# Role of ATRX, a chromatin remodeler, in immunotherapy response

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2024 · —

## Abstract

Background: Cancer immunotherapy is a major breakthrough for many patients with advanced cancer.
However, benefits are still limited to a subset of patients, and we need to better understand the mechanisms of
response and resistance to improve therapeutic efficacy. We have identified loss of function (LoF) mutations in
JAK1 or JAK2 (immediate downstream signaling molecule of interferon receptor) that are associated with
resistance to PD-1 blockade. We also found these mutations in human melanoma cell lines by screening PD-
L1 expression with IFN-g treatment (48 cell lines). Tumors harbor LoF in JAK1/2, completely lost PD-L1
expression. Interestingly, one of them harbors no mutation with an active signaling pathway, yet lost PD-L1
expression. We explored why some human cancer cells lost adaptive PD-L1 expression even with intact
interferon signaling and hypothesized that the epigenetic perturbation is mediating this phenotype. With this
approach, we observed reduced PD-L1 expression with ATRX siRNA which was further tested with in vivo
mouse models. In vivo mouse experiments with ATRX KO MC38 cells, anti-PD-1 antibody therapy produced
either accelerated tumor growth or no effect. The current study is designed to understand the mechanism of
resistance mediated by loss of ATRX in cancer immunotherapy.
Objective/hypothesis: ATRX, a SWI/SNF-like chromatin remodeler is modulating the accessibility of
interferon responsive genes that are associated with immunotherapy response.
Specific aims: I have two aims for this study. The first aim is to interrogate the mechanisms of immune
evasion with loss of ATRX using various tools to probe epigenetic state. The second aim is to establish in vivo
tumor growth with ATRX KO using various murine cancer models.
Study design: Aim 1. Subaim1) Generate ATRX KO B16 cells followed by Assess epigenetics state with IFN-g
stimulation (both MC38 and B16 ATRX KO clones) using ChIP/ATAC-seq. Subaim 2) Correlate genomic
studies (ChIP/ATAC) with Chromatin-Associated RNA-sequence (ChAR). Subaim 3) Assess the impact of
epigenetic modifiers in IFN-g response in ATRX KO clones (using various epigenetic modifiers, such as HDAC
inhibitor, demethylating agents and EZH2 inhibitor). Subaim 4) Coculture assay with murine T cells with ATRX
wild-type parent cells and KO clones.
Aim 2. Subaim 1) In vivo experiments with MC38 and B16 models with ATRX KO. Subaim2) Kras mutant
murine lung cancer cell line models with ATRX KO. Subaim 3) ATRX KO in lung cancer and melanoma
genetically engineered mouse models using sleeping beauty transposase vector system.
Relevant to Military health: Improving treatment of many types of advanced cancers is critically important to
the health of Veterans. Many Veterans suffer from significant morbidity when they are diagnosed with cancer
that limits their therapeutic options. Immunotherapy is generally well tolerated and has a significant potential for
durable response, however, the benefit is limited to a subset...

## Key facts

- **NIH application ID:** 10873020
- **Project number:** 5I01BX005588-03
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** Daniel SANGHOON Shin
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873020

## Citation

> US National Institutes of Health, RePORTER application 10873020, Role of ATRX, a chromatin remodeler, in immunotherapy response (5I01BX005588-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873020. Licensed CC0.

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