# A blueprint for neutrophil heterogeneity and reprogramming in cancer

> **NIH NIH DP2** · UNIVERSITY OF PENNSYLVANIA · 2022 · $1,462,500

## Abstract

Project Summary Chengcheng Jin, Ph.D
Neutrophils are the most abundant immune cells in human blood. They are multi-functional innate myeloid cells
that play key roles in pathogen infection, tissue repair, as well as cancer. As a main composition of the tumor-
associated immune cells in multiple cancer types, neutrophils have emerged as a critical player to promote
cancer progression via diverse mechanisms, such as mediating tissue remodeling, driving local inflammation,
suppressing anti-tumor T cells. However, no viable strategy is currently available to target neutrophils for cancer
therapy. This reveals fundamental questions and challenges: are tumor-associated neutrophils (TAN) distinct
from normal blood neutrophils? Do all the neutrophils in the TME function identically and carry out the broad
range of tumor-promoting activities? Is it possible to selectively target the tumor-promoting neutrophils without
impairing those essential for protecting us from bacterial infection?
Our vision is to develop an in-depth and broad understanding of transcriptional and epigenetic reprogramming
of neutrophils in the tumor microenvironment (TME). This will reveal novel regulatory mechanisms unique to
tumor-promoting neutrophils that can serve as targets of precision cancer immunotherapies while preserving
immune surveillance in healthy tissues. Our strategy is to take an integrated approach that leverages the unique
expertise and knowledge that we have established in genetically engineered mouse models. Specifically, we will
(1) combine phenotypic, transcriptional and chromatin profiling of neutrophils in different TME at the single-cell
level, (2) apply fate mapping and spatial transcriptomics to reveal the neutrophil dynamics in TME, (3) establish
and utilize novel genetic perturbation tools to identify and functionally validate key regulators of neutrophil
function in cancer.
By analyzing the tissue/tumor-associated neutrophils from different microenvironment, we have identified distinct
neutrophil subsets that are induced by different components of the TME. Therefore, our overall hypothesis is
that specific factors in the tumor microenvironment such as the local microbiota and tissue-resident immune cells,
as well as the genetic makeup and immunogenicity of cancer cells may differentially regulate the neutrophils.
Our goal is to identify cell-extrinsic factors from the TME that reprogram neutrophils to functionally discrete
subsets. Meanwhile, we will apply novel techniques to track TANs and dissect neutrophil-intrinsic pathways that
direct their functional diversification in cancer.
Our study will provide a blueprint for transcriptional control of neutrophil responses in cancer and opens
possibilities for stage/gene/environment-specific therapeutic modulation of neutrophil function in cancer.
Furthermore, the conceptual and technological advances generated here will build the foundation for future
investigations into neutrophils in additional cancer ty...

## Key facts

- **NIH application ID:** 10472807
- **Project number:** 1DP2CA280834-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Chengcheng Jin
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,462,500
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10472807

## Citation

> US National Institutes of Health, RePORTER application 10472807, A blueprint for neutrophil heterogeneity and reprogramming in cancer (1DP2CA280834-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10472807. Licensed CC0.

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