CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors Journal Article
| Authors: | Skoulidis, F.; Araujo, H. A.; Do, M. T.; Qian, Y.; Sun, X.; Cobo, A. G.; Le, J. T.; Montesion, M.; Palmer, R.; Jahchan, N.; Juan, J. M.; Min, C.; Yu, Y.; Pan, X.; Arbour, K. C.; Vokes, N.; Schmidt, S. T.; Molkentine, D.; Owen, D. H.; Memmott, R.; Patil, P. D.; Marmarelis, M. E.; Awad, M. M.; Murray, J. C.; Hellyer, J. A.; Gainor, J. F.; Dimou, A.; Bestvina, C. M.; Shu, C. A.; Riess, J. W.; Blakely, C. M.; Pecot, C. V.; Mezquita, L.; Tabbó, F.; Scheffler, M.; Digumarthy, S.; Mooradian, M. J.; Sacher, A. G.; Lau, S. C. M.; Saltos, A. N.; Rotow, J.; Johnson, R. P.; Liu, C.; Stewart, T.; Goldberg, S. B.; Killam, J.; Walther, Z.; Schalper, K.; Davies, K. D.; Woodcock, M. G.; Anagnostou, V.; Marrone, K. A.; Forde, P. M.; Ricciuti, B.; Venkatraman, D.; Van Allen, E. M.; Cummings, A. L.; Goldman, J. W.; Shaish, H.; Kier, M.; Katz, S.; Aggarwal, C.; Ni, Y.; Azok, J. T.; Segal, J.; Ritterhouse, L.; Neal, J. W.; Lacroix, L.; Elamin, Y. Y.; Negrao, M. V.; Le, X.; Lam, V. K.; Lewis, W. E.; Kemp, H. N.; Carter, B.; Roth, J. A.; Swisher, S.; Lee, R.; Zhou, T.; Poteete, A.; Kong, Y.; Takehara, T.; Paula, A. G.; Parra Cuentas, E. R.; Behrens, C.; Wistuba, I. I.; Zhang, J.; Blumenschein, G. R.; Gay, C.; Byers, L. A.; Gibbons, D. L.; Tsao, A.; Lee, J. J.; Bivona, T. G.; Camidge, D. R.; Gray, J. E.; Lieghl, N.; Levy, B.; Brahmer, J. R.; Garassino, M. C.; Gandara, D. R.; Garon, E. B.; Rizvi, N. A.; Scagliotti, G. V.; Wolf, J.; Planchard, D.; Besse, B.; Herbst, R. S.; Wakelee, H. A.; Pennell, N. A.; Shaw, A. T.; Jänne, P. A.; Carbone, D. P.; Hellmann, M. D.; Rudin, C. M.; Albacker, L.; Mann, H.; Zhu, Z.; Lai, Z.; Stewart, R.; Peters, S.; Johnson, M. L.; Wong, K. K.; Huang, A.; Winslow, M. M.; Rosen, M. J.; Winters, I. P.; Papadimitrakopoulou, V. A.; Cascone, T.; Jewsbury, P.; Heymach, J. V. |
| Article Title: | CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors |
| 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. © The Author(s) 2024. |
| Keywords: | immunohistochemistry; cancer chemotherapy; controlled study; protein expression; survival analysis; gene mutation; human cell; overall survival; genetics; mutation; bevacizumab; cisplatin; nonhuman; paclitaxel; chemotherapy; cancer staging; flow cytometry; genetic analysis; cd8+ t lymphocyte; cell proliferation; biological marker; mouse; animal; metabolism; animals; mice; animal tissue; carboplatin; ticilimumab; cancer immunotherapy; progression free survival; multiple cycle treatment; tumor volume; carcinoma, non-small-cell lung; lung neoplasms; animal experiment; animal model; cohort analysis; lung cancer; genetic transcription; antineoplastic activity; drug effect; drug resistance; pathology; drug resistance, neoplasm; inhibitor; protein serine threonine kinase; histology; carcinogenesis; monoclonal antibody; lung tumor; regulatory t lymphocyte; immunology; antibodies, monoclonal; lung adenocarcinoma; double stranded dna; genetic transfection; immunotherapy; cd4+ t lymphocyte; cytotoxic t lymphocyte; western blotting; brain metastasis; lentivirus vector; platinum; upregulation; virus load; th1 cell; tissue microarray; neoadjuvant chemotherapy; tumor growth; tumor; drug therapy; cytotoxic t lymphocyte antigen 4; immunoglobulin g2a; k ras protein; oligonucleotide; dna extraction; pemetrexed; fluorescence activated cell sorting; disease exacerbation; genomic dna; tumor resistance; protein inhibitor; immunocompetence; inducible nitric oxide synthase; programmed death 1 ligand 1; non small cell lung cancer; inhibition; tumor microenvironment; nitric oxide; immune evasion; protein kinase lkb1; stk11 protein, human; transcription factor nrf2; chemoimmunotherapy; immune checkpoint inhibitor; high throughput sequencing; kelch like ech associated protein 1; ctla-4 antigen; cell component; dna sequencing; cancer; humans; human; male; female; article; rna sequencing; hek293 cell line; pembrolizumab; crispr cas system; durvalumab; whole exome sequencing; immune checkpoint inhibitors; crispr-cas9 system; chemiluminescence immunoassay; pharmacogenetic testing; b7-h1 antigen; ctla4 protein, human; genetic profile; protein serine-threonine kinases; kelch-like ech-associated protein 1; keap1 protein, human; crispr-cas system guide rna; amp-activated protein kinase kinases; hydroxymethylglutaryl coenzyme a reductase kinase kinase; 3ll cell line |
| Journal Title: | Nature |
| Volume: | 635 |
| Issue: | 8038 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-11-14 |
| Start Page: | 462 |
| End Page: | 471 |
| Language: | English |
| DOI: | 10.1038/s41586-024-07943-7 |
| PUBMED: | 39385035 |
| PROVIDER: | scopus |
| PMCID: | PMC11560846 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Erratum issued, see DOI: 10.1038/s41586-025-08767-9 -- Source: Scopus |
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