Next Article in Journal
Increase Paclitaxel Sensitivity to Better Suppress Serous Epithelial Ovarian Cancer via Ablating Androgen Receptor/Aryl Hydrocarbon Receptor-ABCG2 Axis
Previous Article in Journal
Natural Killer Cells as Key Players of Tumor Progression and Angiogenesis: Old and Novel Tools to Divert Their Pro-Tumor Activities into Potent Anti-Tumor Effects
Previous Article in Special Issue
MicroRNAs and Long Non-Coding RNAs and Their Hormone-Like Activities in Cancer
Article Menu
Issue 4 (April) cover image

Export Article

Open AccessFeature PaperArticle
Cancers 2019, 11(4), 462; https://doi.org/10.3390/cancers11040462

Ntrk1 Promotes Resistance to PD-1 Checkpoint Blockade in Mesenchymal Kras/p53 Mutant Lung Cancer

1
Department of Thoracic/Head & Neck Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
2
Department of Chemistry, Indiana University of Pennsylvania, 1011 South Drive, Indiana, PA 15705, USA
3
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
4
Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
5
Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
6
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
Received: 23 January 2019 / Revised: 26 March 2019 / Accepted: 27 March 2019 / Published: 2 April 2019
  |  
PDF [2914 KB, uploaded 2 April 2019]
  |     |  

Abstract

The implementation of cancer immunotherapeutics for solid tumors including lung cancers has improved clinical outcomes in a small percentage of patients. However, the majority of patients show little to no response or acquire resistance during treatment with checkpoint inhibitors delivered as a monotherapy. Therefore, identifying resistance mechanisms and novel combination therapy approaches is imperative to improve responses to immune checkpoint inhibitors. To address this, we performed an in vivo shRNA dropout screen that focused on genes encoding for FDA-approved drug targets (FDAome). We implanted epithelial and mesenchymal Kras/p53 (KP) mutant murine lung cancer cells expressing the FDAome shRNA library into syngeneic mice treated with an anti-PD-1 antibody. Sequencing for the barcoded shRNAs revealed Ntrk1 was significantly depleted from mesenchymal tumors challenged with PD-1 blockade, suggesting it provides a survival advantage to tumor cells when under immune system pressure. Our data confirmed Ntrk1 transcript levels are upregulated in tumors treated with PD-1 inhibitors. Additionally, analysis of tumor-infiltrating T cell populations revealed that Ntrk1 can promote CD8+ T cell exhaustion. Lastly, we found that Ntrk1 regulates Jak/Stat signaling to promote expression of PD-L1 on tumor cells. Together, these data suggest that Ntrk1 activates Jak/Stat signaling to regulate expression of immunosuppressive molecules including PD-L1, promoting exhaustion within the tumor microenvironment. View Full-Text
Keywords: non-small cell lung cancer; immunotherapy; PD-1/PD-L1 checkpoint blockade non-small cell lung cancer; immunotherapy; PD-1/PD-L1 checkpoint blockade
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

Konen, J.M.; Rodriguez, B.L.; Fradette, J.J.; Gibson, L.; Davis, D.; Minelli, R.; Peoples, M.D.; Kovacs, J.; Carugo, A.; Bristow, C.; Heffernan, T.; Gibbons, D.L. Ntrk1 Promotes Resistance to PD-1 Checkpoint Blockade in Mesenchymal Kras/p53 Mutant Lung Cancer. Cancers 2019, 11, 462.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Cancers EISSN 2072-6694 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top