# Steroid hormone regulation of immune responses

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $384,018

## Abstract

PROJECT SUMMARY
Signals present within the tumor microenvironment (TME) undermine the ability of the immune system to fight
cancer. In particular, these signals together with chronic stimulation disable effector CD8+ T cell responses by
promoting the development of a dysfunctional or “exhausted” T cell state. As dysfunctional CD8+ T cells are
defective in their ability to elicit cytotoxicity and produce pro-inflammatory cytokines, they are poor mediators of
tumor clearance. Moreover, dysfunctional CD8+ T cells can produce IL-10, indicating that they can also
contribute to immune suppression with the TME. Thus, dysfunctional CD8+ T cells present not only an obstacle
but also a liability for the generation of productive anti-tumor immunity. Accordingly, understanding both the T
cell intrinsic and extrinsic signals that promote dysfunctional phenotype is of key importance in devising novel
therapies to improve anti-cancer T cell responses.
We have examined the gene programs underlying T cell dysfunction in CD8+ tumor-infiltrating lymphocytes
(TILs). We have thus discovered that NR3C1, the gene encoding the glucocorticoid receptor (GR), is
preferentially expressed by CD8+ TILs that exhibit severe dysfunctional phenotype. Glucocorticoids (GCs) are
steroid hormones and ligands for GR. Although both natural and synthetic glucocorticoids are known to
be potent immune-suppressive agents, the precise molecular mechanisms by which they suppress
effector T cell responses are poorly understood. Our preliminary data indicate that GC-GR signaling is
indeed active in CD8+ TILs and that tumor-associated macrophages (TAMs) are a local source of steroid in the
TME. We further find that mice that lack expression of NR3C1 specifically in CD8+ T cells exhibit improved
tumor growth control and that NR3C1-deficient CD8+ TILs exhibit improved effector function concomitant with
dramatically reduced expression of co-inhibitory receptors such as Tim-3 and PD-1. In line with these data, we
find that GC-GR signaling promotes co-inhibitory receptor expression and dampens both the cytotoxic capacity
and pro-inflammatory cytokine production of CD8+ T cells in vitro. Interestingly, we find that GC-GR signaling
potently synergizes with the immunoregulatory cytokine IL-27 to further augment the expression of co-inhibitory
receptors and dampen pro-inflammatory cytokine production and cytotoxic capacity in CD8+ T cells while
concomitantly inducing IL-10 production. Based on our preliminary data, we hypothesize that GC-GR
signaling is a key component of the immune suppressive network in the TME that disables anti-tumor T cell
responses by: 1) direct promotion of dysfunction-associated gene programs in effector T cells; and 2)
synergizing with signals in the TME such as IL-27.
We propose the following specific aims: 1) Molecularly dissect the role of steroid signaling in CD8+ and CD4+ T
cells in the TME and 2) Define the GC-GR signaling circuit and the basis for synergy with IL-27 in i...

## Key facts

- **NIH application ID:** 9959385
- **Project number:** 5R01CA229400-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** ANA C ANDERSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $384,018
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959385

## Citation

> US National Institutes of Health, RePORTER application 9959385, Steroid hormone regulation of immune responses (5R01CA229400-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9959385. Licensed CC0.

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