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.
Highlights
Lung cancer is the leading cause of cancer-related deaths, killing more people in the U.S than the three most prevalent cancer types combined [1,2]
The 393P epithelial cells are a non-metastatic line, whereas the 344P mesenchymal line is an aggressive and metastatic cell line, and each were originally derived from KrasG12D/+ /p53R172H∆g primary lung tumors as previously described by our laboratory [19]
Once tumors reached 150–200 mm3, they were treated with either an isotype control antibody or a PD-1 blocking antibody. 344P tumors, which responded to PD-1 treatment initially but eventually demonstrated resistance (Supplementary Figure S1), were collected at two time points of anti-PD-1 treatment to identify genes that synergize to prevent the development of resistance
Summary
Lung cancer is the leading cause of cancer-related deaths, killing more people in the U.S than the three most prevalent cancer types combined [1,2]. A better understanding of the complexities of lung cancer progression, the contributing microenvironmental factors and how to target them would benefit patient outcomes. Research focusing on systemic and tumor-infiltrating immune cell populations and their impact on shaping cancer progression in solid tumor types has provided compelling evidence for immune escape as a crucial survival mechanism. These studies have revealed that tumors avoid immune detection through a variety of complex mechanisms.
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