Th17 Cells Contribute to Combination MEK Inhibitor and Anti-PD-L1 Therapy Resistance in KRAS/p53 Mutant Lung Cancers

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 11

PMID 33972557

Citations 36

Authors

David H Peng

B Leticia Rodriguez

Lixia Diao

Pierre-Olivier Gaudreau

Aparna Padhye

Jessica M Konen

Joshua K Ochieng

Caleb A Class

Jared J Fradette

Laura Gibson

Limo Chen

Jing Wang

Lauren A Byers

Don L Gibbons

Affiliations

Soon will be listed here.

Abstract

Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in patients treated with PD-1 blockade predicted poorer overall survival and response in melanoma and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.

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References

Chen L, Gibbons D, Goswami S, Cortez M, Ahn Y, Byers L . Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun. 2014; 5:5241. PMC: 4212319. DOI: 10.1038/ncomms6241. View

Uemura M, Trinh V, Haymaker C, Jackson N, Kim D, Allison J . Selective inhibition of autoimmune exacerbation while preserving the anti-tumor clinical benefit using IL-6 blockade in a patient with advanced melanoma and Crohn's disease: a case report. J Hematol Oncol. 2016; 9(1):81. PMC: 5011857. DOI: 10.1186/s13045-016-0309-7. View

Peng D, Kundu S, Fradette J, Diao L, Tong P, Byers L . ZEB1 suppression sensitizes KRAS mutant cancers to MEK inhibition by an IL17RD-dependent mechanism. Sci Transl Med. 2019; 11(483). PMC: 6878763. DOI: 10.1126/scitranslmed.aaq1238. View

Blumenschein Jr G, Smit E, Planchard D, Kim D, Cadranel J, De Pas T . A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†. Ann Oncol. 2015; 26(5):894-901. PMC: 4855243. DOI: 10.1093/annonc/mdv072. View

Della Corte C, Barra G, Ciaramella V, Di Liello R, Vicidomini G, Zappavigna S . Antitumor activity of dual blockade of PD-L1 and MEK in NSCLC patients derived three-dimensional spheroid cultures. J Exp Clin Cancer Res. 2019; 38(1):253. PMC: 6567578. DOI: 10.1186/s13046-019-1257-1. View

Cho J, Hong M, Ha S, Kim Y, Cho B, Lee I . Genome-wide identification of differentially methylated promoters and enhancers associated with response to anti-PD-1 therapy in non-small cell lung cancer. Exp Mol Med. 2020; 52(9):1550-1563. PMC: 8080767. DOI: 10.1038/s12276-020-00493-8. View

Kimura A, Kishimoto T . IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010; 40(7):1830-5. DOI: 10.1002/eji.201040391. View

Smyth G . Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2006; 3:Article3. DOI: 10.2202/1544-6115.1027. View

Muranski P, Restifo N . Essentials of Th17 cell commitment and plasticity. Blood. 2013; 121(13):2402-14. PMC: 3612853. DOI: 10.1182/blood-2012-09-378653. View

10.

Sullivan R, Hamid O, Gonzalez R, Infante J, Patel M, Hodi F . Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat Med. 2019; 25(6):929-935. DOI: 10.1038/s41591-019-0474-7. View

11.

Eng C, Kim T, Bendell J, Argiles G, Tebbutt N, Di Bartolomeo M . Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019; 20(6):849-861. DOI: 10.1016/S1470-2045(19)30027-0. View

12.

Lou Y, Diao L, Parra Cuentas E, Denning W, Chen L, Fan Y . Epithelial-Mesenchymal Transition Is Associated with a Distinct Tumor Microenvironment Including Elevation of Inflammatory Signals and Multiple Immune Checkpoints in Lung Adenocarcinoma. Clin Cancer Res. 2016; 22(14):3630-42. PMC: 4947453. DOI: 10.1158/1078-0432.CCR-15-1434. View

13.

Dong C . TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008; 8(5):337-48. DOI: 10.1038/nri2295. View

14.

Riaz N, Havel J, Makarov V, Desrichard A, Urba W, Sims J . Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab. Cell. 2017; 171(4):934-949.e16. PMC: 5685550. DOI: 10.1016/j.cell.2017.09.028. View

15.

Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A . Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3(7):RESEARCH0034. PMC: 126239. DOI: 10.1186/gb-2002-3-7-research0034. View

16.

Skoulidis F, Goldberg M, Greenawalt D, Hellmann M, Awad M, Gainor J . Mutations and PD-1 Inhibitor Resistance in -Mutant Lung Adenocarcinoma. Cancer Discov. 2018; 8(7):822-835. PMC: 6030433. DOI: 10.1158/2159-8290.CD-18-0099. View

17.

Campa M, Mansouri B, Warren R, Menter A . A Review of Biologic Therapies Targeting IL-23 and IL-17 for Use in Moderate-to-Severe Plaque Psoriasis. Dermatol Ther (Heidelb). 2015; 6(1):1-12. PMC: 4799039. DOI: 10.1007/s13555-015-0092-3. View

18.

Hatton R . TGF-β in Th17 cell development: the truth is out there. Immunity. 2011; 34(3):288-90. PMC: 3097895. DOI: 10.1016/j.immuni.2011.03.009. View

19.

Gibbons D, Lin W, Creighton C, Rizvi Z, Gregory P, Goodall G . Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression. Genes Dev. 2009; 23(18):2140-51. PMC: 2751985. DOI: 10.1101/gad.1820209. View

20.

Akbay E, Koyama S, Liu Y, Dries R, Bufe L, Silkes M . Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade. J Thorac Oncol. 2017; 12(8):1268-1279. PMC: 5532066. DOI: 10.1016/j.jtho.2017.04.017. View