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

Journal

Nature

ISSN: 1476-4687

Titre abrégé: Nature

Pays: England

ID NLM: 0410462

Informations de publication

Date de publication:
09 Oct 2024

Historique:

received: 27 10 2023

accepted: 13 08 2024

medline: 10 10 2024

pubmed: 10 10 2024

entrez: 9 10 2024

Statut: aheadofprint

Résumé

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 ICB

Identifiants

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

pubmed: 39385035

doi: 10.1038/s41586-024-07943-7

pii: 10.1038/s41586-024-07943-7

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Informations de copyright

Références

Brahmer, J. R. et al. Five-year survival outcomes with nivolumab plus ipilimumab versus chemotherapy as first-line treatment for metastatic non–small-cell lung cancer in CheckMate 227. J. Clin. Oncol. 41, 1200–1212 (2023).

pubmed: 36223558 doi: 10.1200/JCO.22.01503

de Castro, G. et al. Five-year outcomes with pembrolizumab versus chemotherapy asfirst-line therapy in patients with non–small-cell lung cancer and programmed death ligand-1 tumor proportion score ≥ 1% in the KEYNOTE-042 study. J. Clin. Oncol. 41, 1986–1991 (2023).

pubmed: 36306479 doi: 10.1200/JCO.21.02885

Johnson, M. L. et al. Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non–small-cell lung cancer: the phase III POSEIDON study. J. Clin. Oncol. 41, 1213–1227 (2023).

pubmed: 36327426 doi: 10.1200/JCO.22.00975

Gandhi, L. et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med. 378, 2078–2092 (2018).

pubmed: 29658856 doi: 10.1056/NEJMoa1801005

Skoulidis, F. et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 8, 822–835 (2018).

pubmed: 29773717 pmcid: 6030433 doi: 10.1158/2159-8290.CD-18-0099

Arbour, K. C. et al. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clin. Cancer Res. 24, 334–340 (2018).

pubmed: 29089357 doi: 10.1158/1078-0432.CCR-17-1841

Cristescu, R. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018).

pubmed: 30309915 pmcid: 6718162 doi: 10.1126/science.aar3593

Singh, A. et al. NRF2 activation promotes aggressive lung cancer and associates with poor clinical outcomes. Clin. Cancer Res. 27, 877–888 (2021).

pubmed: 33077574 doi: 10.1158/1078-0432.CCR-20-1985

Ricciuti, B. et al. Diminished efficacy of Programmed Death-(Ligand) 1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status. J. Thorac. Oncol. 17, 399–410 (2022).

pubmed: 34740862 doi: 10.1016/j.jtho.2021.10.013

West, H. J. et al. Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in KRAS-mutated non-small cell lung cancer with STK11, KEAP1, or TP53 comutations: subgroup results from the phase III IMpower150 trial. J. Immunother. Cancer 10, e003027 (2022).

pubmed: 35190375 pmcid: 8862451 doi: 10.1136/jitc-2021-003027

Alessi, J. V. et al. Clinicopathologic and genomic factors impacting efficacy of first-line chemoimmunotherapy in advanced NSCLC. J. Thorac. Oncol. 18, 731–743 (2023).

pubmed: 36775193 pmcid: 10500613 doi: 10.1016/j.jtho.2023.01.091

Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015).

pubmed: 26069186 pmcid: 4527963 doi: 10.1158/2159-8290.CD-14-1236

Koyama, S. et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. Cancer Res. 76, 999–1008 (2016).

pubmed: 26833127 pmcid: 4775354 doi: 10.1158/0008-5472.CAN-15-1439

Best, S. A. et al. Synergy between the KEAP1/NRF2 and PI3K pathways drives non-small-cell lung cancer with an altered immune microenvironment. Cell Metab. 27, 935–943 (2018).

pubmed: 29526543 doi: 10.1016/j.cmet.2018.02.006

Kitajima, S. et al. Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer. Cancer Discov. 9, 34–45 (2019).

pubmed: 30297358 doi: 10.1158/2159-8290.CD-18-0689

Deng, J. et al. ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1 mutant lung cancer. Nat. Cancer 2, 503–514 (2021).

pubmed: 34142094 pmcid: 8205437 doi: 10.1038/s43018-021-00208-6

Marzio, A. et al. EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion. Cell 185, 169–183 (2022).

