# Targeting epigenetic heterogeneity to improve lung cancer immunotherapy response

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $349,988

## Abstract

Immunotherapies, particularly those that inhibit the PD1/PD-L1 interaction and drive T cells to recognize
and kill tumor cells, have shown striking responses in a small subset of late stage, treatment refractory squamous
lung tumors. However, the majority of patients do not have a lasting response. One way to boost response is to
include an epigenetic inhibitor, such as one targeting the Polycomb Repressive Complex 2 (PRC2), to influence
the tumor cell and microenvironment heterogeneity. My central hypothesis is that EZH2 inhibitors will boost
immunotherapy response in squamous tumors, both by increasing the PD-L1 expressing tumor
propagating cells (TPCs) and by depleting immunosuppressive tumor associated neutrophils. The
overarching goal of the proposed study is to validate combining EZH2 inhibition with PD1/PD-L1 targeted
immunotherapy and learn the molecular mechanisms when the treatment is successful as well as when it is not
successful.
 In Aim 1, I will use both mouse models and human patient derived organoid cultures, and serial orthotopic
transplantation to examine NGFR and PD-L1 expression and tumor propagation abilities of lung SCC cells after
EZH2 inhibitor treatment. I will also test if non-TPC cells can de-differentiate and continue to fuel tumor growth
by sorting for presence or absence of the putative TPC cell surface marker nerve growth factor receptor (NGFR).
The epigenetic and transcriptional consequences of EZH2 inhibition on squamous lung tumor cells will be
assessed by ChIP-seq and RNA-seq. In Aim 2, I will focus on the tumor associated neutrophils (TANs). I will
compare TANs from placebo treated mice to those from EZH2 inhibitor treated mice for abundance, migration
capacity and ability to suppress T cells. I will also use an EZH2 conditional knock-out mouse model to further
characterize how EZH2 loss affects TANs. Again ChIP-seq and RNA-seq will be used to dissect the molecular
changes driven by EZH2 inhibition in the neutrophil populations. In Aim 3, I will treat immune-competent
squamous lung cancer bearing mice with the EZH2 inhibitor GSK126 or EPZ-6438 (Tazemetostat), and the
immunotherapy PD-1 antibody and follow tumor growth by magnetic resonance imaging. I will characterize
tumor phenotypes in responders and non-responders and examine tumors that develop acquired resistance to
this therapeutic drug combination. Completion of these aims will solidify the efficacy of a promising therapeutic
combination and uncover mechanisms by which tumor hierarchies and microenvironments are changed by EZH2
inhibitors in squamous lung cancers. Given that one arm of a Phase 1/2 clinical trial combining EZH2 inhibition
with anti-PDL1 just began recruiting late stage non-small cell lung cancer patients, learning the phenotypes and
mechanisms of responders and non-responders will be extremely timely for any Phase 2/3 trials that ensue.

## Key facts

- **NIH application ID:** 9891032
- **Project number:** 5R01CA237643-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Christine Fillmore Brainson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $349,988
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891032

## Citation

> US National Institutes of Health, RePORTER application 9891032, Targeting epigenetic heterogeneity to improve lung cancer immunotherapy response (5R01CA237643-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891032. Licensed CC0.

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