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

Affiliations

• Department of Thoracic and Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
• Foundation Medicine, Cambridge, MA, USA.
• Pionyr Immunotherapeutics, South San Francisco, CA, USA.
• D2G Oncology, Mountain View,CA, USA.
• Tango Therapeutics, Boston, MA, USA.
• Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Department of Genomic Medicine and the Institute for Data Science in Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
• Division of Medical Oncology, Ohio State University–James Comprehensive Cancer Center, Columbus, OH, USA.
• Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
• Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
• Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
• Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
• Department of Genetics, Stanford University, Stanford, CA, USA.
• Massachussetts General Hospital, Boston, MA, USA.
• Department of Oncology, Mayo Clinic, Rochester, MN, USA.
• Department of Medicine, University of Chicago, Chicago, IL, USA.
• Columbia University, New York, NY, USA.
• University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.
• University of California San Francisco, San Francisco, CA, USA.
• UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
• Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona, Spain.
• Ospedale Michele e Pietro Ferrero, Cuneo, Italy.
• Department of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
• Department of Radiology, Massachussetts General Hospital, Boston, MA, USA.
• Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
• Department of Medical Oncology, NYU Langone Perlmutter Cancer Center, New York, NY, USA.
• Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
• Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Division of Hematology–Oncology, University of California San Diego, La Jolla, CA, USA.
• Yale School of Medicine, New Haven, CT, USA.
• North Shore University Hospital, Manhasset, NY, USA.
• Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
• Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
• David Geffen School of Medicine at the University of California, Los Angeles, CA, USA.
• Icahn School of Medicine at Mount Sinai, New York, NY, USA.
• Department of Pathology, University of Chicago, Chicago, USA.
• Institut Gustave Roussy, Villejuif, France.
• Department of Thoracic Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
• Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
• Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
• Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
• University of Colorado Cancer Center, Denver, CO, USA.
• Synthekine, Menlo Park, CA, USA.
• University of Turin, Orbassano, Italy.
• Novartis Institute for Biomedical Research, Cambridge, MA, USA.
• AstraZeneca, Gaithersburg, MD, USA.
• AstraZeneca, Cambridge, UK.
• Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne, Switzerland.
• Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN, USA.
• Division of Hematology & Medical Oncology, NYU Langone Perlmutter Cancer Center, New York, NY, USA.
• Pfizer, New York, NY, USA.

PMID:  39385035  DOI: 10.1038/s41586-024-07943-7

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 beneft from dual ICB. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical beneft 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 . Unbiased genetic screens identifed 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 efcacy—a fnding that was confrmed 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+ efector subsets. Dual ICB potently engaged CD4+ efector 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 efcacy. 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.

对于患有晚期非小细胞肺癌（NSCLC）的患者，与单独使用PD-(L)1抑制剂治疗相比，使用CTLA4抑制剂和PD-1或PD-L1抑制剂（以下简称PD-(L)1抑制剂）进行双重免疫检查点阻断（ICB）治疗与更高的抗肿瘤活性和免疫相关毒性相关。然而，目前尚无经过验证的生物标志物来确定哪些患者将从双重ICB治疗中受益。我们在此展示了，在随机III期POSEIDON试验中，携带STK11和/或KEAP1肿瘤抑制基因突变的NSCLC患者，从联合化疗的PD-L1抑制剂durvalumab（度伐利尤单抗）和CTLA4抑制剂tremelimumab（特瑞普利单抗）双重ICB治疗中获益，但单独使用durvalumab时并未获益。无偏见的基因筛选显示，这两个肿瘤抑制基因的突变是PD-(L)1抑制耐药的独立驱动因素，且研究显示Keap1的突变是双重ICB疗效的最强基因预测因子——这一发现已在多种Kras驱动的NSCLC小鼠模型中得到证实。在小鼠模型和患者中，KEAP1和STK11改变与不利的肿瘤微环境相关，该微环境特征是免疫抑制性髓系细胞的过多，以及CD8+细胞毒性T细胞的减少，但相对保留了CD4+效应亚群。双重ICB有效激活了CD4+效应细胞，并重新编程了肿瘤的髓系细胞群体，使其向诱导型iNOS表达的杀肿瘤表型转变，这与CD4+和CD8+ T细胞一起，促进了抗肿瘤效应。这些数据支持使用化疗联合双重ICB以减轻携带STK11和/或KEAP1改变的NSCLC患者对PD-(L)1抑制的耐药性。