pubmed: 34963055 doi: 10.1016/j.cell.2021.12.005

Sitthideatphaiboon, P. et al. STK11/LKB1 mutations in NSCLC are associated with KEAP1/NRF2-dependent radiotherapy resistance targetable by glutaminase inhibition. Clin. Cancer Res. 27, 1720–1733 (2021).

pubmed: 33323404 doi: 10.1158/1078-0432.CCR-20-2859

Wohlhieter, C. A. et al. Concurrent mutations in STK11 and KEAP1 promote ferroptosis protection and SCD1 dependence in lung cancer. Cell Rep. 33, 108444 (2020).

pubmed: 33264619 pmcid: 7722473 doi: 10.1016/j.celrep.2020.108444

Paz-Ares, L. et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 22, 198–211 (2021).

pubmed: 33476593 doi: 10.1016/S1470-2045(20)30641-0

Garassino, M. C. et al. Associations of tissue tumor mutational burden and mutational status with clinical outcomes with pembrolizumab plus chemotherapy versus chemotherapy for metastatic NSCLC. JTO Clin. Res. Rep. 4, 100431 (2023).

pubmed: 36793385

Gainor, J. F. et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin. Cancer Res. 22, 4585–4593 (2016).

pubmed: 27225694 pmcid: 5026567 doi: 10.1158/1078-0432.CCR-15-3101

Mazieres, J. et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann. Oncol. 30, 1321–1328 (2019).

pubmed: 31125062 pmcid: 7389252 doi: 10.1093/annonc/mdz167

Negrao, M. V. et al. Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer. J. Immunother. Cancer 9, e002891 (2021).

pubmed: 34376553 pmcid: 8356172 doi: 10.1136/jitc-2021-002891

Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

pubmed: 25765070 pmcid: 4993154 doi: 10.1126/science.aaa1348

Hellmann, M. D. et al. Nivolumab plus Ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).

pubmed: 29658845 pmcid: 7193684 doi: 10.1056/NEJMoa1801946

Biton, J. et al. TP53, STK11, and EGFR mutations predict tumor immune profile and the response to anti-PD-1 in lung adenocarcinoma. Clin. Cancer Res. 24, 5710–5723 (2018).

pubmed: 29764856 doi: 10.1158/1078-0432.CCR-18-0163

Papillon-Cavanagh, S., Doshi, P., Dobrin, R., Szustakowski, J. & Walsh, A. M. STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort. ESMO Open 5, e000706 (2020).

pubmed: 32312757 pmcid: 7199918 doi: 10.1136/esmoopen-2020-000706

Yarchoan, M. et al. PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight 4, e126908 (2019).

pubmed: 30895946 pmcid: 6482991 doi: 10.1172/jci.insight.126908

Olson, D. J. et al. Pembrolizumab plus Ipilimumab following anti-PD-1/L1 failure in melanoma. J. Clin. Oncol. 39, 2647–2655 (2021).

pubmed: 33945288 pmcid: 8376314 doi: 10.1200/JCO.21.00079

Paz-Ares, L. G. et al. First-Line nivolumab plus ipilimumab with chemotherapy versus chemotherapy alone for metastatic NSCLC in CheckMate 9LA: 3-year clinical update and outcomes in patients with brain metastases or select somatic mutations. J. Thorac. Oncol. 18, 204–222 (2023).

doi: 10.1016/j.jtho.2022.10.014

Rogers, Z. N. et al. A quantitative and multiplexed approach to uncover the fitness landscape of tumor suppression in vivo. Nat. Methods 14, 737–742 (2017).

pubmed: 28530655 pmcid: 5495136 doi: 10.1038/nmeth.4297

Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007).

pubmed: 17676035 doi: 10.1038/nature06030

Hollstein, P. E. et al. The AMPK-related kinases SIK1 and SIK3 mediate key tumor-suppressive effects of LKB1 in NSCLC. Cancer Discov. 9, 1606–1627 (2019).

pubmed: 31350328 pmcid: 6825547 doi: 10.1158/2159-8290.CD-18-1261

Murray, C. W. et al. An LKB1–SIK axis suppresses lung tumor growth and controls differentiation. Cancer Discov. 9, 1590–1605 (2019).

pubmed: 31350327 pmcid: 6825558 doi: 10.1158/2159-8290.CD-18-1237

Galan-Cobo, A. et al. LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence in KRAS-mutant lung adenocarcinoma. Cancer Res. 79, 3251–3267 (2019).

pubmed: 31040157 pmcid: 6606351 doi: 10.1158/0008-5472.CAN-18-3527

Qian, Y. et al. MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma. Cancer Cell 41, 1363–1380 (2023).

