# Th17 generation, action and therapeutic relevance in chronic lymphocytic leukemia

> **NIH NIH R01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2022 · $503,583

## Abstract

PROJECT SUMMARY/ABSTRACT
Survival and growth of cancer cells depend on environmental cues delivered by cell contact and soluble factors.
These shape disease biology and aggressiveness, reflected by the effectiveness of therapeutic regimens in
blocking trophic inputs. This principle is exemplified in the relatively common and still incurable chronic
lymphocytic leukemia (CLL), a disease of clonal CD5+ B cells requiring ongoing signaling from membrane
receptors and cells within the tumor microenvironment. While considerable information has been gleaned about
the bi-directional dialogue between CLL B cells and autologous T cells, little information is available about
individual T-cell subsets, particularly Th17 cells, a unique subset of T helper cells. The scientific premise of
this proposal comes from our findings that in CLL: [1] higher levels of Th17-related cytokines and numbers of
circulating Th17 cells associate with better clinical outcomes; [2] leukemic B cells promote Th17 generation from
autologous CD4 T cells in vitro; [3] expression of miR155, which promotes Th17 cell differentiation, is significantly
higher in Th17 cells from CLL patients than in healthy subjects; [4] Th17 cells modulate CLL B-cell survival and
growth in vitro and in vivo; and [5] treatment of naïve CLL T cells from CLL patients with the PI3K inhibitor
idelalisib, significantly enhances Th17-cell generation. These findings underlie our central hypothesis that CLL
B cells promote the generation of Th17 cells, which exert anti-tumor effects within the leukemic compartment.
We expect that enhancing idelalisib's ability to positively affect Th17 generation and function will significantly
improve its clinical value. Our long-range goal is to define this cellular bi-directional communication more clearly
at the molecular level, so as to manipulate these interactions to therapeutic advantage. To advance our
hypotheses and goal, we propose studies to: elucidate cellular and molecular mechanism(s) whereby leukemic
B cells regulate Th17 cell generation in CLL, focusing on the STAT3/miR155 pathway (Aim 1); determine the
influence of Th17 cells on leukemic B-cell survival, growth and maturation in vitro and in vivo (Aim 2) and
investigate the effects of idelalisib on Th17-cell generation and function in CLL (Aim 3). The proposed work is
innovative as it is the first to explore underlying mechanisms by which leukemic B cells regulate the generation
and function of Th17 cells and the impact this regulation has on clinical outcome; it is also the first study of
genome-wide miR expression in T cells from CLL patients. Also, these innovative studies will have considerable
impact on CLL, since we will identify mechanisms generating Th17s in CLL and the impact this T-cell subset has
on leukemic B cell growth, proliferation and maturation. Finally, we will determine if lower Th17-cell numbers in
CLL patients with poor outcomes results from inherent differences in the CLL T or B cells. Thi...

## Key facts

- **NIH application ID:** 10296682
- **Project number:** 5R01CA238523-03
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Nicholas Chiorazzi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $503,583
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296682

## Citation

> US National Institutes of Health, RePORTER application 10296682, Th17 generation, action and therapeutic relevance in chronic lymphocytic leukemia (5R01CA238523-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10296682. Licensed CC0.

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