# Immunosuppressive Programs Driven by IRE1 signaling in ovarian cancer

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $46,036

## Abstract

PROJECT SUMMARY/ABSTRACT:
Ovarian Carcinomas (OvCa) are the most life-threatening gynecological malignancy in the United States,
claiming the lives of 14,000 women every year. The 5-year survival rate for metastatic OvCa is 27%, and
standard treatments and therapies such as chemotherapy and surgical intervention are largely ineffectual, and
can often promote drug resistance and recurrence of the cancer. The recent advent of cancer immunotherapy
has proven effective in treating other cancers, but shown minimal efficacy in OvCa. Understanding the
mechanisms that enable OvCa to escape immune control is crtical to developing more effective treatments.
Ovarian Tumors have evolved strategies that enable them to thrive under adverse conditions while suppressing
the protective function of immune cells. Recent studies demonstrate that these cancers provoke severe
metabolic stress in myeloid cells to escape immune control, but it remains unknown how myeloid cells
integrate and interpret metabolic stress signals in the tumor milieu. Our group determined that adverse
conditions in the tumor microenvironment disrupt the protein-folding capacity of the endoplasmic reticulum (ER)
in infiltrating immune cells. This process causes “ER stress” and elicits persistent responses via the IRE1α-XBP1
pathway, that alter key immunometabolic processes required for the initiation and maintenance of anti-tumor
immunity. Multiple studies have shown that myeloid derived suppressor cells (MDSCs) and neutrophils can
regulate anti-tumor T cell functions by depleting key amino acids from the TME. Our preliminary findings indicate
that IRE1α-XBP1 signaling is required to sustain the capacity of MDSCs to express Arginase 1 (Arg1) and
suppress T cell proliferation, by an unknown mechanism. The main goal of this proposal is to identify and
understand the transcriptional and functional consequences of ER stress in tumor associated myeloid cells.
Therefore, our central hypothesis is that maladaptive activation of ER stress sensors regulates the function of
myeloid cell subsets in the tumor by altering their transcriptional programming to induce immunosuppressive
phenotypes. Specifically, we postulate that the IRE1α-activated XBP1 transcription factor is a direct
transcriptional inducer of Arg1. We also hypothesize that ER stress-driven gene signatures will delineate new
transcriptional programs controlled by IRE1α-XBP1 in tumor associated neutrophils. Lastly, we will define how
IRE1α-XBP1 ablation in tumor associated neutrophils modulates the cytotoxic activity of T cells and the
development of protective anti-tumor immunity. Understanding the consequences of ER stress in tumor
associated myeloid cells will be crucial to comprehensively define T cell dysfunction in ovarian cancer, and to
develop new therapeutic interventions that augment T cell effector capacity in a harsh tumor microenvironment.
The proposed project is mechanistically and translationally relevant as it has the potenti...

## Key facts

- **NIH application ID:** 10313801
- **Project number:** 1F31CA257631-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Alexander Emmanuelli
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313801

## Citation

> US National Institutes of Health, RePORTER application 10313801, Immunosuppressive Programs Driven by IRE1 signaling in ovarian cancer (1F31CA257631-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10313801. Licensed CC0.

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