TY - JOUR
T1 - Ntrk1 promotes resistance to PD-1 checkpoint blockade in Mesenchymal Kras/p53 mutant lung cancer
AU - Konen, Jessica M.
AU - Rodriguez, B. Leticia
AU - Fradette, Jared J.
AU - Gibson, Laura
AU - Davis, Denali
AU - Minelli, Rosalba
AU - Peoples, Michael D.
AU - Kovacs, Jeffrey
AU - Carugo, Alessandro
AU - Bristow, Christopher
AU - Heffernan, Timothy
AU - Gibbons, Don L.
N1 - Funding Information:
Funding: This research was funded by the NIH R37 CA214609-01A1, CPRIT-MIRA RP160652-P3, Rexanna’s Foundation for Fighting Lung Cancer to D.L.G. J.M.K. is supported by a UT Lung SPORE Career Enhancement Award (P50 CA070907). DLG is an R Lee Clark Fellow of the University of Texas MD Anderson Cancer Center, supported by the Jeane F Shelby Scholarship Fund. The work was also supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program and the MD Anderson Cancer Center Support Grant (CCSG CA016672).
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/4
Y1 - 2019/4
N2 - 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.
AB - 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.
KW - Immunotherapy
KW - Non-small cell lung cancer
KW - PD-1/PD-L1 checkpoint blockade
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U2 - 10.3390/cancers11040462
DO - 10.3390/cancers11040462
M3 - Article
C2 - 30986992
AN - SCOPUS:85064836337
SN - 2072-6694
VL - 11
JO - Cancers
JF - Cancers
IS - 4
M1 - 462
ER -