, Laura Mezquita, Fabrizio Tabbó, Matthias Scheffler, Subba Digumarthy, Meghan J. Mooradian, Adrian G. Sacher, Sally C. M. Lau, Andreas N. Saltos, Julia Rotow, Rocio Perez Johnson, Corinne Liu, Tyler Stewart, Sarah B. Goldberg, Jonathan Killam, Zenta Walther, Kurt Schalper, Kurtis D. Davies, Mark G. Woodcock, Valsamo Anagnostou, Kristen A. Marrone, Patrick M. Forde, Biagio Ricciuti, Deepti Venkatraman, Eliezer M. Allen, Amy L. Cummings, Jonathan W. Goldman, Hiram Shaish, Melanie Kier, Sharyn Katz, Charu Aggarwal, Ying Ni, Joseph T. Azok, Jeremy Segal, Lauren Ritterhouse, Joel W. Neal, Ludovic Lacroix, Yasir Y. Elamin, Marcelo V. Negrao, Xiuning Le, Vincent K. Lam, Whitney E. Lewis, Haley N. Kemp, Brett Carter, Jack A. Roth, Stephen Swisher, Richard Lee, Teng Zhou, Alissa Poteete, Yifan Kong, Tomohiro Takehara, Alvaro Guimaraes Paula, Edwin R. Parra Cuentas, Carmen Behrens, Ignacio I. Wistuba, Jianjun Zhang, George R. Blumenschein, Carl Gay, Lauren A. Byers, Don L. Gibbons, Anne Tsao, J. Jack Lee, Trever G. Bivona, D. Ross Camidge, Jhannelle E. Gray, Natasha B. Leighl, Benjamin Levy, Julie R. Brahmer, Marina C. Garassino, David R. Gandara, Edward B. Garon, Naiyer A. Rizvi, Giorgio Vittorio Scagliotti, Jürgen Wolf, David Planchard, Benjamin Besse, Roy S. Herbst, Heather A. Wakelee, Nathan A. Pennell, Alice T. Shaw, Pasi A. Jänne, David P. Carbone, Matthew D. Hellmann, Charles M. Rudin, Lee Albacker, Helen Mann, Zhou Zhu, Zhongwu Lai, Ross Stewart, Solange Peters, Melissa L. Johnson, Kwok K. Wong, Alan Huang, Monte M. Winslow, Michael J. Rosen, Ian P. Winters, Vassiliki A. Papadimitrakopoulou, Tina Cascone, Philip Jewsbury and John V. Heymach ()
Additional contact information
Ferdinandos Skoulidis: University of Texas MD Anderson Cancer Center
Haniel A. Araujo: University of Texas MD Anderson Cancer Center
Minh Truong Do: University of Texas MD Anderson Cancer Center
Yu Qian: University of Texas MD Anderson Cancer Center
Xin Sun: University of Texas MD Anderson Cancer Center
Ana Galan Cobo: University of Texas MD Anderson Cancer Center
John T. Le: University of Texas MD Anderson Cancer Center
Meagan Montesion: Foundation Medicine
Rachael Palmer: Pionyr Immunotherapeutics
Nadine Jahchan: Pionyr Immunotherapeutics
Joseph M. Juan: D2G Oncology
Chengyin Min: Tango Therapeutics
Yi Yu: Tango Therapeutics
Xuewen Pan: Tango Therapeutics
Kathryn C. Arbour: Memorial Sloan Kettering Cancer Center
Natalie Vokes: University of Texas MD Anderson Cancer Center
Stephanie T. Schmidt: Department of Genomic Medicine and the Institute for Data Science in Oncology, University of Texas MD Anderson Cancer Center
David Molkentine: University of Texas MD Anderson Cancer Center
Dwight H. Owen: Division of Medical Oncology, Ohio State University–James Comprehensive Cancer Center
Regan Memmott: Division of Medical Oncology, Ohio State University–James Comprehensive Cancer Center
Pradnya D. Patil: Cleveland Clinic
Melina E. Marmarelis: Perelman School of Medicine at the University of Pennsylvania
Mark M. Awad: Dana-Farber Cancer Institute
Joseph C. Murray: Johns Hopkins University School of Medicine
Jessica A. Hellyer: Stanford University
Justin F. Gainor: Massachussetts General Hospital
Anastasios Dimou: Mayo Clinic
Christine M. Bestvina: University of Chicago
Catherine A. Shu: Columbia University
Jonathan W. Riess: University of California Davis Comprehensive Cancer Center
Collin M. Blakely: University of California San Francisco
Chad V. Pecot: UNC Lineberger Comprehensive Cancer Center
Laura Mezquita: Hospital Clinic de Barcelona
Fabrizio Tabbó: Ospedale Michele e Pietro Ferrero
Matthias Scheffler: University Hospital Cologne
Subba Digumarthy: Massachussetts General Hospital
Meghan J. Mooradian: Massachussetts General Hospital
Adrian G. Sacher: Princess Margaret Cancer Centre
Sally C. M. Lau: NYU Langone Perlmutter Cancer Center
Andreas N. Saltos: H. Lee Moffitt Cancer Center
Julia Rotow: Dana-Farber Cancer Institute
Rocio Perez Johnson: Memorial Sloan Kettering Cancer Center
Corinne Liu: Memorial Sloan Kettering Cancer Center
Tyler Stewart: University of California San Diego
Sarah B. Goldberg: Yale School of Medicine
Jonathan Killam: North Shore University Hospital
Zenta Walther: Yale School of Medicine
Kurt Schalper: Yale School of Medicine
Kurtis D. Davies: University of Colorado Anschutz Medical Campus
Mark G. Woodcock: UNC Lineberger Comprehensive Cancer Center
Valsamo Anagnostou: Johns Hopkins University School of Medicine
