# (8) Genomic determinants of the T-cell regulome in immune checkpoint blockade

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $639,149

## Abstract

RESEARCH SUMMARY
Immune checkpoint blockade (ICB) therapies—including ipilimumab (IPI; developed against cytotoxic T
lymphocyte-antigen 4), nivolumab (NIVO; anti-programmed death 1 antibody) and their combination
(IPI/NIVO)—have demonstrated durable survival benefits in melanoma. Despite high response rates, >50% of
patients do not respond to these treatments. In addition, patients often develop immune-related adverse events
with severe morbidity, substantially reducing quality of life. Efforts to identify biomarkers of ICB outcomes have
mainly centered on the tumor microenvironment because anti-tumor T cell immunity is the primary target of
ICB, the focus has been predominantly on tumor T-cell infiltration. While promising tumor-based surrogates of
ICB have been proposed, none of these markers alone or in combination fully explains variability in ICB
outcome. Hence, there is a continuing need to identify more powerful biomarkers of ICB outcomes that would
also serve as potential novel targets for more effective and less toxic treatments. We propose a novel
hypothesis that ICB outcomes are strongly impacted by host immunity, shown in recent reports to be
influenced by underlying inherited factors. It was demonstrated that phenotypic variation in T-cell subsets,
including CD8+ T cells, is attributed to germline genetic variation. In a recent study, we showed that this
inherited component maps to the non-coding regulatory genome, impacting transcriptional regulation of T-cell
differentiation and function. Based on these data, we hypothesize that circulating CD8+ T cells, a primary target
of NIVO and IPI/NIVO therapies, are controlled by germline genetic variation in the CD8+ non-coding regulatory
genome (regulome), and that this genetic variability modulates ICB efficacy and toxicity. The goal of the
proposed study is to discover inherited signatures of the CD8+ T cell regulome that predict ICB efficacy and
toxicity. Using samples from 600 melanoma patients from a clinical trial of NIVO and IPI/NIVO, we will perform
a comprehensive analysis of whole-genome sequencing (WGS) and a whole-transcriptome analysis on
peripheral blood pre-treatment CD8+ T cells to identify non-coding transcriptome signatures that predict ICB
efficacy (Aim 1). We will use the genetic information from WGS to comprehensively assess open chromatin
states in pre-treatment CD8+ T cells from the same 600 patients to identify epigenetic signatures controlled by
inherited genetic variation, predicting ICB response and immune-related toxicity (Aim 2). Our preliminary data
have revealed novel genomic imprints in the non-coding regulome that predict ICB response with high clinical
accuracy, thus substantially supporting our hypotheses and design. For the first time, our study will elucidate
the effect of inherited anti-tumor host immunity on ICB outcomes. As we suggest, besides imminent
applicability to personalized prediction of ICB treatment benefits, the integration of genomic info...

## Key facts

- **NIH application ID:** 9994845
- **Project number:** 5R01CA227505-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Tomas Kirchhoff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $639,149
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994845

## Citation

> US National Institutes of Health, RePORTER application 9994845, (8) Genomic determinants of the T-cell regulome in immune checkpoint blockade (5R01CA227505-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9994845. Licensed CC0.

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