# The role of transcription elongation defects in immunotherapy resistance in cancers

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $446,129

## Abstract

Immunotherapy has had unprecedented success in the clinic. However, the majority of patients treated with the
immune checkpoint inhibitors (ICB) do not gain clinical benefits from these treatments. The mechanisms of
resistance to ICB are not fully understood. Through comprehensive computational and follow-up experimental
validations, we have found that a subset of cancers is characterized by severe defects in the RNA Polymerase
II – mediated transcription elongation, resulting in genome-wide deregulation of mRNA synthesis, splicing and
processing (Transcription Elongation defect: TEdeff). TEdeff strongly affected immune-related pathways, and
impaired tumor cell response to pro-inflammatory immune attacks in vitro and in vivo. As such, we found that
TEdeff predicted poor response to immunotherapeutic agents in the clinic, including immune checkpoint
inhibitors, in 4 different cohorts. We propose that 1) loss of transcriptional elongation functions leads to
epigenetic and transcriptional defects of pro-inflammatory pathway genes, and that TEdeff can be reversed by
restoring the expression of key genes. In addition, 2) we propose that TEdeff paradoxically attracts T-cells due
to the activation of innate sensing pathways, but confers resistance to anti-tumor immune attack through both
tumor-extrinsic (by regulating tumor-infiltrating lymphocyte function) and –intrinsic (by regulating tumor cell
signaling) mechanisms. Therefore, this proposal has a high promise of the molecular characterization of a
novel major tumor phenotype, and identifying strategies for its reversal or targeting in the clinic. Given that
TEdeff is observed in >25% of all cancers, this proposal is of high clinical significance.

## Key facts

- **NIH application ID:** 9928903
- **Project number:** 5R01CA234038-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Fukun Guo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $446,129
- **Award type:** 5
- **Project period:** 2019-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928903

## Citation

> US National Institutes of Health, RePORTER application 9928903, The role of transcription elongation defects in immunotherapy resistance in cancers (5R01CA234038-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9928903. Licensed CC0.

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