# Project 3- Integrated Stress and Interferon Responses

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $296,020

## Abstract

ABSTRACT
Development and progression of cancer occurs in spite of anti-tumorigenic effects of Type 1 interferon cytokines
(IFN1, including IFNα and IFNβ). IFN1 counteract tumor development and progression directly (by suppression
of malignant cells) and indirectly (by stimulation of anti-tumor immunity). Our work in the past funding period
revealed that the integrated stress response (ISR) induced in the tumor microenvironment help malignant and
benign tumor cells to evade the anti-tumorigenic effects of IFN1. We found that ISR-driven inactivation of IFN1
receptor IFNAR1 deprives tumor cells from ability to respond to IFN1 and plays an important role in tumor growth
and progression. Furthermore, our work revealed an important role of IFNAR1 inactivation in the ISR-induced
death of activated intra-tumoral cytotoxic T lymphocytes and, accordingly, in generation of the immune privileged
niche that helps to overcome anti-tumor immunity. Our new pilot experiments also suggested that inactivation of
IFNAR1 decreases the tumoricidal activity of cytotoxic T lymphocytes and undermines the efficacy of adoptive
transfer of chimeric antigen receptor T cells and of inhibitors of immune checkpoints.
New preliminary studies from our group and our collaborators (Projects 1-2) also revealed that additional
innovative mechanisms promoting tumorigenesis depend on inactivation of the IFNAR1 pathway in a manner
that involve ATF4 and its regulated miRNAs (e.g. miR-211 and miR-217) and include the suppression of
translation of the mRNAs for IFNAR1 and the IFN-stimulated genes (IGSs). In our current proposal, we aim to
define these mechanisms and target them to augment anti-cancer therapies. We will test an integrated
hypothesis that, in the tumor microenvironment, the ISR-driven inactivation of the IFNAR1 pathway in the
cytotoxic T lymphocytes plays a pivotal role in tumor growth and progression. Furthermore, efforts to restore
IFNAR1 signaling can stimulate anti-cancer immune responses and improve the outcome of therapeutic
approaches. To test this hypothesis, we propose to delineate the mechanisms underlying ISR-induced IFNAR1-
dependent and independent inactivation of the IFN1 pathway and its role in the loss of viability of intratumoral
cytotoxic lymphocytes and the generation of the immune privileged niches (Aim 1). We will also delineate the
mechanisms underlying ISR-driven inactivation of the tumoricidal activities of cytotoxic T lymphocytes and
determine whether targeting these mechanisms can augment anti-cancer immunity (Aim 2).
Completion of these studies should improve our knowledge on the role of ISR in generating the immune
privileged niches that provide safe harbor for malignant cells and drive tumor growth and progression.
Furthermore, identification and characterization of the mechanisms leading to IFNAR1 pathway inactivation will
enable us to identify specific targets for improving the efficacy of anti-cancer immune therapies.

## Key facts

- **NIH application ID:** 10247664
- **Project number:** 5P01CA165997-08
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Serge Y Fuchs
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $296,020
- **Award type:** 5
- **Project period:** 2013-09-18 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247664

## Citation

> US National Institutes of Health, RePORTER application 10247664, Project 3- Integrated Stress and Interferon Responses (5P01CA165997-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10247664. Licensed CC0.

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