# Enhancing immune therapy in pancreatic cancer by targeting IL-6

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $315,158

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) is accompanied by profound systemic immunosuppression that
renders this disease non-responsive to immunotherapy. One hallmark of PDAC is the dense stroma consisting
of activated fibroblasts termed `pancreatic stellate cells' (PSC) that surround each tumor. Although these
stromal cells produce numerous factors that may support tumor growth, recent publications also suggest a
contradictory role for the stroma in protecting against metastasis. Even more surprising was the observation
that depletion of PSC from genetic models of PDAC led to improved efficacy of immunotherapy. These data
highlight the significance of the proposal, and how little is known regarding the intricate interactions between
stroma and immune cells present within the tumor microenvironment. These results also suggest that the
immune response against tumors is restrained by PSC, and that targeting key pathways in the stroma may
augment the efficacy of immunotherapy. In line with these observations, a recent publication from our group
demonstrated that patient-derived PSC secrete soluble factors to promote myeloid-derived suppressor cell
(MDSC) differentiation. Detailed analyses revealed that STAT3 signaling was required for this process, and
was due to copious amounts of interleukin-6 (IL-6) secreted from PSC. These data demonstrated a novel role
for stromal PSC as a source of factors that suppress immunity in PDAC, and have fueled our interest in
targeting IL-6 to enhance immunotherapy. Our preliminary data show that in vivo administration of antibodies
(Ab) targeting interleukin-6 (IL-6) and PD-L1 limit tumor progression in both subcutaneous, and autochthonous,
mutant KRas-driven models of PDAC. We also demonstrate this treatment combination results in increased
infiltration of T cells into pancreatic tumors, and reduced levels of PSC within these same tumors. We
hypothesize that stromal IL-6 is a major barrier promoting immune suppression in PDAC, and that it
can be targeted to augment the response to immunotherapy. This proposal will address three Specific
Aims. First, we will determine the mechanisms by which combined blockade of IL-6 and PD-L1 elicits antitumor
efficacy in PDAC, focusing on phenotypic and functional properties of T cells and MDSC (Aim 1). The relative
importance of PD-L1 expression on the tumor or host tissues in mediating efficacy of this treatment will be
investigated. Next, we will determine if taxane-based chemotherapy augments the efficacy of IL-6 and PD-L1
blockade in autochthonous, mutant KRas-driven PDAC models (Aim 2). Finally, we will use a dual
recombinase system (Flp-FRT and Cre-loxP) to develop mice with spontaneously arising, mutant KRas-driven
PDAC and IL-6 deleted fibroblasts, and primary patient PSC to define the role of stromal IL-6 in promoting
pancreatic cancer progression and immune suppression (Aim 3). This proposal will enhance our understanding
of how the stroma influences carcinogenesis and i...

## Key facts

- **NIH application ID:** 9972869
- **Project number:** 5R01CA208253-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Gregory B. Lesinski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $315,158
- **Award type:** 5
- **Project period:** 2016-08-12 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972869

## Citation

> US National Institutes of Health, RePORTER application 9972869, Enhancing immune therapy in pancreatic cancer by targeting IL-6 (5R01CA208253-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9972869. Licensed CC0.

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