# Regulators of Cancer Immunotherapy Response

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2022 · $598,991

## Abstract

PROJECT SUMMARY
Despite enormous success in treating several types of cancer, immune checkpoint blocker (ICB) therapy still
only shows efficacies in a subset of patients. Identifying novel regulators of immunotherapy response as well
as improving the response rate of cancer immunotherapies remain open questions. Recently, we used
CRISPR screens in mouse models to investigate T-cell infiltration, proliferation, and killing efficacy, and
identified PBAF of the SWI/SNF chromatin remodeling complex as one novel regulator of T-cell mediated
cytotoxicity. We also developed a computational model, TIDE, to identify gene signatures of CD8 T-cell
dysfunction in immune hot tumors and T-cell exclusion in immune cold tumors. The resulting signatures,
computed from tumor profiles in non-immunotherapy setting, show promising results in predicting melanoma
and lung cancer patient response to immune checkpoint blockade based on pre-treatment tumor expression
profiles.
This proposed project aims to improve the TIDE biomarkers, identify novel regulators, and elucidate their
mechanisms underlying ICB response. In Aim 1, we will develop machine learning approaches on large
collection of clinical tumor transcriptome profiles from non-ICB settings to refine the TIDE predictive biomarker
of ICB response, and develop a web server to comprehensively evaluate different ICB response biomarkers in
all the available ICB cohorts. In Aim 2, we will conduct in vivo CRISPR screens in mouse syngeneic tumor
models to identify cancer-cell intrinsic regulators of ICB response, which can serve as novel targets to improve
ICB response. In Aim 3, we will elucidate the mechanism underlying two novel regulators of ICB response and
characterize their effects on the tumor immune microenvironment using single-cell RNA-seq, single-cell ATAC-
seq, and computational modeling. Our investigative team has combined expertise in computational
methodology
immunotherapy.
immunology
and big data mining, functional genomics profiling
Our proposed studies, if successfully executed,
and translational benefits to cancer immunotherapy.
and screening, cancer immunology and
could provide new insights into cancer

## Key facts

- **NIH application ID:** 10385780
- **Project number:** 5R01CA234018-04
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** MYLES A BROWN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $598,991
- **Award type:** 5
- **Project period:** 2019-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10385780

## Citation

> US National Institutes of Health, RePORTER application 10385780, Regulators of Cancer Immunotherapy Response (5R01CA234018-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10385780. Licensed CC0.

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