# Identifying the role of Ntrk1 in immunosuppression in Kras/p53 mutant lung cancer

> **NIH NIH F32** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $70,146

## Abstract

Project Summary
Lung cancer is the leading cause of cancer-related deaths in the United States, and the 5-year survival rate of
all lung cancer patients combined is only about 18%. The implementation of cancer immunotherapeutics for solid
tumors such as lung cancers has shown great promise and provided the possibility for improved outcome 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 potential combination therapy approaches is a critical need to improve response rates to
immune checkpoint inhibitors and patient prognosis. To address this, a clinically relevant in vivo shRNA dropout
screen focused on genes encoding for FDA-approved drug targets (FDAome) was performed in epithelial and
mesenchymal Kras/p53 (KP) mutant murine lung cancer cells. Mice were then treated with either isotype or anti-
PD-1 antibody. Sequencing for the barcoded shRNAs revealed that Ntrk1 was significantly depleted from
mesenchymal tumors challenged with PD-1 blockade compared to isotype treated tumors, suggesting it provides
a survival advantage to these tumor cells when under immune system pressure. Preliminary data confirmed
Ntrk1 transcript levels are upregulated in mesenchymal tumors treated with PD-1 inhibitors and cell lines derived
from resistant tumors, and analysis of human NSCLC cell lines revealed that Ntrk1 mRNA levels correlate with
a more aggressive, mesenchymal cell phenotype. Additionally, Ntrk1 overexpressing cells upregulate PD-L1
expression when co-cultured with splenocytes through upregulation of JAK signaling. Stable knockdown of Ntrk1
in mesenchymal murine KP mutant lung cancer cells reduced tumor growth in vivo and analysis of tumor-
infiltrating T cell populations via flow cytometry showed that CD8+ T cell exhaustion was significantly reduced,
whereas overexpression of Ntrk1 promoted CD8+ T cell exhaustion, thus decreasing effector status. These
tumors also have an altered microenvironment, with upregulation of classically immunosuppressive cytokines
such as IL-10. PD-1 protein levels were also significantly increased in Ntrk1-high human NSCLC cell lines,
providing additional evidence that Ntrk1 may be a modulator of immune system functionality in human lung
disease. The central hypothesis of the proposed work is that Ntrk1 upregulation causes acquired resistance to
PD-1 blockade via aberrant JAK signaling and downstream CD8+ T cell dysfunction, thereby promoting tumor
cell survival. A variety of powerful tools will be utilized to test this hypothesis, including time-lapse imaging of
dynamic T cell-tumor cell interactions, genetically-engineered and syngeneic preclinical models of lung cancer
to analyze immune subpopulations as a function of Ntrk1 expression, and IHC analyses of human NSCLC tissue
samples. The goal of the proposed work is to provide strong evi...

## Key facts

- **NIH application ID:** 9906415
- **Project number:** 1F32CA239292-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jessica Konen
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $70,146
- **Award type:** 1
- **Project period:** 2019-12-09 → 2022-12-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906415

## Citation

> US National Institutes of Health, RePORTER application 9906415, Identifying the role of Ntrk1 in immunosuppression in Kras/p53 mutant lung cancer (1F32CA239292-01A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9906415. Licensed CC0.

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