Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers
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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.
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RAS-targeted therapy abrogated RAS-MAPK/PI3K-AKT-involved immune evasion, synergizing with α-PD-1/PD-L1.
“RAS-targeted therapy abrogated RAS-MAPK/PI3K-AKT-involved immune evasion, synergizing with α-PD-1/PD-L1 [213, 214].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [213]
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- Authors
- 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.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Gibbons, Don. L.
- ORCID
- Venue
- Nature Communications
- Published
- 2021-05-10
- Volume
- 12
- Issue
- 1
- Pages
- 2606-2606
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8110980
- OpenAlex
- W3162226089
- Cited by
- 72
- References
- 45
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 12 · 2023: 17 · 2022: 20 · 2021: 3
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons @ Butler University (Butler University) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health and Human Services (R37 CA214609, P30CA16672)
- LUNGevity Foundation
- Cancer Prevention and Research Institute of Texas (RP160652-P3, P30 CA16672, RP160652, CPRIT-MIRA RP160652-P3)
- National Institutes of Health (CA-16 672, RP160652-P3)
- University of Texas MD Anderson Cancer Center (#CA16672, NCI P30 CA16672, P30CA 16672)
- National Cancer Institute (P30CA16672, CA-16672, F32CA239292, NCI P30-CA16672, P50CA070907, R37CA214609, P30CA016672)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- Th17 cells, MEK inhibitor resistance, PD-L1 blockade, KRAS mutation, TP53 mutation, lung cancer, MAPK signaling, IL-17A, IL-22, tumor immune microenvironment, combination therapy resistance, metastasis, non-small cell lung cancer, melanoma, anti-PD-1 therapy
- MeSH terms
- Antineoplastic Agents, Immunological, Immune Checkpoint Inhibitors, Animals, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Drug Synergism, Female, Humans, Immunohistochemistry, Lung Neoplasms, Male, Neoplasm Invasiveness, Neoplasm Metastasis, CD4-Positive T-Lymphocytes, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Mice, Knockout, Drug Resistance, Neoplasm, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Th17 Cells, B7-H1 Antigen
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