# The role of translation initiation factor eIF5B in lung cancer pathogenesis

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $452,600

## Abstract

PROJECT SUMMARY
Lung cancer cells express high levels of PD-L1, a ligand of the PD-1 receptor on T-cells, allowing tumors to
directly suppress T cell activity. Anti-PD-1/PD-L1 antibodies induce potent anti-tumor immunity and have been
approved as a first-line therapy for lung cancer. However, only ~20% of all non-small cell lung cancers
(NSCLCs) benefit from checkpoint blockade. A further understanding of the mechanisms that regulate the
immune checkpoint in lung cancer is therefore needed. To address this, my laboratory used CRISPR-based
screening to identify regulators of PD-L1 in lung cancer cells, revealing potent induction of PD-L1 upon
activation of the integrated stress response (ISR) pathway. Mechanistically, ISR activation resulted in
enhanced PD-L1 translation and suppression of anti-tumor immunity. We further demonstrated that ISR-
dependent translation of PD-L1 requires the alternative translation initiation factor eIF5B. The canonical role of
this GTPase is to catalyze ribosomal subunit joining, ensuring 80S ribosome assembly and efficient start codon
selection. eIF5B overexpression and/or amplification is frequent in human lung cancers and is associated with
poor prognosis. Remarkably, eIF5B overexpression is sufficient to induce PD-L1 protein levels even in the
absence of ISR activation. These findings uncovered a new mechanism of immune checkpoint activation and
suggested that eIF5B may be a novel target for lung cancer intervention. We further demonstrated that
enforced expression of eIF5B accelerates proliferation in lung cancer cells, in mouse syngeneic models, and in
human bronchial epithelial cells suggesting that it also promotes tumor growth in a cell-autonomous manner.
We propose to elucidate the role of eIF5B in lung tumorigenesis by testing the following central hypothesis:
EIF5B functions as an oncogene in human lung cancer by inducing PD-L1 translation and by driving a
tumor-promoting translational program. Three Specific Aims will be pursued in order to test this
hypothesis: In Aim 1, we will dissect the mechanisms through which eIF5B promotes translation of PD-L1 and
additional oncogenic mRNAs in lung cancer. In Aim 2, we will functionally evaluate the oncogenic activity of
eIF5B using a novel transgenic mouse model with conditional eIF5B overexpression. In Aim 3, we will
characterize the effects of eIF5B loss of function on cell autonomous tumor growth versus its effect on T cell
responses in the KrasLSL-G12D; Tp53 fl/fl mouse model using a newly generated conditional floxed knockout
allele and a heterozygous germline knockout mouse. These aims will take advantage of our expertise, and
that of our collaborators, to evaluate eIF5B oncogenic activity, and elucidate the mechanisms through which
this translation initiation factor promotes lung tumorigenesis. We anticipate that these studies will provide new
insights into mechanisms of translational control in tumor progression and immune evasion.

## Key facts

- **NIH application ID:** 10883646
- **Project number:** 5R01CA273585-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Kathryn Ann O'Donnell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $452,600
- **Award type:** 5
- **Project period:** 2023-07-06 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883646

## Citation

> US National Institutes of Health, RePORTER application 10883646, The role of translation initiation factor eIF5B in lung cancer pathogenesis (5R01CA273585-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10883646. Licensed CC0.

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