# Molecular Determinants and Therapeutic Consequences of Immune Heterogeneity in Cancer

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $820,052

## Abstract

PROJECT SUMMARY
 Inter-tumoral heterogeneity – the fact that every tumor has distinct genetic, epigenetic, and stromal
features – poses a challenge for precision cancer therapy. While genetic variants that influence a tumor’s
response to targeted therapy (i.e. “actionable mutations”) have received great attention, comparatively less is
known about the causes of variation in the tumor microenvironment (TME). Nevertheless, such variation in the
TME is likely to be of critical importance, as prior work has shown that the response to immunotherapy
correlates with the abundance of T cells and other immune populations within a tumor [1,2]. We and others
have shown, in the context of pancreatic ductal adenocarcinoma (PDA), that tumor-derived factors shape the
microenvironment in vivo, dictating the relative abundance of different stromal populations. For example,
tumor-derived GM-CSF recruits myeloid cells to the tumor, fostering an immunosuppressive environment [3,4],
while tumor-derived Sonic Hedgehog causes an accumulation of myofibroblasts and other changes in the TME
[5,6]. However, additional cancer cell-derived factors that act in similar fashion remain to be identified,
representing an unexploited source of novel targets. In our preliminary work, we found that human PDA
exhibits a wide spectrum of immune activity. Surprisingly, and in contrast to other tumor types, the presence or
absence of an active immune signature was unrelated to the neo-antigen burden of a given tumor.
 We therefore hypothesize that cancer cell-intrinsic factors critically shape the immune
microenvironment and drive immune heterogeneity. We further hypothesize that (i) a tumor’s immune
makeup determines its response to immunotherapy and (ii) anti-tumor responses can be improved by
modulating the immune infiltrate. Here, we propose an innovative approach to delineate the biology of
immune heterogeneity in PDA, including novel implantable and genetically engineered mouse models studied
in parallel with samples from an extensive tumor bank and prospectively collected from two clinical
immunotherapy trials. Cellular, molecular, and clinical consequences of inter-tumoral heterogeneity will be
assessed in the context of response to immunotherapy. Our ultimate goal is to understand and manipulate the
immune microenvironment in PDA for therapeutic benefit, and we will approach this goal through the following
three interrelated Specific Aims:
Aim 1. Identify the molecular mechanism(s) underlying heterogeneity of immune infiltration
Aim 2. Assess the impact of immune heterogeneity on the response to immunotherapy
Aim 3. Elucidate the causes and consequences of immune heterogeneity in human PDA

## Key facts

- **NIH application ID:** 10001329
- **Project number:** 5R01CA229803-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** BEN Z STANGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $820,052
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001329

## Citation

> US National Institutes of Health, RePORTER application 10001329, Molecular Determinants and Therapeutic Consequences of Immune Heterogeneity in Cancer (5R01CA229803-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001329. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*