Kristen A. Marrone: Johns Hopkins University School of Medicine
Patrick M. Forde: Johns Hopkins University School of Medicine
Biagio Ricciuti: Dana-Farber Cancer Institute
Deepti Venkatraman: Dana-Farber Cancer Institute
Eliezer M. Allen: Dana-Farber Cancer Institute
Amy L. Cummings: David Geffen School of Medicine at the University of California
Jonathan W. Goldman: David Geffen School of Medicine at the University of California
Hiram Shaish: Columbia University
Melanie Kier: Icahn School of Medicine at Mount Sinai
Sharyn Katz: Perelman School of Medicine at the University of Pennsylvania
Charu Aggarwal: Perelman School of Medicine at the University of Pennsylvania
Ying Ni: Cleveland Clinic
Joseph T. Azok: Cleveland Clinic
Jeremy Segal: University of Chicago
Lauren Ritterhouse: Foundation Medicine
Joel W. Neal: Stanford University
Ludovic Lacroix: Institut Gustave Roussy
Yasir Y. Elamin: University of Texas MD Anderson Cancer Center
Marcelo V. Negrao: University of Texas MD Anderson Cancer Center
Xiuning Le: University of Texas MD Anderson Cancer Center
Vincent K. Lam: Johns Hopkins University School of Medicine
Whitney E. Lewis: University of Texas MD Anderson Cancer Center
Haley N. Kemp: University of Texas MD Anderson Cancer Center
Brett Carter: University of Texas MD Anderson Cancer Center
Jack A. Roth: University of Texas MD Anderson Cancer Center
Stephen Swisher: University of Texas MD Anderson Cancer Center
Richard Lee: University of Texas MD Anderson Cancer Center
Teng Zhou: University of Texas MD Anderson Cancer Center
Alissa Poteete: University of Texas MD Anderson Cancer Center
Yifan Kong: University of Texas MD Anderson Cancer Center
Tomohiro Takehara: University of Texas MD Anderson Cancer Center
Alvaro Guimaraes Paula: University of Texas MD Anderson Cancer Center
Edwin R. Parra Cuentas: University of Texas MD Anderson Cancer Center
Carmen Behrens: University of Texas MD Anderson Cancer Center
Ignacio I. Wistuba: University of Texas MD Anderson Cancer Center
Jianjun Zhang: University of Texas MD Anderson Cancer Center
George R. Blumenschein: University of Texas MD Anderson Cancer Center
Carl Gay: University of Texas MD Anderson Cancer Center
Lauren A. Byers: University of Texas MD Anderson Cancer Center
Don L. Gibbons: University of Texas MD Anderson Cancer Center
Anne Tsao: University of Texas MD Anderson Cancer Center
J. Jack Lee: University of Texas MD Anderson Cancer Center
Trever G. Bivona: University of California San Francisco
D. Ross Camidge: University of Colorado Cancer Center
Jhannelle E. Gray: H. Lee Moffitt Cancer Center
Natasha B. Leighl: Princess Margaret Cancer Centre
Benjamin Levy: Johns Hopkins University School of Medicine
Julie R. Brahmer: Johns Hopkins University School of Medicine
Marina C. Garassino: University of Chicago
David R. Gandara: University of California Davis Comprehensive Cancer Center
Edward B. Garon: David Geffen School of Medicine at the University of California
Naiyer A. Rizvi: Synthekine
Giorgio Vittorio Scagliotti: University of Turin
Jürgen Wolf: University Hospital Cologne
David Planchard: Institut Gustave Roussy
Benjamin Besse: Institut Gustave Roussy
Roy S. Herbst: Yale School of Medicine
Heather A. Wakelee: Stanford University
Nathan A. Pennell: Cleveland Clinic
Alice T. Shaw: Novartis Institute for Biomedical Research
Pasi A. Jänne: Dana-Farber Cancer Institute
David P. Carbone: Division of Medical Oncology, Ohio State University–James Comprehensive Cancer Center
Matthew D. Hellmann: AstraZeneca
Charles M. Rudin: Memorial Sloan Kettering Cancer Center
Lee Albacker: Foundation Medicine
Helen Mann: AstraZeneca
Zhou Zhu: AstraZeneca
Zhongwu Lai: AstraZeneca
Ross Stewart: AstraZeneca
Solange Peters: Lausanne University
Melissa L. Johnson: Sarah Cannon Research Institute, Tennessee Oncology
Kwok K. Wong: NYU Langone Perlmutter Cancer Center
Alan Huang: Tango Therapeutics
Monte M. Winslow: D2G Oncology
Michael J. Rosen: D2G Oncology
Ian P. Winters: D2G Oncology
Vassiliki A. Papadimitrakopoulou: Pfizer
Tina Cascone: University of Texas MD Anderson Cancer Center
Philip Jewsbury: AstraZeneca
John V. Heymach: University of Texas MD Anderson Cancer Center

Nature, 2024, vol. 635, issue 8038, 462-471

Abstract: Abstract 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 trial3. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07943-7

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