pubmed: 37327788 pmcid: 11161201 doi: 10.1016/j.ccell.2023.05.015

Parra, E. R. et al. Immune cellular patterns of distribution affect outcomes of patients with non-small cell lung cancer. Nat. Commun. 14, 2364 (2023).

pubmed: 37185575 pmcid: 10130161 doi: 10.1038/s41467-023-37905-y

Wei, S. C. et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170, 1120–1133 (2017).

pubmed: 28803728 pmcid: 5591072 doi: 10.1016/j.cell.2017.07.024

Wei, S. C. et al. Negative co-stimulation constrains t cell differentiation by imposing boundaries on possible cell states. Immunity 50, 1084–1098 (2019).

pubmed: 30926234 pmcid: 6664799 doi: 10.1016/j.immuni.2019.03.004

Carthon, B. C. et al. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin. Cancer Res. 16, 2861–2871 (2010).

pubmed: 20460488 pmcid: 2919850 doi: 10.1158/1078-0432.CCR-10-0569

Kruse, B. et al. CD4

pubmed: 37316667 pmcid: 10307640 doi: 10.1038/s41586-023-06199-x

Hirschhorn, D. et al. T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants. Cell 186, 1432–1447 (2023).

pubmed: 37001503 pmcid: 10994488 doi: 10.1016/j.cell.2023.03.007

Gungabeesoon, J. et al. A neutrophil response linked to tumor control in immunotherapy. Cell 186, 1448–1464 (2023).

pubmed: 37001504 pmcid: 10132778 doi: 10.1016/j.cell.2023.02.032

Proulx-Rocray, F. et al. The prognostic impact of KRAS, TP53, STK11 and KEAP1 mutations and their influence on the NLR in NSCLC patients treated with immunotherapy. Cancer Treat. Res. Commun. 37, 100767 (2023).

pubmed: 37832364 doi: 10.1016/j.ctarc.2023.100767

Yofe, I. et al. Anti-CTLA-4 antibodies drive myeloid activation and reprogram the tumor microenvironment through FcγR engagement and type I interferon signaling. Nat. Cancer 3, 1336–1350 (2022).

pubmed: 36302895 doi: 10.1038/s43018-022-00447-1

Waight, J. D. et al. Selective FcγR Co-engagement on APCs Modulates the activity of therapeutic antibodies targeting T cell antigens. Cancer Cell 33, 1033–1047 (2018).

pubmed: 29894690 pmcid: 6292441 doi: 10.1016/j.ccell.2018.05.005

Arce Vargas, F. et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell 33, 649–663 (2018).

pubmed: 29576375 pmcid: 5904288 doi: 10.1016/j.ccell.2018.02.010

Kitajima, S. et al. MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer. Cancer Cell 40, 1128–1144 (2022).

pubmed: 36150391 pmcid: 9561026 doi: 10.1016/j.ccell.2022.08.015

Li, R. et al. Inhibition of granulocytic myeloid-derived suppressor cells overcomes resistance to immune checkpoint inhibition in LKB1-deficient non-small cell lung cancer. Cancer Res. 81, 3295–3308 (2021).

pubmed: 33853830 pmcid: 8776246 doi: 10.1158/0008-5472.CAN-20-3564

Vokes, N. I. et al. Harmonization of tumor mutational burden quantification and association with response to immune checkpoint blockade in non-small-cell lung cancer. JCO Precis. Oncol. 3, 1–12 (2019).

doi: 10.1200/PO.19.00171

Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9, 34 (2017).

pubmed: 28420421 pmcid: 5395719 doi: 10.1186/s13073-017-0424-2

Chakravarty, D. et al. OncoKB: a precision oncology knowledge base. JCO Precis. Oncol. 1, 1–16 (2017).

doi: 10.1200/PO.17.00011

Frampton, G. M. et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat. Biotechnol. 31, 1023–1031 (2013).

pubmed: 24142049 pmcid: 5710001 doi: 10.1038/nbt.2696

Parra, E. R. et al. Immuno-profiling and cellular spatial analysis using five immune oncology multiplex immunofluorescence panels for paraffin tumor tissue. Sci. Rep. 11, 8511 (2021).

pubmed: 33875760 pmcid: 8055659 doi: 10.1038/s41598-021-88156-0

Schmidt, S. T. Shared nearest neighbors approach and interactive browser for network analysis of a comprehensive non–small-cell lung cancer data set. JCO Clin. Cancer Inform. 6, e2200040 (2022).

