Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers

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

doi:10.1038/s41467-021-22875-w

Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers

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

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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.

Original language	English (US)
Article number	2606
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22875-w
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Functional Proteomics Reverse Phase Protein Array Core
Bioinformatics Shared Resource
Research Histology, Pathology and Imaging Core
Research Animal Support Facility

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10.1038/s41467-021-22875-w

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Peng, D. H., Rodriguez, B. L., Diao, L., Gaudreau, P. O., Padhye, A., Konen, J. M., Ochieng, J. K., Class, C. A., Fradette, J. J., Gibson, L., Chen, L., Wang, J., Byers, L. A., & Gibbons, D. L. (2021). Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers. Nature communications, 12(1), Article 2606. https://doi.org/10.1038/s41467-021-22875-w

Peng, DH , Rodriguez, BL , Diao, L, Gaudreau, PO, Padhye, A, Konen, JM, Ochieng, JK, Class, CA, Fradette, JJ, Gibson, L, Chen, L, Wang, J , Byers, LA & Gibbons, DL 2021, 'Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers', Nature communications, vol. 12, no. 1, 2606. https://doi.org/10.1038/s41467-021-22875-w

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title = "Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers",

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.",

author = "Peng, {David H.} and Rodriguez, {B. Leticia} and Lixia Diao and Gaudreau, {Pierre Olivier} and Aparna Padhye and Konen, {Jessica M.} and Ochieng, {Joshua K.} and Class, {Caleb A.} and Fradette, {Jared J.} and Laura Gibson and Limo Chen and Jing Wang and Byers, {Lauren A.} and Gibbons, {Don L.}",

note = "Funding Information: D.L.G. declares advisory board work for Janssen, AstraZeneca, GlaxoSmithKline, and Sanofi. D.L.G. receives research grant funding from AstraZeneca, Janssen, Astellas, Ribon Therapeutics, NGM Therapeutics, and Takeda. L.A.B. declares consulting work for AstraZeneca, AbbVie, GenMab, BergenBio, Pharma Mar, SA. L.A.B. receives research grant funding from AbbVie, AstraZeneca, GenMab, Tolero Pharmaceuticals. All other authors declare that they have no competing interests. Funding Information: This study made use of the Research Histology, Pathology, and Imaging Core, supported by P30 CA16672 DHHS/NCI Cancer Center Support Grant (CCSG). The Flow Cytometry Lab South Campus Core facility at MDACC is supported by CCSG NCI P30 CA16672. The authors declare that all other data and source data file supporting findings in this study are available within the paper. This work was supported by NIH R37CA214609, CPRIT-MIRA RP160652-P3, and Rexanna{\textquoteright}s Foundation for Fighting Lung Cancer to D.L.G., LUNGevity Foundation award to D.L.G. & L.A.B, and F32CA239292 to J.M.K. The work was also supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program. Source data are provided with this paper. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s41467-021-22875-w",

language = "English (US)",

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T1 - Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers

AU - Peng, David H.

AU - Rodriguez, B. Leticia

AU - Diao, Lixia

AU - Gaudreau, Pierre Olivier

AU - Padhye, Aparna

AU - Konen, Jessica M.

AU - Ochieng, Joshua K.

AU - Class, Caleb A.

AU - Fradette, Jared J.

AU - Gibson, Laura

AU - Chen, Limo

AU - Wang, Jing

AU - Byers, Lauren A.

AU - Gibbons, Don L.

N1 - Funding Information: D.L.G. declares advisory board work for Janssen, AstraZeneca, GlaxoSmithKline, and Sanofi. D.L.G. receives research grant funding from AstraZeneca, Janssen, Astellas, Ribon Therapeutics, NGM Therapeutics, and Takeda. L.A.B. declares consulting work for AstraZeneca, AbbVie, GenMab, BergenBio, Pharma Mar, SA. L.A.B. receives research grant funding from AbbVie, AstraZeneca, GenMab, Tolero Pharmaceuticals. All other authors declare that they have no competing interests. Funding Information: This study made use of the Research Histology, Pathology, and Imaging Core, supported by P30 CA16672 DHHS/NCI Cancer Center Support Grant (CCSG). The Flow Cytometry Lab South Campus Core facility at MDACC is supported by CCSG NCI P30 CA16672. The authors declare that all other data and source data file supporting findings in this study are available within the paper. This work was supported by NIH R37CA214609, CPRIT-MIRA RP160652-P3, and Rexanna’s Foundation for Fighting Lung Cancer to D.L.G., LUNGevity Foundation award to D.L.G. & L.A.B, and F32CA239292 to J.M.K. The work was also supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program. Source data are provided with this paper. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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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Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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