pubmed: 35944232 pmcid: 9470146 doi: 10.1200/CCI.22.00040

Aran, D., Hu, Z. & Butte, A. J. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol. 18, 220 (2017).

pubmed: 29141660 pmcid: 5688663 doi: 10.1186/s13059-017-1349-1

Kaufman, J. M. et al. LKB1 loss induces characteristic patterns of gene expression in human tumors associated with NRF2 activation and attenuation of PI3K-AKT. J. Thorac. Oncol. 9, 794–804 (2014).

pubmed: 24828662 pmcid: 4026179 doi: 10.1097/JTO.0000000000000173

Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).

pubmed: 23550210 pmcid: 4160307 doi: 10.1126/scisignal.2004088

Li, T. et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 48, W509–W514 (2020).

pubmed: 32442275 pmcid: 7319575 doi: 10.1093/nar/gkaa407

Sanjana, N. E., Shalem, O. & Zhang, F. Improved vectors and genome-wide libraries for CRISPR screening. Nat. Methods 11, 783–784 (2014).

pubmed: 25075903 pmcid: 4486245 doi: 10.1038/nmeth.3047

Manguso, R. T. et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 547, 413–418 (2017).

pubmed: 28723893 pmcid: 5924693 doi: 10.1038/nature23270

Li, W. et al. MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol. 15, 554 (2014).

pubmed: 25476604 pmcid: 4290824 doi: 10.1186/s13059-014-0554-4

Li, W. et al. Quality control, modeling, and visualization of CRISPR screens with MAGeCK-VISPR. Genome Biol. 16, 281 (2015).

pubmed: 26673418 pmcid: 4699372 doi: 10.1186/s13059-015-0843-6

Chiou, S. H. et al. A conditional system to specifically link disruption of protein-coding function with reporter expression in mice. Cell Rep. 7, 2078–2086 (2014).

pubmed: 24931605 pmcid: 4113058 doi: 10.1016/j.celrep.2014.05.031

AACR Project Genie Consortium. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discov. 7, 818–831 (2017).

doi: 10.1158/2159-8290.CD-17-0151

Westcott, P. M. K. & To, M. D. The genetics and biology of KRAS in lung cancer. Chin. J. Cancer 32, 63–70 (2013).

pubmed: 22776234 pmcid: 3845615 doi: 10.5732/cjc.012.10098

Doench, J. G. et al. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR–Cas9. Nat. Biotechnol. 34, 184–191 (2016).

pubmed: 26780180 pmcid: 4744125 doi: 10.1038/nbt.3437

Rogers, Z. N. et al. Mapping the in vivo fitness landscape of lung adenocarcinoma tumor suppression in mice. Nat. Genet. 50, 483–486 (2018).

pubmed: 29610476 pmcid: 6061949 doi: 10.1038/s41588-018-0083-2

Winters, I. P. et al. Multiplexed in vivo homology-directed repair and tumor barcoding enables parallel quantification of Kras variant oncogenicity. Nat. Commun. 8, 2053 (2017).

pubmed: 29233960 pmcid: 5727199 doi: 10.1038/s41467-017-01519-y

Chiou, S.-H. et al. Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing. Genes Dev. 29, 1576–1585 (2015).

pubmed: 26178787 pmcid: 4526740 doi: 10.1101/gad.264861.115

Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001).

pubmed: 11751630 pmcid: 312845 doi: 10.1101/gad.943001

Li, C. et al. Quantitative in vivo analyses reveal a complex pharmacogenomic landscape in lung adenocarcinoma. Cancer Res. 81, 4570–4580 (2021).

pubmed: 34215621 pmcid: 8416777 doi: 10.1158/0008-5472.CAN-21-0716

DuPage, M., Dooley, A. L. & Jacks, T. Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase. Nat. Protoc. 4, 1064–1072 (2009).

pubmed: 19561589 pmcid: 2757265 doi: 10.1038/nprot.2009.95

Wang, R. et al. Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma. Nat. Med. 27, 141–151 (2021).

pubmed: 33398161 pmcid: 8074162 doi: 10.1038/s41591-020-1125-8

Cummings, A. L. et al. Mutational landscape influences immunotherapy outcomes among patients with non-small-cell lung cancer with human leukocyte antigen supertype B44. Nat. Cancer 1, 1167–1175 (2020).